ORCID Profile
0000-0003-4430-4260
Current Organisations
Lawrence Livermore National Laboratory
,
The University of Edinburgh
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Publisher: Oxford University Press (OUP)
Date: 22-01-2015
DOI: 10.1093/IJE/DYU277
Publisher: Cold Spring Harbor Laboratory
Date: 08-02-2022
DOI: 10.1101/2022.02.08.479569
Abstract: CpG methylation levels can help to explain inter-in idual differences in phenotypic traits. Few studies have explored whether identifying CpG subsets based on biological and statistical properties can maximise predictions while minimising array content. Variance component analyses and penalised regression (epigenetic predictors) were used to test the influence of (i) the number of CpGs considered, (ii) mean CpG methylation variability and (iii) methylation QTL status on the variance captured in eighteen traits by blood DNA methylation. Training and test sets comprised ≤4,450 and ≤2,578 unrelated in iduals from Generation Scotland, respectively. As the number of CpG sites under consideration decreased, so too did the estimates from the variance components and prediction analyses. Methylation QTL status and mean CpG variability did not influence variance components. However, relative effect sizes were 15% larger for epigenetic predictors based on CpGs with methylation QTLs compared to sites without methylation QTLs. Relative effect sizes were 45% larger for predictors based on CpGs with mean beta-values between 10%-90% compared to those using hypo- or hypermethylated CpGs (beta-value ≤10% or ≥90%). Arrays with fewer CpGs could reduce costs, leading to increased s le sizes for analyses. Our results show that reducing array content can restrict prediction metrics and careful attention must be given to the biological and distribution properties of CpGs in array content selection.
Publisher: Cold Spring Harbor Laboratory
Date: 11-04-2020
DOI: 10.1101/2020.04.06.20055517
Abstract: Dementia pathogenesis begins years before clinical symptom onset, necessitating the understanding of premorbid risk mechanisms. Here, we investigated potential pathogenic mechanisms by assessing DNA methylation associations with dementia risk factors in Alzheimer’s disease (AD)-free participants. Associations between dementia risk measures (family history, genetic risk score (GRS), and dementia risk scores (combining lifestyle, demographic and genetic factors) and whole-blood DNA methylation were assessed in discovery and replication s les (n=∼400 – ∼5,000) from Generation Scotland. AD genetic risk and two risk scores were associated with differential methylation. The GRS predominantly associated with methylation differences in cis but also identified a genomic region implicated in Parkinson’s disease. Loci associated with the risk scores were enriched for those previously associated with body mass index and alcohol consumption. Dementia risk measures show widespread association with blood-based methylation, which indicates differences in the processes affected by genetic and demographic/lifestyle risk factors.
Publisher: Wiley
Date: 13-06-2011
DOI: 10.1111/J.1532-5415.2011.03477.X
Abstract: To examine the relationship between the incidence of dementia and chronic kidney disease (CKD). Longitudinal data analyses. Baseline data and follow-up data from the Osaki-Tajiri Project. The Tajiri Project dementia prevalence study in 1998 involved 497 community-dwelling, older men and women (346 with Clinical Dementia Rating score (CDR) of 0 (healthy), 119 with a CDR of 0.5 (questionable dementia), and 32 with a CDR of 1 or greater (dementia)). Two hundred fifty-four participants with CDR of 0 and 0.5 who were reclassified as converters (n=28) or nonconverters (n=230) to dementia in the incidence study in 2003 were followed. The prevalence of CKD and the onset of dementia were retrospectively analyzed, and the effects of other vascular risk factors on converters and CKD were analyzed. Weighted logistic regression showed CKD to be significantly associated with incident dementia after adjustment for age, sex, education, hypertension, diabetes mellitus, dyslipidemia, ischemic heart disease, and anemia. The odds ratio for conversion to dementia for those with CKD compared to those without was 5.3 (95% confidence interval=1.7, 16.2). Apart from dyslipidemia, there were no associations between dementia and the other vascular risk factors. CKD was strongly associated with the incidence of dementia independent of age, sex, education, and other vascular risk factors.
Publisher: Public Library of Science (PLoS)
Date: 17-01-2017
Publisher: Springer Science and Business Media LLC
Date: 23-09-2015
Abstract: The association between APOE genotype and cognitive function suggests a positive role for the e2 allele and a negative role for the e4 allele. Both alleles have relatively low frequencies in the general population hence, meta-analyses have been based on many small, heterogeneous studies. Here, we report the APOE -cognition associations in the largest single analysis to date. APOE status and cognitive ability were measured in 18 337 participants from the Generation Scotland study between 2006 and 2011. The age range was 18–94 years with a mean of 47 (SD 15). Four cognitive domains were assessed: verbal declarative memory (paragraph recall), processing speed (digit symbol substitution), verbal fluency (phonemic verbal fluency), and vocabulary (Mill Hill synonyms). Linear regression was used to assess the associations between APOE genetic status and cognition. Possession of the e4 allele was associated with lower scores on the measures of memory and processing speed in subjects aged . Across all age ranges, the e4 allele was linked to better verbal fluency scores. In younger subjects (≤60 years) the e4 allele was linked to higher vocabulary scores. There were no associations between the e2 allele and cognitive ability. As seen in previous meta-analyses, the APOE e4 allele is linked to poorer cognitive performance in the domains of memory and processing speed. By contrast, positive associations were seen between the e4 allele and measures of verbal fluency and vocabulary. All associations were relatively small and, in many cases, nominally significant despite the very large s le size.
Publisher: eLife Sciences Publications, Ltd
Date: 25-11-2021
Publisher: Springer Science and Business Media LLC
Date: 18-12-2017
Publisher: eLife Sciences Publications, Ltd
Date: 13-01-2022
DOI: 10.7554/ELIFE.71802
Abstract: Protein biomarkers have been identified across many age-related morbidities. However, characterising epigenetic influences could further inform disease predictions. Here, we leverage epigenome-wide data to study links between the DNA methylation (DNAm) signatures of the circulating proteome and incident diseases. Using data from four cohorts, we trained and tested epigenetic scores (EpiScores) for 953 plasma proteins, identifying 109 scores that explained between 1% and 58% of the variance in protein levels after adjusting for known protein quantitative trait loci (pQTL) genetic effects. By projecting these EpiScores into an independent s le (Generation Scotland n = 9537) and relating them to incident morbidities over a follow-up of 14 years, we uncovered 137 EpiScore-disease associations. These associations were largely independent of immune cell proportions, common lifestyle and health factors, and biological aging. Notably, we found that our diabetes-associated EpiScores highlighted previous top biomarker associations from proteome-wide assessments of diabetes. These EpiScores for protein levels can therefore be a valuable resource for disease prediction and risk stratification.
Publisher: American Medical Association (AMA)
Date: 09-2018
Publisher: Cold Spring Harbor Laboratory
Date: 11-01-2023
DOI: 10.1101/2023.01.10.23284387
Abstract: Blood DNA methylation can inform us about the biological mechanisms that underlie common disease states. Previous epigenome-wide analyses of common diseases often focus solely on the prevalence or incidence of in idual conditions and rely on small s le sizes, which may limit power to discover disease-associated loci. We conduct blood-based epigenome-wide association studies on the prevalence of 14 common disease states in Generation Scotland (n in iduals ≤18,413, n CpGs =752,722). We also utilise health record linkage to perform epigenome-wide analyses on the incidence of 19 disease states. We present a structured literature review on existing epigenome-wide analyses for all 19 disease states to assess the degree of replication within the existing literature and the novelty of the present findings. We identify 69 associations between CpGs and the prevalence of four disease states at baseline, of which 58 are novel. We also uncover 64 CpGs that associate with the incidence of two disease states (COPD and type 2 diabetes), of which 56 are novel. These associations were independent from common lifestyle risk factors. We highlight poor replication across the existing literature. Here, replication was defined by the reporting of at least one common gene in studies examining the same disease state. Existing blood-based epigenome-wide analyses showed evidence of replication for only 4/19 disease states (with up-to-15% of unique genes replicated for lung cancer). Our summary data and structured review of the literature provide an important platform to guide future studies that examine the role of blood DNA methylation in complex disease states.
Publisher: Springer Science and Business Media LLC
Date: 08-11-2018
Publisher: Springer Science and Business Media LLC
Date: 20-02-2014
Publisher: Cold Spring Harbor Laboratory
Date: 03-05-2023
DOI: 10.1101/2023.05.01.23288879
Abstract: The circulating proteome offers insights into the biological pathways that underlie disease. Here, we test relationships between 1,468 Olink protein levels and the incidence of 23 age-related diseases and mortality, over 16 years of electronic health linkage in the UK Biobank (N=47,600). We report 3,201 associations between 961 protein levels and 21 incident outcomes, identifying proteomic indicators of multiple morbidities. Next, protein-based scores (ProteinScores) are developed using penalised Cox regression. When applied to test sets, six ProteinScores improve Area Under the Curve (AUC) estimates for the 10-year onset of incident outcomes beyond age, sex and a comprehensive set of 24 lifestyle factors, clinically-relevant biomarkers and physical measures. Furthermore, the ProteinScore for type 2 diabetes outperformed a polygenic risk score, a metabolomic score and HbA1c – a clinical marker used to monitor and diagnose type 2 diabetes. These data characterise early proteomic contributions to major age-related disease and demonstrate the value of the plasma proteome for risk stratification.
Publisher: Cold Spring Harbor Laboratory
Date: 18-10-2020
DOI: 10.1101/2020.10.16.20213884
Abstract: The use of prescription drugs with anticholinergic properties has been associated with multiple negative health outcomes in older people. Moreover, recent evidence suggests that associated adverse effects may occur even decades after stopping anticholinergic use. Despite the implicated importance of examining longitudinal patterns of anticholinergic prescribing for different age groups, few such data are available. We performed an age-period-cohort analysis to study trends in anticholinergic burden between the years 1990 and 2015 utilising data from ,000 UK Biobank participants with linked prescription data from primary care. Anticholinergic burden in the s le increased between three- and nine-fold over 25 years and was significant for both period/cohort- and age-effects across all models. When adjusted for total number of prescriptions, the effect of age reversed. Anticholinergic burden was also associated with various lifestyle- and demographic factors. The increase in anticholinergic prescribing is mostly due to an increase in polypharmacy and is attributable to both ageing of participants, as well as period/cohort-related changes in prescribing practices. There is evidence for deprescribing of anticholinergic medications in older age. Further research is needed to clarify the implications of rising anticholinergic use for public health and to contextualise this rise in light of other relevant prescribing practices.
Publisher: Springer Science and Business Media LLC
Date: 10-10-2009
DOI: 10.1007/S10519-009-9302-Z
Abstract: It is unknown whether the relationship between raised inflammatory biomarker levels and late-life cognitive ability is causal. We explored this issue by testing the association between genetic regulators of plasma C-reactive protein (CRP) and cognition. Data were analysed from four cohorts based in central Scotland (Total N = 4,782). Associations were tested between variants in the CRP gene and both plasma CRP levels and a battery of neuropsychological tests, including a vocabulary-based estimate of peak prior cognitive ability and a general (summary) cognitive factor score, or 'g'. CRP levels were associated with a number of variants in the CRP gene (SNPs), including rs1205, rs1130864, rs1800947, and rs1417938 (P range 4.2e-06 to 0.041). Higher CRP levels were also associated with vocabulary-adjusted cognitive ability, used here to estimate lifetime cognitive change (P range 1.7e-04 to 0.038). After correction for multiple testing and adjustment for age and sex, no statistically significant associations were found between the SNPs and cognition. CRP is unlikely to be a causal determinant of late-life cognitive ability.
Publisher: Springer Science and Business Media LLC
Date: 16-04-2018
DOI: 10.1038/S41467-018-03819-3
Abstract: Depression is a polygenic trait that causes extensive periods of disability. Previous genetic studies have identified common risk variants which have progressively increased in number with increasing s le sizes of the respective studies. Here, we conduct a genome-wide association study in 322,580 UK Biobank participants for three depression-related phenotypes: broad depression, probable major depressive disorder (MDD), and International Classification of Diseases (ICD, version 9 or 10)-coded MDD. We identify 17 independent loci that are significantly associated ( P 5 × 10 −8 ) across the three phenotypes. The direction of effect of these loci is consistently replicated in an independent s le, with 14 loci likely representing novel findings. Gene sets are enriched in excitatory neurotransmission, mechanosensory behaviour, post synapse, neuron spine and dendrite functions. Our findings suggest that broad depression is the most tractable UK Biobank phenotype for discovering genes and gene sets that further our understanding of the biological pathways underlying depression.
Publisher: Elsevier BV
Date: 09-2022
Publisher: Cold Spring Harbor Laboratory
Date: 10-04-2021
DOI: 10.1101/2021.04.08.21255064
Abstract: Preterm birth is associated with dysconnectivity of structural brain networks and is a leading cause of neurocognitive impairment in childhood. Variation in DNA methylation (DNAm) is associated with early exposure to extrauterine life but there has been little research exploring its relationship with brain development. Using genome-wide DNA methylation data from saliva of 258 neonates, we investigated the impact of gestational age on the methylome and performed functional analysis to identify enriched gene sets from probes that contributed to differentially methylated probes (DMPs) or regions (DMRs). We tested the hypothesis that variation in DNAm could underpin the association between preterm birth and atypical brain development by linking DMPs with measures of white matter connectivity derived from diffusion MRI metrics: peak width of skeletonised mean diffusivity (PSMD), fractional anisotropy (PSFA) and neurite density index (PSNDI). Gestational age at birth was associated with widespread differential methylation, with genome-wide significant associations observed for 8,870 CpG probes ( p .6×10 −8 ) and 1,767 differentially methylated regions. Functional analysis identified 14 enriched gene ontology terms pertaining to cell-cell contacts and cell-extracellular matrix contacts. Principal component analysis of probes with genome-wide significance revealed a first principal component (PC1) that explained 23.5% of variance in DNAm, and this was negatively associated with gestational age at birth. PC1 was associated with PSMD (β=0.349, p =8.37×10 −10 ) and PSNDI (β=0.364, p =4.15×10 −5 ), but not with PSFA (β=−0.035, p =0.510) these relationships mirrored the imaging metrics’ associations with gestational age at birth. Gestational age at birth has a profound and widely distributed effect on the neonatal saliva methylome. Enriched gene ontology terms related to cell-cell contacts reveal pathways that could mediate the effect of early life environmental exposures on development. Finally, associations between differential DNAm and image markers of white matter tract microstructure suggest that variation in DNAm may provide a link between preterm birth and the dysconnectivity of developing brain networks that characterises atypical brain development in preterm infants.
Publisher: Springer Science and Business Media LLC
Date: 29-06-2021
DOI: 10.1186/S13059-021-02398-9
Abstract: Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field. Leveraging DNA methylation and SNP data from more than 40,000 in iduals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels. This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2017
DOI: 10.1161/CIRCGENETICS.116.001487
Abstract: Genome-wide association studies have identified loci influencing circulating lipid concentrations in humans further information on novel contributing genes, pathways, and biology may be gained through studies of epigenetic modifications. To identify epigenetic changes associated with lipid concentrations, we assayed genome-wide DNA methylation at cytosine–guanine dinucleotides (CpGs) in whole blood from 2306 in iduals from 2 population-based cohorts, with replication of findings in 2025 additional in iduals. We identified 193 CpGs associated with lipid levels in the discovery stage ( P .08E-07) and replicated 33 (at Bonferroni-corrected P .05), including 25 novel CpGs not previously associated with lipids. Genes at lipid-associated CpGs were enriched in lipid and amino acid metabolism processes. A differentially methylated locus associated with triglycerides and high-density lipoprotein cholesterol (HDL-C cg27243685 P =8.1E-26 and 9.3E-19) was associated with cis -expression of a reverse cholesterol transporter ( ABCG1 P =7.2E-28) and incident cardiovascular disease events (hazard ratio per SD increment, 1.38 95% confidence interval, 1.15–1.66 P =0.0007). We found significant cis -methylation quantitative trait loci at 64% of the 193 CpGs with an enrichment of signals from genome-wide association studies of lipid levels ( P TC =0.004, P HDL-C =0.008 and P triglycerides =0.00003) and coronary heart disease ( P =0.0007). For ex le, genome-wide significant variants associated with low-density lipoprotein cholesterol and coronary heart disease at APOB were cis -methylation quantitative trait loci for a low-density lipoprotein cholesterol–related differentially methylated locus. We report novel associations of DNA methylation with lipid levels, describe epigenetic mechanisms related to previous genome-wide association studies discoveries, and provide evidence implicating epigenetic regulation of reverse cholesterol transport in blood in relation to occurrence of cardiovascular disease events.
Publisher: Springer Science and Business Media LLC
Date: 15-08-2017
DOI: 10.1038/S41598-017-08346-7
Abstract: Aging is a complex biological process regulated by multiple cellular pathways and molecular mechanisms including epigenetics. Using genome-wide DNA methylation data measured in a large collection of Scottish old in iduals, we performed discovery association analysis to identify age-methylated CpGs and replicated them in two independent Danish cohorts. The double-replicated CpGs were characterized by distribution over gene regions and location in relation to CpG islands. The replicated CpGs were further characterized by involvement in biological pathways to study their functional implications in aging. We identified 67,604 age-associated CpG sites reaching genome-wide significance of FWER .05, 86% demethylated with increasing age. Double-replication resulted in 5,168 CpGs (39% age-methylated and 61% age-demethylated) which were characterized by high concentration of age-methylated CpGs at 1stExon and TSS200 and a dominant pattern of age-demethylated CpGs at other gene regions, and by overwhelming age-related methylation in CpG islands and demethylation at shore/shelf and open sea. The differential distribution patterns over gene regions for methylated and demethylated CpGs both relate to reduced gene activity during aging. Pathway analysis showed that age-dependent methylations were especially involved in cellular signalling activities while demethylations particularly linked to functions of the extracellular matrix, all implicated in the aging process and age-related disease risk.
Publisher: BMJ
Date: 08-2015
Publisher: Springer Science and Business Media LLC
Date: 03-08-2018
Publisher: Public Library of Science (PLoS)
Date: 06-07-2023
DOI: 10.1371/JOURNAL.PMED.1004247
Abstract: DNA methylation is a dynamic epigenetic mechanism that occurs at cytosine-phosphate-guanine dinucleotide (CpG) sites. Epigenome-wide association studies (EWAS) investigate the strength of association between methylation at in idual CpG sites and health outcomes. Although blood methylation may act as a peripheral marker of common disease states, previous EWAS have typically focused only on in idual conditions and have had limited power to discover disease-associated loci. This study examined the association of blood DNA methylation with the prevalence of 14 disease states and the incidence of 19 disease states in a single population of over 18,000 Scottish in iduals. DNA methylation was assayed at 752,722 CpG sites in whole-blood s les from 18,413 volunteers in the family-structured, population-based cohort study Generation Scotland (age range 18 to 99 years). EWAS tested for cross-sectional associations between baseline CpG methylation and 14 prevalent disease states, and for longitudinal associations between baseline CpG methylation and 19 incident disease states. Prevalent cases were self-reported on health questionnaires at the baseline. Incident cases were identified using linkage to Scottish primary (Read 2) and secondary (ICD-10) care records, and the censoring date was set to October 2020. The mean time-to-diagnosis ranged from 5.0 years (for chronic pain) to 11.7 years (for Coronavirus Disease 2019 (COVID-19) hospitalisation). The 19 disease states considered in this study were selected if they were present on the World Health Organisation’s 10 leading causes of death and disease burden or included in baseline self-report questionnaires. EWAS models were adjusted for age at methylation typing, sex, estimated white blood cell composition, population structure, and 5 common lifestyle risk factors. A structured literature review was also conducted to identify existing EWAS for all 19 disease states tested. The MEDLINE, Embase, Web of Science, and preprint servers were searched to retrieve relevant articles indexed as of March 27, 2023. Fifty-four of approximately 2,000 indexed articles met our inclusion criteria: assayed blood-based DNA methylation, had in iduals in each comparison group, and examined one of the 19 conditions considered. First, we assessed whether the associations identified in our study were reported in previous studies. We identified 69 associations between CpGs and the prevalence of 4 conditions, of which 58 were newly described. The conditions were breast cancer, chronic kidney disease, ischemic heart disease, and type 2 diabetes mellitus. We also uncovered 64 CpGs that associated with the incidence of 2 disease states (COPD and type 2 diabetes), of which 56 were not reported in the surveyed literature. Second, we assessed replication across existing studies, which was defined as the reporting of at least 1 common site in studies that examined the same condition. Only 6/19 disease states had evidence of such replication. The limitations of this study include the nonconsideration of medication data and a potential lack of generalizability to in iduals that are not of Scottish and European ancestry. We discovered over 100 associations between blood methylation sites and common disease states, independently of major confounding risk factors, and a need for greater standardisation among EWAS on human disease.
Publisher: Cold Spring Harbor Laboratory
Date: 13-10-2020
DOI: 10.1101/2020.10.08.20205245
Abstract: Low-level chronic inflammation increases with age and is associated with cognitive decline. DNA methylation (DNAm) levels may provide more stable reflections of cumulative inflammatory burden than traditional serum approaches. Using structural and diffusion MRI data from 521 in iduals aged 73, we demonstrate that a DNAm proxy of C-Reactive Protein (CRP) shows significantly (on average 6.4-fold) stronger associations with brain structural outcomes than serum CRP. We additionally find that DNAm CRP has an inverse association with global and domain-specific (speed, visuospatial and memory) cognitive functioning, and that brain structure partially mediates this CRP-cognitive association (up to 29.4%), dependent on lifestyle and health factors. These data support the hypothesis that chronic systemic inflammation may contribute to neurodegenerative brain changes which underlie differences in cognitive ability in later life. DNA methylation-based predictors could be used as proxies for chronic inflammatory status.
Publisher: Research Square Platform LLC
Date: 31-03-2023
DOI: 10.21203/RS.3.RS-2720355/V1
Abstract: Understanding the genetic basis of neuro-related proteins is essential for dissecting the molecular basis of human behavioral traits and the disease etiology of neuropsychiatric disorders. Here, the SCALLOP Consortium conducted a genome-wide association meta-analysis of over 12,500 in iduals for 184 neuro-related proteins in human plasma. The analysis identified 117 cis-regulatory protein quantitative trait loci (cis-pQTL) and 166 trans-pQTL. The mapped pQTL capture on average 50% of each protein's heritability. Mendelian randomization analyses revealed multiple proteins showing potential causal effects on neuro-related traits such as sleeping, smoking, feelings, alcohol intake, mental health, and psychiatric disorders. Integrating with established drug information, we validated 13 out of 13 matched combinations of protein targets and diseases or side effects with available drugs, while suggesting hundreds of re-purposing and new therapeutic targets. This consortium effort provides a large-scale proteogenomic resource for biomedical research on human behaviors and other neuro-related phenotypes.
Publisher: Wiley
Date: 10-2015
DOI: 10.1111/JOPY.12220
Abstract: Associations between markers of ostensible psychological characteristics and social and health inequalities are pervasive but difficult to explain. In some cases, there may be causal influence flowing from social and health inequalities to psychological differences, whereas sometimes it may be the other way around. Here, we focus on the possibility that some markers that we often consider as indexing different domains of in idual differences may in fact reflect at least partially overlapping genetic and/or phenotypic bases. For ex le, in idual differences in cognitive abilities and educational attainment appear to reflect largely overlapping genetic influences, whereas cognitive abilities and health literacy may be almost identical phenomena at the phenotypic, never mind genetic, level. We make the case for employing molecular genetic data and quantitative genetic techniques to better understand the associations of psychological in idual differences with social and health inequalities. We illustrate these arguments by using published findings from the Lothian Birth Cohort and the Generation Scotland studies. We also present novel findings pertaining to longitudinal stability and change in older age personality traits and some correlates of the change, molecular genetic data-based heritability estimates of Neuroticism and Extraversion, and the genetic correlations of these personality traits with markers of social and health inequalities.
Publisher: Wiley
Date: 2018
Publisher: Springer Science and Business Media LLC
Date: 31-12-2019
DOI: 10.1186/S13073-019-0693-Z
Abstract: Advanced age is associated with cognitive and physical decline and is a major risk factor for a multitude of disorders. There is also a gap in life expectancy between males and females. DNA methylation differences have been shown to be associated with both age and sex. Here, we investigate age-by-sex differences in blood-based DNA methylation in an unrelated cohort of 2586 in iduals between the ages of 18 and 87 years, with replication in a further 4450 in iduals between the ages of 18 and 93 years. Linear regression models were applied, with stringent genome-wide significance thresholds ( p 3.6 × 10 −8 ) used in both the discovery and replication data. A second, highly conservative mixed linear model method that better controls the false-positive rate was also applied, using the same genome-wide significance thresholds. Using the linear regression method, 52 autosomal and 597 X-linked CpG sites, mapping to 251 unique genes, replicated with concordant effect size directions in the age-by-sex interaction analysis. The site with the greatest difference mapped to GAGE10 , an X-linked gene. Here, DNA methylation levels remained stable across the male adult age range (DNA methylation by age r = 0.02) but decreased across female adult age range (DNA methylation by age r = − 0.61). One site (cg23722529) with a significant age-by-sex interaction also had a quantitative trait locus (rs17321482) that is a genome-wide significant variant for prostate cancer. The mixed linear model method identified 11 CpG sites associated with the age-by-sex interaction. The majority of differences in age-associated DNA methylation trajectories between sexes are present on the X chromosome. Several of these differences occur within genes that have been implicated in sexually dimorphic traits.
Publisher: Oxford University Press (OUP)
Date: 02-03-2010
DOI: 10.1093/HMG/DDQ097
Abstract: Understanding human cognitive ageing is important to improve the health of an increasing elderly population. Serum uric acid levels have been linked to many ageing illnesses and are also linked to cognitive functioning, though the direction of the association is equivocal. SLC2A9, a urate transporter, influences uric acid levels. This study first tested four SLC2A9 SNPs, previously associated with uric acid levels, in approximately 1000 Scots: the Lothian Birth Cohort 1936 (LBC1936). These participants were tested on general cognitive ability at ages 11 and 70. At age 70, they took a battery of erse cognitive tests. Two replication cohorts were investigated. First, the LBC1921, who were tested on general cognitive ability at age 11. At ages 79 (n = 520), 83 (n = 281) and age 87 (n = 177), they completed cognitive ability test batteries. Second, the Edinburgh Type 2 Diabetes Study (ET2DS) were tested for cognitive abilities aged between 60 and 75 years (n = 1066). All analyses were adjusted for age, gender, body mass index and either childhood cognitive ability test score (LBC) or vocabulary-a measure of prior cognitive ability in ET2DS. Significant associations were detected with SLC2A9 and a general memory factor in LBC1936 and other in idual cognitive ability tests (lowest P = 0.0002). The association with logical memory replicated in LBC1921 at all ages (all P 0.1). If the positive associations withstand, then this study could suggest that higher uric acid levels may be associated with increased performance on memory-related tasks.
Publisher: Springer Science and Business Media LLC
Date: 18-04-2017
DOI: 10.1038/TP.2017.73
Abstract: The association between telomere length (TL) dynamics on cognitive performance over the life-course is not well understood. This study meta-analyses observational and causal associations between TL and six cognitive traits, with stratifications on APOE genotype, in a Mendelian Randomization (MR) framework. Twelve European cohorts ( N =17 052 mean age=59.2±8.8 years) provided results for associations between qPCR-measured TL (T/S-ratio scale) and general cognitive function, mini-mental state exam (MMSE), processing speed by digit symbol substitution test (DSST), visuospatial functioning, memory and executive functioning (STROOP). In addition, a genetic risk score (GRS) for TL including seven known genetic variants for TL was calculated, and used in associations with cognitive traits as outcomes in all cohorts. Observational analyses showed that longer telomeres were associated with better scores on DSST ( β =0.051 per s.d.-increase of TL 95% confidence interval (CI): 0.024, 0.077 P =0.0002), and MMSE ( β =0.025 95% CI: 0.002, 0.047 P =0.03), and faster STROOP ( β =−0.053 95% CI: −0.087, −0.018 P =0.003). Effects for DSST were stronger in APOE ɛ4 non-carriers ( β =0.081 95% CI: 0.045, 0.117 P =1.0 × 10 −5 ), whereas carriers performed better in STROOP ( β =−0.074 95% CI: −0.140, −0.009 P =0.03). Causal associations were found for STROOP only ( β =−0.598 per s.d.-increase of TL 95% CI: −1.125, −0.072 P =0.026), with a larger effect in ɛ4-carriers ( β =−0.699 95% CI: −1.330, −0.069 P =0.03). Two-s le replication analyses using CHARGE summary statistics showed causal effects between TL and general cognitive function and DSST, but not with STROOP. In conclusion, we suggest causal effects from longer TL on better cognitive performance, where APOE ɛ4-carriers might be at differential risk.
Publisher: Public Library of Science (PLoS)
Date: 14-02-2017
Publisher: American Medical Association (AMA)
Date: 06-2018
Publisher: Impact Journals, LLC
Date: 28-09-2016
Publisher: Springer Science and Business Media LLC
Date: 29-06-2018
Publisher: Springer Science and Business Media LLC
Date: 11-06-2018
DOI: 10.1038/S41467-018-04558-1
Abstract: Understanding the difference in genetic regulation of gene expression between brain and blood is important for discovering genes for brain-related traits and disorders. Here, we estimate the correlation of genetic effects at the top-associated cis -expression or -DNA methylation (DNAm) quantitative trait loci ( cis -eQTLs or cis -mQTLs) between brain and blood ( r b ). Using publicly available data, we find that genetic effects at the top cis -eQTLs or mQTLs are highly correlated between independent brain and blood s les ( $$\\hat r_b = 0.70$$ r ^ b = 0.70 for cis -eQTLs and $$\\hat r_ b = 0.78$$ r ^ b = 0.78 for cis -mQTLs). Using meta-analyzed brain cis -eQTL/mQTL data ( n = 526 to 1194), we identify 61 genes and 167 DNAm sites associated with four brain-related phenotypes, most of which are a subset of the discoveries (97 genes and 295 DNAm sites) using data from blood with larger s le sizes ( n = 1980 to 14,115). Our results demonstrate the gain of power in gene discovery for brain-related phenotypes using blood cis -eQTL/mQTL data with large s le sizes.
Publisher: Cambridge University Press (CUP)
Date: 19-07-2010
DOI: 10.1017/S1041610210001201
Abstract: Background: Cognitive assessment of older persons, particularly those with impairment, is h ered by measurement error and the ethical issues of testing people with dementia. A potential source of valuable information about end-of-life cognitive status can be gained from those who knew the respondent well – mostly relatives or friends. This study tested the association between last cognitive assessment before death and a retrospective informant assessment of cognition. Methods: Data were analyzed from 248 participants from the Medical Research Council Cognitive Function and Ageing Study who were aged 71 to 102 years at death. Late-life cognition was assessed 0 to 8 years before death using the Mini-mental State Examination (MMSE) and the informant measure was taken 0 to 7 years after death using a Retrospective Informant Interview (RInI). Results: Zero-inflated Poisson regression showed a strong association between MMSE scores and RInI scores – those scoring 29–30 on the MMSE had a RInI score four times lower than those who scored (p 0.001). The time between MMSE and death was also a significant predictor with each additional year increasing RInI scores by 12.4% (p 0.001). The time between death and RInI was only a significant predictor when including measures that were taken four years or more after death. Conclusions: Cognitive scores from retrospective informant interviews are strongly associated with late-life MMSE scores taken close to death. This suggests that the RInI can be used as a proxy measure of cognition in the period leading up to death.
Publisher: Springer Science and Business Media LLC
Date: 25-04-2017
DOI: 10.1038/MP.2017.62
Publisher: Springer Science and Business Media LLC
Date: 26-01-2016
DOI: 10.1038/MP.2015.225
Publisher: Springer Science and Business Media LLC
Date: 02-03-2018
DOI: 10.1038/S41467-018-03371-0
Abstract: The identification of genes and regulatory elements underlying the associations discovered by GWAS is essential to understanding the aetiology of complex traits (including diseases). Here, we demonstrate an analytical paradigm of prioritizing genes and regulatory elements at GWAS loci for follow-up functional studies. We perform an integrative analysis that uses summary-level SNP data from multi-omics studies to detect DNA methylation (DNAm) sites associated with gene expression and phenotype through shared genetic effects (i.e., pleiotropy). We identify pleiotropic associations between 7858 DNAm sites and 2733 genes. These DNAm sites are enriched in enhancers and promoters, and % of them are mapped to distal genes. Further pleiotropic association analyses, which link both the methylome and transcriptome to 12 complex traits, identify 149 DNAm sites and 66 genes, indicating a plausible mechanism whereby the effect of a genetic variant on phenotype is mediated by genetic regulation of transcription through DNAm.
Publisher: Springer Science and Business Media LLC
Date: 27-09-2018
Publisher: Elsevier BV
Date: 05-2014
Publisher: Cold Spring Harbor Laboratory
Date: 30-11-2020
DOI: 10.1101/2020.11.27.20239764
Abstract: Modifiable lifestyle factors influence the risk of developing many neurological diseases. These factors have been extensively linked with blood-based genome-wide DNA methylation (DNAm), but it is unclear if the signatures from blood translate to the target tissue of interest - the brain. To investigate this, we apply blood-derived epigenetic predictors of four lifestyle traits to genome-wide DNAm from five post-mortem brain regions and the last blood s le prior to death in 14 in iduals in the Lothian Birth Cohort 1936 (LBC1936). Using these matched s les, we found that correlations between blood and brain DNAm scores for smoking, high density lipoprotein (HDL) cholesterol, alcohol and body mass index (BMI) were highly variable across brain regions. Smoking scores in the dorsolateral prefrontal cortex had the strongest correlations with smoking scores in blood (r=0.5, n=14) and smoking behaviour (r=0.56, n=9). This was also the brain region which exhibited the strongest correlations for DNAm at site cg05575921 - the single strongest correlate of smoking in blood - in relation to blood (r=0.61, n=14) and smoking behaviour (r=-0.65, n=9). This suggested a particular vulnerability to smoking-related differential methylation in this region. Our work contributes to understanding how lifestyle factors affect the brain and suggests that lifestyle-related DNAm is likely to be both brain region dependent and in many cases poorly proxied for by blood. Though these pilot data provide a rarely-available opportunity for the comparison of methylation patterns across multiple brain regions and the blood, due to the limited s le size available our results must be considered as preliminary and should therefore be used as a basis for further investigation. Graphical abstract 203mm x 127mm (DPI 300) Abbreviated summary [50 words]: We apply blood-derived epigenetic signatures of lifestyle traits to matched blood and brain s les, uncovering variability in how well blood translates across brain regions and a relationship between smoking and the prefrontal cortex . Our preliminary results contribute to understanding how lifestyle-related DNA methylation affects the brain in health and disease.
Publisher: Springer Science and Business Media LLC
Date: 31-10-2017
DOI: 10.1038/MP.2017.210
Publisher: Springer Science and Business Media LLC
Date: 06-09-2011
Publisher: Cold Spring Harbor Laboratory
Date: 20-10-2022
DOI: 10.1101/2022.10.18.22281194
Abstract: Preterm birth is closely associated with a phenotype that includes brain dysmaturation and neurocognitive impairment, commonly termed Encephalopathy of Prematurity (EoP), of which systemic inflammation is considered a key driver. DNA methylation (DNAm) signatures of inflammation from peripheral blood associate with poor brain imaging outcomes in adult cohorts. However, the robustness of DNAm inflammatory scores in infancy, their relation to comorbidities of preterm birth characterised by inflammation, neonatal neuroimaging metrics of EoP, and saliva cross-tissue applicability are unknown. Using salivary DNAm from 258 neonates (n = 155 preterm, gestational age at birth 23.28 – 34.84 weeks, n = 103 term, gestational age at birth 37.00 – 42.14 weeks), we investigated the impact of a DNAm surrogate for C-reactive protein (DNAm CRP) on brain structure and other clinically defined inflammatory exposures. We assessed i) if DNAm CRP estimates varied between preterm infants at term equivalent age and term infants, ii) how DNAm CRP related to different types of inflammatory exposure (maternal, fetal and postnatal) and iii) whether elevated DNAm CRP associated with poorer measures of neonatal brain volume and white matter connectivity. Higher DNAm CRP was linked to preterm status (−0.0107 ± 0.0008, compared with - 0.0118 ± 0.0006 among term infants p 0.001), as well as perinatal inflammatory diseases, including histologic chorioamnionitis, sepsis, bronchopulmonary dysplasia, and necrotising enterocolitis (OR range |2.00 | to |4.71|, p 0.01). Preterm infants with higher DNAm CRP scores had lower brain volume in deep grey matter, white matter, and hippoc i and amygdalae (β range |0.185| to |0.218|). No such associations were observed for term infants. Association magnitudes were largest for measures of white matter microstructure among preterms, where elevated epigenetic inflammation associated with poorer global measures of white matter integrity (β range |0.206| to |0.371|), independent of other confounding exposures. Epigenetic biomarkers of inflammation provide an index of innate immunity in relation to neonatal health. Such DNAm measures complement biological and clinical metrics when investigating the determinants of neurodevelopmental differences.
Publisher: Springer Science and Business Media LLC
Date: 13-08-2012
Publisher: Springer Science and Business Media LLC
Date: 08-01-2018
Publisher: Cold Spring Harbor Laboratory
Date: 05-07-2021
DOI: 10.1101/2021.06.30.21259731
Abstract: Depression is a disabling and highly prevalent condition where genetic and epigenetic differences, such as DNA methylation (DNAm), contribute to prediction of disease liability. We investigated the association between polygenic risk scores (PRS) for depression and DNAm by conducting a methylome-wide association study (MWAS) in Generation Scotland (N=8,898, mean age=49.8 years) with replication in the Lothian Birth Cohorts of 1921 and 1936 and adults in Avon Longitudinal Study of Parents and Children (ALSPAC) (N combined =2,049, mean age=79.1, 69.6 and 47.2 years, respectively). We also conducted a replication MWAS in the ALSPAC children (N=423, mean age=17.1 years). Wide-spread associations were found between PRS constructed using genetic risk variants for depression and DNAm in cytosine-guanine dinucleotide (CpG) probes that localised to genes involved in immune responses and neural development (N CpG =599, p Bonferroni .05, p .5×10 −8 ). The effect sizes for the significant associations were highly correlated between the discovery and replication s les in adults (r=0.83) and in adolescents (r=0.76). Additional analysis on the methylome-wide associations was conducted for each lead genetic risk variant. Over 40% of the independent genetic risk variants showed associations with CpG probe DNAm located in both the same ( cis ) and distal probes ( trans ) to the genetic loci (p Bonferroni .045). Subsequent Mendelian randomisation analysis showed that DNAm and depression are mutually causal (p FDR .039), and there is a greater number of causal effects found from DNAm to depression (DNAm to depression: p FDR ranged from 0.045 to 2.06×10 −120 depression to DNAm: p FDR ranged from 0.046 to 2.1×10 −23 ). Polygenic risk scores for depression, especially those constructed from genome-wide significant genetic risk variants, showed epigenome-wide methylation association differences in the methylome associated with immune responses and brain development. We also found evidence from Mendelian randomisation evidence that DNAm may be causal to depression, as well as a causal consequence of depression.
Publisher: Cold Spring Harbor Laboratory
Date: 23-10-2019
DOI: 10.1101/815035
Abstract: The Apolipoprotein E ( APOE ) ε4 allele is the strongest genetic risk factor for late onset Alzheimer’s disease, while the ε2 allele confers protection. Previous studies report differential DNA methylation of APOE between ε4 and ε2 carriers, but associations with epigenome-wide methylation have not previously been characterised. Using the EPIC array, we investigated epigenome-wide differences in whole blood DNA methylation patterns between Alzheimer’s disease-free APOE ε4 (n=2469) and ε2 (n=1118) carriers from the two largest single-cohort DNA methylation s les profiled to date. Using a discovery, replication and meta-analysis study design, methylation differences were identified using epigenome-wide association analysis and differentially methylated region (DMR) approaches. Results were explored using pathway and methylation quantitative trait loci (meQTL) analyses. We obtained replicated evidence for DNA methylation differences in a ~ 169kb region, which encompasses part of APOE and several upstream genes. Meta-analytic approaches identified DNA methylation differences outside of APOE: differentially methylated positions were identified in DHCR24, LDLR and ABCG1 (2.59 x 10 −100 ≤ P ≤2.44 x 10 −8 ) and DMRs were identified in SREBF2 and LDLR (1.63 x 10 −4 ≤ P ≤3.01 x 10 −2 ). Pathway and meQTL analyses implicated lipid-related processes and high density lipoprotein cholesterol was identified as a partial mediator of the methylation differences in ABCG1 and DHCR24 . APOE ε4 vs. ε2 carrier status is associated with epigenome-wide methylation differences in the blood. The loci identified are located in trans as well as cis to APOE and implicate genes involved in lipid homeostasis.
Publisher: Public Library of Science (PLoS)
Date: 12-12-2012
Publisher: Oxford University Press (OUP)
Date: 19-06-2018
DOI: 10.1093/BIOINFORMATICS/BTY462
Abstract: The genomic architecture of human complex diseases is thought to be attributable to single markers, polygenic components and epistatic components. No study has examined the ability of tree-based methods to detect epistasis in the presence of a polygenic signal. We sought to apply decision tree-based methods, C5.0 and logic regression, to detect epistasis under several simulated conditions, varying strength of interaction and linkage disequilibrium (LD) structure. We then applied the same methods to the phenotype of educational attainment in a large population cohort. LD pruning improved the power and reduced the type I error. C5.0 had a conservative type I error rate whereas logic regression had a type I error rate that exceeded 5%. Despite the more conservative type I error, C5.0 was observed to have higher power than logic regression across several conditions. In the presence of a polygenic signal, power was generally reduced. Applying both methods on educational attainment in a large population cohort yielded numerous interacting SNPs notably a SNP in RCAN3 which is associated with reading and spelling and a SNP in NPAS3, a neurodevelopmental gene. All methods used are implemented and freely available in R. Supplementary data are available at Bioinformatics online.
Publisher: Elsevier BV
Date: 09-2020
Publisher: Springer Science and Business Media LLC
Date: 26-01-2018
DOI: 10.1038/S41467-017-02697-5
Abstract: DNA methylation age is an accurate biomarker of chronological age and predicts lifespan, but its underlying molecular mechanisms are unknown. In this genome-wide association study of 9907 in iduals, we find gene variants mapping to five loci associated with intrinsic epigenetic age acceleration (IEAA) and gene variants in three loci associated with extrinsic epigenetic age acceleration (EEAA). Mendelian randomization analysis suggests causal influences of menarche and menopause on IEAA and lipoproteins on IEAA and EEAA. Variants associated with longer leukocyte telomere length (LTL) in the telomerase reverse transcriptase gene ( TERT ) paradoxically confer higher IEAA ( P 2.7 × 10 −11 ). Causal modeling indicates TERT -specific and independent effects on LTL and IEAA. Experimental hTERT-expression in primary human fibroblasts engenders a linear increase in DNA methylation age with cell population doubling number. Together, these findings indicate a critical role for hTERT in regulating the epigenetic clock, in addition to its established role of compensating for cell replication-dependent telomere shortening.
Publisher: Informa Healthcare
Date: 2008
DOI: 10.3111/13696990701748837
Abstract: The cost of the biological drug abatacept may be partly offset by reductions in the cost of productivity losses due to employee absences and reduced effectiveness at work because of rheumatoid arthritis (RA). This was a 1-year productivity cost model based on epidemiologic and economic data. The setting was private industry in the US and the primary outcome measure was the difference in the costs of lost productivity and drug treatment with and without abatacept ('cost difference'). The lost productivity cost of RA for a firm of 10,000 was $1.69 million, largely due to the cost of RA-related absenteeism ($1.55 million) rather than to worker displacement ($0.12 million) or care-giving for spouses with RA ($0.02 million). In the base case analysis (excluding presenteeism), 37% of the acquisition cost of abatacept was offset by reductions in the cost of RA-related productivity losses. In some industry groups (Utilities and Finance), and in models that included presenteeism, reductions in lost productivity costs exceeded the abatacept cost. Much of the acquisition cost of abatacept may be offset by reductions in the cost of productivity losses due to RA. Abatacept treatment could be cost saving in some industry groups.
Publisher: Springer Science and Business Media LLC
Date: 15-11-2016
DOI: 10.1038/MP.2016.192
Publisher: Cold Spring Harbor Laboratory
Date: 23-09-2014
Abstract: Epigenetic mechanisms such as DNA methylation (DNAm) are essential for regulation of gene expression. DNAm is dynamic, influenced by both environmental and genetic factors. Epigenetic drift is the ergence of the epigenome as a function of age due to stochastic changes in methylation. Here we show that epigenetic drift may be constrained at many CpGs across the human genome by DNA sequence variation and by lifetime environmental exposures. We estimate repeatability of DNAm at 234,811 autosomal CpGs in whole blood using longitudinal data (2–3 repeated measurements) on 478 older people from two Scottish birth cohorts—the Lothian Birth Cohorts of 1921 and 1936. Median age was 79 yr and 70 yr, and the follow-up period was ∼10 yr and ∼6 yr, respectively. We compare this to methylation heritability estimated in the Brisbane Systems Genomics Study, a cross-sectional study of 117 families (offspring median age 13 yr parent median age 46 yr). CpG repeatability in older people was highly correlated (0.68) with heritability estimated in younger people. Highly heritable sites had strong underlying cis -genetic effects. Thirty-seven and 1687 autosomal CpGs were associated with smoking and sex, respectively. Both sets were strongly enriched for high repeatability. Sex-associated CpGs were also strongly enriched for high heritability. Our results show that a large number of CpGs across the genome, as a result of environmental and/or genetic constraints, have stable DNAm variation over the human lifetime. Moreover, at a number of CpGs, most variation in the population is due to genetic factors, despite some sites being highly modifiable by the environment.
Publisher: Cold Spring Harbor Laboratory
Date: 28-06-2019
DOI: 10.1101/19001123
Abstract: DNA methylation (DNAm) is associated with environmental risk factors for major depressive disorder (MDD) but has not yet been tested for its ability to discriminate in iduals with MDD from unaffected in iduals. Using penalized regression based on genome-wide CpG methylation, we trained a DNAm risk score of MDD (DNAm-RS) in 1,223 cases and 1,824 controls and tested in a second independent s le of 363 prevalent cases and 1,417 controls. Using DNA from 1,607 unaffected in iduals, we tested whether DNAm-RS could discriminate the 190 incident cases of lifetime MDD from the 1,417 in iduals who remained unaffected at follow-up. A weighted linear combination of 196 CpG sites were derived from the training s le to form a DNAm-RS. The DNAm-RS explained 1.75% of the variance in MDD risk in an independent case-control s le and significantly predicted future incident episodes of MDD at follow up (R 2 =0.52%). DNAm-RS and MDD polygenic risk scores together additively explained 3.99% of the variance in prevalent MDD. The DNAm-RS was also significantly associated with lifestyle factors associated with MDD, including smoking status (β=0.440, p= ×10 −16 ) and alcohol use (β=0.092, p=9.85×10 −5 ). The DNAm-RS remained significantly associated with MDD after adjustment for these environmental factors (independent association: β=0.338, p=1.17×10 −7 association post-adjustment: β=0.081, p=0.0006). A novel risk score of MDD based on DNAm data significantly discriminated MDD cases from controls in an independent dataset, and controls who would subsequently develop MDD from those who remained unaffected. DNAm-RS captured the effects of exposure to key lifestyle risk factors for MDD, revealing a potential role in risk stratification.
Publisher: American Thoracic Society
Date: 08-2022
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2015
DOI: 10.1161/CIRCGENETICS.115.001225
Abstract: Smoking is an important cardiovascular disease risk factor, but the mechanisms linking smoking to blood pressure are poorly understood. Data on 141 317 participants (62 666 never, 40 669 former, 37 982 current smokers) from 23 population-based studies were included in observational and Mendelian randomization meta-analyses of the associations of smoking status and smoking heaviness with systolic and diastolic blood pressure, hypertension, and resting heart rate. For the Mendelian randomization analyses, a genetic variant rs16969968/rs1051730 was used as a proxy for smoking heaviness in current smokers. In observational analyses, current as compared with never smoking was associated with lower systolic blood pressure and diastolic blood pressure and lower hypertension risk, but with higher resting heart rate. In observational analyses among current smokers, 1 cigarette/day higher level of smoking heaviness was associated with higher (0.21 bpm 95% confidence interval 0.19 0.24) resting heart rate and slightly higher diastolic blood pressure (0.05 mm Hg 95% confidence interval 0.02 0.08) and systolic blood pressure (0.08 mm Hg 95% confidence interval 0.03 0.13). However, in Mendelian randomization analyses among current smokers, although each smoking increasing allele of rs16969968/rs1051730 was associated with higher resting heart rate (0.36 bpm/allele 95% confidence interval 0.18 0.54), there was no strong association with diastolic blood pressure, systolic blood pressure, or hypertension. This would suggest a 7 bpm higher heart rate in those who smoke 20 cigarettes/day. This Mendelian randomization meta-analysis supports a causal association of smoking heaviness with higher level of resting heart rate, but not with blood pressure. These findings suggest that part of the cardiovascular risk of smoking may operate through increasing resting heart rate.
Publisher: Wiley
Date: 09-2015
Publisher: Springer Science and Business Media LLC
Date: 11-06-2018
Publisher: Elsevier BV
Date: 07-2015
Publisher: Cold Spring Harbor Laboratory
Date: 02-12-2020
DOI: 10.1101/2020.12.01.404681
Abstract: Protein biomarkers have been identified across many age-related morbidities. However, characterising epigenetic influences could further inform disease predictions. Here, we leverage epigenome-wide data to study links between the DNAm signatures of the circulating proteome and incident diseases. Using data from four cohorts, we trained and tested epigenetic scores (EpiScores) for 953 plasma proteins, identifying 109 scores that explained between 1% and 58% of the variance in protein levels after adjusting for known protein quantitative trait loci (pQTL) genetic effects. By projecting these EpiScores into an independent s le, (Generation Scotland n=9,537) and relating them to incident morbidities over a follow-up of 14 years, we uncovered 137 EpiScore – disease associations. These associations were largely independent of immune cell proportions, common lifestyle and health factors and biological aging. Notably, we found that our diabetes-associated EpiScores highlighted previous top biomarker associations from proteome-wide assessments of diabetes. These EpiScores for protein levels can therefore be a valuable resource for disease prediction and risk stratification.
Publisher: AIP Publishing
Date: 20-02-2019
DOI: 10.1063/1.5082563
Abstract: A better understanding of the reaction of Mg and B in the solid-phase regime is needed for the low-temperature synthesis of MgB2 films. Here, we study the kinetics of reactive inter-diffusion of Mg and B multilayers on glassy carbon substrates in the temperature range of 400−650°C. Results show that, at these temperatures, inter-diffusion is characterized by a single activation energy of ∼0.45eV. The formation of the superconducting MgB2 phase with critical temperatures of 25–31 K occurs at reaction temperatures of 450°C and above, with the rate of inter-diffusion obeying a power law with a kinetic exponent of ∼0.3. This suggests that rate-limiting processes are the nucleation and growth of MgB2 grains rather than diffusion and interfacial reactions. Implications of these results to the low-temperature synthesis of MgB2 films are discussed.
Publisher: Wiley
Date: 04-2010
Publisher: Springer Science and Business Media LLC
Date: 11-05-2016
DOI: 10.1038/NATURE17671
Publisher: Elsevier BV
Date: 02-2014
Publisher: Springer Science and Business Media LLC
Date: 05-04-2016
DOI: 10.1038/MP.2016.45
Publisher: Oxford University Press (OUP)
Date: 27-11-2016
DOI: 10.1093/IJE/DYX233
Publisher: Springer Science and Business Media LLC
Date: 24-11-2017
DOI: 10.1038/S41598-017-16391-5
Abstract: Low socioeconomic status (SES) is associated with earlier onset of age-related chronic conditions and reduced life-expectancy, but the underlying biomolecular mechanisms remain unclear. Evidence of DNA-methylation differences by SES suggests a possible association of SES with epigenetic age acceleration (AA). We investigated the association of SES with AA in more than 5,000 in iduals belonging to three independent prospective cohorts from Italy, Australia, and Ireland. Low SES was associated with greater AA (β = 0.99 years 95% CI 0.39,1.59 p = 0.002 comparing extreme categories). The results were consistent across different SES indicators. The associations were only partially modulated by the unhealthy lifestyle habits of in iduals with lower SES. In iduals who experienced life-course SES improvement had intermediate AA compared to extreme SES categories, suggesting reversibility of the effect and supporting the relative importance of the early childhood social environment. Socioeconomic adversity is associated with accelerated epigenetic aging, implicating biomolecular mechanisms that may link SES to age-related diseases and longevity.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2009
Publisher: Cold Spring Harbor Laboratory
Date: 28-05-2021
DOI: 10.1101/2021.05.27.446006
Abstract: The prevalence of clonal haematopoiesis of indeterminate potential (CHIP) in healthy in iduals increases rapidly from age 60 onwards and has been associated with increased risk for malignancy, heart disease and ischemic stroke. CHIP is driven by somatic mutations in stem cells that are also drivers of myeloid malignancies. Since mutations in stem cells often drive leukaemia, we hypothesised that stem cell fitness substantially contributes to transformation from CHIP to leukaemia. Stem cell fitness is defined as the proliferative advantage over cells carrying no or only neutral mutations. It is currently unknown whether mutations in different CHIP genes lead to distinct fitness advantages that could form the basis for patient stratification. We set out to quantify the fitness effects of CHIP drivers over a 12 year timespan in older age, using longitudinal error-corrected sequencing data. We developed a new method based on drift-induced fluctuation (DIF) filtering to extract fitness effects from longitudinal data, and thus quantify the growth potential of variants within each in idual. Our approach discriminates naturally drifting populations of cells and faster growing clones, while taking into account in idual mutational context. We show that gene-specific fitness differences can outweigh inter-in idual variation and therefore could form the basis for personalised clinical management.
Publisher: Springer Science and Business Media LLC
Date: 08-01-2018
Publisher: Cold Spring Harbor Laboratory
Date: 11-07-2018
DOI: 10.1101/367326
Abstract: Evaluation of biological age, as opposed to chronological age, is of high relevance for interventions to increase healthy aging. Highly reproducible age-associated DNA methylation (DNAm) changes can be integrated into algorithms for epigenetic age predictions. These predictors have mostly been trained to correlate with chronological age, but they are also indicative for biological aging. For ex le accelerated epigenetic age of blood is associated with higher risk of all-cause mortality in later life. The perceived age of facial images (face-age) is also associated with all-cause mortality and other aging-associated traits. In this study, we therefore tested the hypothesis that an epigenetic predictor for biological age might be trained on face-age as surrogate for biological age, rather than on chronological age. Our data demonstrate that facial aging and DNAm changes in blood provide two independent measures for biological aging.
Publisher: Elsevier BV
Date: 12-2017
Publisher: The Royal Society
Date: 22-04-2014
Abstract: Human cognitive ability shows consistent, positive associations with fitness components across the life-course. Underlying genetic variation should therefore be depleted by selection, which is not observed. Genetic variation in general cognitive ability (intelligence) could be maintained by a mutation–selection balance, with rare variants contributing to its genetic architecture. This study examines the association between the total number of rare stop-gain/loss, splice and missense exonic variants and cognitive ability in childhood and old age in the same in iduals. Exome array data were obtained in the Lothian Birth Cohorts of 1921 and 1936 (combined N = 1596). General cognitive ability was assessed at age 11 years and in late life (79 and 70 years, respectively) and was modelled against the total number of stop-gain/loss, splice, and missense exonic variants, with minor allele frequency less than or equal to 0.01, using linear regression adjusted for age and sex. In both cohorts and in both the childhood and late-life models, there were no significant associations between rare variant burden in the exome and cognitive ability that survived correction for multiple testing. Contrary to our a priori hypothesis, we observed no evidence for an association between the total number of rare exonic variants and either childhood cognitive ability or late-life cognitive ability.
Publisher: Springer Science and Business Media LLC
Date: 22-06-2010
DOI: 10.1007/S10519-010-9372-Y
Abstract: The dopaminergic neurotransmitter system of the brain is involved in working memory and other cognitive functions. Studies suggest an important role for dopamine synthesis and uptake in modulation of human cognitive processes. We studied the association between polymorphisms in the catechol-o-methyl transferase (COMT) and dopamine receptor D2 (DRD2) genes and general cognitive ability in a secondary analysis of 2091 men and women, aged 55-80 years living in Scotland. General cognitive ability 'g' was derived from five cognitive tests of different domains. COMT was not associated with cognitive ability in this population. The DRD2 C:C genotype of rs6277 was associated with decreased general cognitive ability 'g' (p = 0.003), and DRD2 rs1800497 heterozygotes had lowest mean general cognitive ability 'g' (p = 0.007). There was an indication of a potential interaction between the DRD2 SNPs.
Publisher: Springer Science and Business Media LLC
Date: 09-02-2016
DOI: 10.1038/MP.2015.205
Publisher: Oxford University Press (OUP)
Date: 30-04-2019
DOI: 10.1534/GENETICS.118.301861
Abstract: This study highlights dangers in over-interpreting fine-mapping results. Chundru et al. show that genotype imputation accuracy has a large impact on fine-mapping accuracy. They used DNA methylation at CpG-sites with a variant... Genetic variants disrupting DNA methylation at CpG dinucleotides (CpG-SNP) provide a set of known causal variants to serve as models to test fine-mapping methodology. We use 1716 CpG-SNPs to test three fine-mapping approaches (Bayesian imputation-based association mapping, Bayesian sparse linear mixed model, and the J-test), assessing the impact of imputation errors and the choice of reference panel by using both whole-genome sequence (WGS), and genotype array data on the same in iduals (n = 1166). The choice of imputation reference panel had a strong effect on imputation accuracy, with the 1000 Genomes Project Phase 3 (1000G) reference panel (n = 2504 from 26 populations) giving a mean nonreference discordance rate between imputed and sequenced genotypes of 3.2% compared to 1.6% when using the Haplotype Reference Consortium (HRC) reference panel (n = 32,470 Europeans). These imputation errors had an impact on whether the CpG-SNP was included in the 95% credible set, with a difference of ∼23% and ∼7% between the WGS and the 1000G and HRC imputed datasets, respectively. All of the fine-mapping methods failed to reach the expected 95% coverage of the CpG-SNP. This is attributed to secondary cis genetic effects that are unable to be statistically separated from the CpG-SNP, and through a masking mechanism where the effect of the methylation disrupting allele at the CpG-SNP is hidden by the effect of a nearby SNP that has strong linkage disequilibrium with the CpG-SNP. The reduced accuracy in fine-mapping a known causal variant in a low-level biological trait with imputed genetic data has implications for the study of higher-order complex traits and disease.
Publisher: Springer Science and Business Media LLC
Date: 28-04-2020
DOI: 10.1186/S13073-020-00736-3
Abstract: Large numbers of autosomal sites are found differentially methylated in the aging genome. Due to analytical difficulties in dealing with sex differences in X-chromosome content and X-inactivation (XCI) in females, this has not been explored for the X chromosome. Using data from middle age to elderly in iduals (age 55+ years) from two Danish cohorts of monozygotic twins and the Scottish Lothian Birth Cohort 1921, we conducted an X-chromosome-wide analysis of age-associated DNA methylation patterns with consideration of stably inferred XCI status. Through analysing and comparing sex-specific X-linked DNA methylation changes over age late in life, we identified 123, 293 and 55 CpG sites significant (FDR 0.05) only in males, only in females and in both sexes of Danish twins. All findings were significantly replicated in the two Danish twin cohorts. CpG sites escaping XCI are predominantly de-methylated with increasing age across cohorts. In contrast, CpGs highly methylated in both sexes are methylated even further with increasing age. Among the replicated sites in Danish s les, 16 (13%), 24 (8.2%) and 3 (5.5%) CpGs were further validated in LBC1921 (FDR 0.05). The X-chromosome of whole blood leukocytes displays age- and sex-dependent DNA methylation patterns in relation to XCI across cohorts.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2015
Publisher: Springer Science and Business Media LLC
Date: 31-07-2020
DOI: 10.1186/S13148-020-00905-6
Abstract: In iduals of the same chronological age display different rates of biological ageing. A number of measures of biological age have been proposed which harness age-related changes in DNA methylation profiles. These measures include five ‘epigenetic clocks’ which provide an index of how much an in idual’s biological age differs from their chronological age at the time of measurement. The five clocks encompass methylation-based predictors of chronological age (HorvathAge, HannumAge), all-cause mortality (DNAm PhenoAge, DNAm GrimAge) and telomere length (DNAm Telomere Length). A sixth epigenetic measure of ageing differs from these clocks in that it acts as a speedometer providing a single time-point measurement of the pace of an in idual’s biological ageing. This measure of ageing is termed DunedinPoAm. In this study, we test the association between these six epigenetic measures of ageing and the prevalence and incidence of the leading causes of disease burden and mortality in high-income countries ( n ≤ 9537, Generation Scotland: Scottish Family Health Study). DNAm GrimAge predicted incidence of clinically diagnosed chronic obstructive pulmonary disease (COPD), type 2 diabetes and ischemic heart disease after 13 years of follow-up (hazard ratios = 2.22, 1.52 and 1.41, respectively). DunedinPoAm predicted the incidence of COPD and lung cancer (hazard ratios = 2.02 and 1.45, respectively). DNAm PhenoAge predicted incidence of type 2 diabetes (hazard ratio = 1.54). DNAm Telomere Length associated with the incidence of ischemic heart disease (hazard ratio = 0.80). DNAm GrimAge associated with all-cause mortality, the prevalence of COPD and spirometry measures at the study baseline. These associations were present after adjusting for possible confounding risk factors including alcohol consumption, body mass index, deprivation, education and tobacco smoking and surpassed stringent Bonferroni-corrected significance thresholds. Our data suggest that epigenetic measures of ageing may have utility in clinical settings to complement gold-standard methods for disease assessment and management.
Publisher: Elsevier BV
Date: 05-2014
Publisher: Oxford University Press (OUP)
Date: 22-09-2009
DOI: 10.1093/BMB/LDP033
Abstract: Age-associated cognitive decline-or normal (non-pathological, normative, usual) cognitive ageing-is an important human experience which differs in extent between in iduals. The determinants of the differences in age-related cognitive decline are not fully understood. Progress in the field is taking place across many areas of biomedical and psychosocial sciences. The phenotype of normal cognitive ageing is well described. Some mental capabilities are well maintained into old age. From early adulthood, there are declines in mental domains such as processing speed, reasoning, memory and executive functions, some of which is underpinned by a decline in a general cognitive factor. There are contributions to understanding in idual differences in normal cognitive ageing from genetics, general health and medical disorders such as atherosclerotic disease, biological processes such as inflammation, neurobiological changes, diet and lifestyle. Many of these effect sizes are small some are poorly replicated and in some cases, there is the possibility of reverse causation, with prior cognitive ability causing the supposed 'cause' of cognitive ability in old age. Genome-wide scans are a likely source to establish genetic contributions. The role of vascular factors in cognitive ageing is increasingly studied and understood. The same applies to diet, biomarkers such as inflammation and lifestyle factors such as exercise. There are marked advances in brain imaging, affording better in vivo studies of brain correlates of cognitive changes. There is growing appreciation that factors affecting general bodily ageing also influence cognitive functions in old age.
Publisher: Proceedings of the National Academy of Sciences
Date: 08-09-2014
Abstract: We identify several common genetic variants associated with cognitive performance using a two-stage approach: we conduct a genome-wide association study of educational attainment to generate a set of candidates, and then we estimate the association of these variants with cognitive performance. In older Americans, we find that these variants are jointly associated with cognitive health. Bioinformatics analyses implicate a set of genes that is associated with a particular neurotransmitter pathway involved in synaptic plasticity, the main cellular mechanism for learning and memory. In addition to the substantive contribution, this work also serves to show a proxy-phenotype approach to discovering common genetic variants that is likely to be useful for many phenotypes of interest to social scientists (such as personality traits).
Publisher: Springer Science and Business Media LLC
Date: 07-08-2023
DOI: 10.1038/S43587-023-00455-5
Abstract: The concept of aging is complex, including many related phenotypes such as healthspan, lifespan, extreme longevity, frailty and epigenetic aging, suggesting shared biological underpinnings however, aging-related endpoints have been primarily assessed in idually. Using data from these traits and multivariate genome-wide association study methods, we modeled their underlying genetic factor (‘mvAge’). mvAge (effective n = ~1.9 million participants of European ancestry) identified 52 independent variants in 38 genomic loci. Twenty variants were novel (not reported in input genome-wide association studies). Transcriptomic imputation identified age-relevant genes, including VEGFA and PHB1 . Drug-target Mendelian randomization with metformin target genes showed a beneficial impact on mvAge ( P value = 8.41 × 10 −5 ). Similarly, genetically proxied thiazolidinediones ( P value = 3.50 × 10 −10 ), proprotein convertase subtilisin/kexin 9 inhibition ( P value = 1.62 × 10 −6 ), angiopoietin-like protein 4, beta blockers and calcium channel blockers also had beneficial Mendelian randomization estimates. Extending the drug-target Mendelian randomization framework to 3,947 protein-coding genes prioritized 122 targets. Together, these findings will inform future studies aimed at improving healthy aging.
Publisher: Springer Science and Business Media LLC
Date: 24-01-2011
Abstract: Increasing numbers of people are developing type 2 diabetes mellitus, but interventions to prevent and treat the classic microvascular and macrovascular complications have improved, so that people are living longer with the condition. This trend means that novel complications of type 2 diabetes mellitus, which are not targeted by current management strategies, could start to emerge. Cognitive impairment and dementia could come into this category. Type 2 diabetes mellitus is associated with a 1.5-2.5-fold increased risk of dementia. The etiology of dementia and cognitive impairment in people with type 2 diabetes mellitus is probably multifactorial. Chronic hyperglycemia is implicated, perhaps by promoting the development of cerebral microvascular disease. Data suggest that the brains of older people with type 2 diabetes mellitus might be vulnerable to the effects of recurrent, severe hypoglycemia. Other possible moderators of cognitive function include inflammatory mediators, rheological factors and dysregulation of the hypothalamic-pituitary-adrenal axis. Cognitive function should now be included as a standard end point in randomized trials of therapeutic interventions in patients with type 2 diabetes mellitus.
Publisher: Cold Spring Harbor Laboratory
Date: 04-09-2022
DOI: 10.1101/2022.09.04.22279576
Abstract: Anticholinergic drugs block muscarinic receptors in the body. They are commonly prescribed for a variety of indications and their use has previously been associated with dementia and cognitive decline. UK Biobank participants with linked health-care records (n=163,043, aged 40-71 at baseline), for about 17,000 of which MRI data was available, we calculated the total anticholinergic drug burden according to 15 different anticholinergic scales and due to different classes of drugs. We then used linear regression to explore the associations between anticholinergic burden and various measures of cognition and structural MRI, including general cognitive ability, 9 separate cognitive domains, brain atrophy, volumes of 68 cortical and 14 subcortical areas, and fractional anisotropy and median diffusivity of 25 white-matter tracts. Anticholinergic burden was modestly associated with poorer cognition across most anticholinergic scales and cognitive tests (7/9 FDR-adjusted significant associations, standardised betas (β) range: −0.039, −0.003). When using the anticholinergic scale exhibiting the strongest association with cognitive functions, anticholinergic burden due to only some classes of drugs exhibited negative associations with cognitive function, with β-lactam antibiotics (β=-0.035, p FDR .001) and opioids (β=-0.026, p FDR .001) exhibiting the strongest effects. Anticholinergic burden was not associated with any measure of brain macro- or microstructure (p FDR .08). Anticholinergic burden is weakly associated with poorer cognition, but there is little evidence for associations with brain structure. Future studies might focus more broadly on polypharmacy or more narrowly on distinct drug classes, instead of using purported anticholinergic action to study the effects of drugs on cognitive ability.
Publisher: Springer Science and Business Media LLC
Date: 06-04-2023
Publisher: Wiley
Date: 06-04-2022
DOI: 10.1111/EJN.15661
Abstract: Inflammation and ageing‐related DNA methylation patterns in the blood have been linked to a variety of morbidities, including cognitive decline and neurodegenerative disease. However, it is unclear how these blood‐based patterns relate to patterns within the brain and how each associates with central cellular profiles. In this study, we profiled DNA methylation in both the blood and in five post mortem brain regions (BA17, BA20/21, BA24, BA46 and hippoc us) in 14 in iduals from the Lothian Birth Cohort 1936. Microglial burdens were additionally quantified in the same brain regions. DNA methylation signatures of five epigenetic ageing biomarkers (‘epigenetic clocks’), and two inflammatory biomarkers (methylation proxies for C‐reactive protein and interleukin‐6) were compared across tissues and regions. Divergent associations between the inflammation and ageing signatures in the blood and brain were identified, depending on region assessed. Four out of the five assessed epigenetic age acceleration measures were found to be highest in the hippoc us (β range = 0.83–1.14, p ≤ 0.02). The inflammation‐related DNA methylation signatures showed no clear variation across brain regions. Reactive microglial burdens were found to be highest in the hippoc us (β = 1.32, p = 5 × 10 −4 ) however, the only association identified between the blood‐ and brain‐based methylation signatures and microglia was a significant positive association with acceleration of one epigenetic clock (termed DNAm PhenoAge) averaged over all five brain regions (β = 0.40, p = 0.002). This work highlights a potential vulnerability of the hippoc us to epigenetic ageing and provides preliminary evidence of a relationship between DNA methylation signatures in the brain and differences in microglial burdens.
Publisher: Springer Science and Business Media LLC
Date: 13-09-2016
DOI: 10.1038/MP.2016.177
Publisher: Springer Science and Business Media LLC
Date: 06-10-2022
DOI: 10.1038/S43856-022-00189-2
Abstract: Newborn heel prick blood spots are routinely used to screen for inborn errors of metabolism and life-limiting inherited disorders. The potential value of secondary data from newborn blood spot archives merits ethical consideration and assessment of feasibility for public benefit. Early life exposures and behaviours set health trajectories in childhood and later life. The newborn blood spot is potentially well placed to create an unbiased and cost-effective population-level retrospective birth cohort study. Scotland has retained newborn blood spots for all children born since 1965, around 3 million in total. However, a moratorium on research access is currently in place, pending public consultation. We conducted a Citizens’ Jury as a first step to explore whether research use of newborn blood spots was in the public interest. We also assessed the feasibility and value of extracting research data from dried blood spots for predictive medicine. Jurors delivered an agreed verdict that conditional research access to the newborn blood spots was in the public interest. The Chief Medical Officer for Scotland authorised restricted lifting of the current research moratorium to allow a feasibility study. Newborn blood spots from consented Generation Scotland volunteers were retrieved and their potential for both epidemiological and biological research demonstrated. Through the Citizens’ Jury, we have begun to identify under what conditions, if any, should researchers in Scotland be granted access to the archive. Through the feasibility study, we have demonstrated the potential value of research access for health data science and predictive medicine.
Publisher: Oxford University Press (OUP)
Date: 03-12-2013
Publisher: BMJ
Date: 10-2014
DOI: 10.1136/BMJOPEN-2014-006141
Abstract: To investigate whether associations of smoking with depression and anxiety are likely to be causal, using a Mendelian randomisation approach. Mendelian randomisation meta-analyses using a genetic variant (rs16969968/rs1051730) as a proxy for smoking heaviness, and observational meta-analyses of the associations of smoking status and smoking heaviness with depression, anxiety and psychological distress. Current, former and never smokers of European ancestry aged ≥16 years from 25 studies in the Consortium for Causal Analysis Research in Tobacco and Alcohol (CARTA). Binary definitions of depression, anxiety and psychological distress assessed by clinical interview, symptom scales or self-reported recall of clinician diagnosis. The analytic s le included up to 58 176 never smokers, 37 428 former smokers and 32 028 current smokers (total N=127 632). In observational analyses, current smokers had 1.85 times greater odds of depression (95% CI 1.65 to 2.07), 1.71 times greater odds of anxiety (95% CI 1.54 to 1.90) and 1.69 times greater odds of psychological distress (95% CI 1.56 to 1.83) than never smokers. Former smokers also had greater odds of depression, anxiety and psychological distress than never smokers. There was evidence for positive associations of smoking heaviness with depression, anxiety and psychological distress (ORs per cigarette per day: 1.03 (95% CI 1.02 to 1.04), 1.03 (95% CI 1.02 to 1.04) and 1.02 (95% CI 1.02 to 1.03) respectively). In Mendelian randomisation analyses, there was no strong evidence that the minor allele of rs16969968/rs1051730 was associated with depression (OR=1.00, 95% CI 0.95 to 1.05), anxiety (OR=1.02, 95% CI 0.97 to 1.07) or psychological distress (OR=1.02, 95% CI 0.98 to 1.06) in current smokers. Results were similar for former smokers. Findings from Mendelian randomisation analyses do not support a causal role of smoking heaviness in the development of depression and anxiety.
Publisher: eLife Sciences Publications, Ltd
Date: 24-02-2022
Publisher: Cold Spring Harbor Laboratory
Date: 02-03-2023
DOI: 10.1101/2023.03.01.530570
Abstract: The emergence of epigenetic predictors was a pivotal moment in geroscience, propelling the measurement and concept of biological ageing into a quantitative era. However, while current epigenetic clocks have shown strong predictive power, they do not reflect the underlying biological mechanisms driving methylation changes with age. Consequently, biological interpretation of their estimates is limited. Furthermore, our findings suggest that clocks trained on chronological age are confounded by non-age-related phenomena. To address these limitations, we developed a probabilistic model that describes methylation transitions at the cellular level. Our approach reveals two measurable components, acceleration and bias, that directly relate to perturbations of the underlying cellular dynamics. Acceleration is the proportional increase in the speed of methylation transitions across CpG sites, whereas bias is the degree of global change in methylation affecting all CpG sites uniformly. Using data from 7,028 participants from the Generation Scotland study, we found the age acceleration parameter to be associated with physiological traits known to impact healthy ageing. Furthermore, a genome-wide association study of age acceleration identified four genomic loci previously linked with ageing.
Publisher: Springer Science and Business Media LLC
Date: 19-03-2018
DOI: 10.1038/S41537-018-0047-7
Abstract: Recent work has highlighted a possible role for altered epigenetic modifications, including differential DNA methylation, in susceptibility to psychiatric illness. Here, we investigate blood-based DNA methylation in a large family where a balanced translocation between chromosomes 1 and 11 shows genome-wide significant linkage to psychiatric illness. Genome-wide DNA methylation was profiled in whole-blood-derived DNA from 41 in iduals using the Infinium HumanMethylation450 BeadChip (Illumina Inc., San Diego, CA). We found significant differences in DNA methylation when translocation carriers ( n = 17) were compared to related non-carriers ( n = 24) at 13 loci. All but one of the 13 significant differentially methylated positions (DMPs) mapped to the regions surrounding the translocation breakpoints. Methylation levels of five DMPs were associated with genotype at SNPs in linkage disequilibrium with the translocation. Two of the five genes harbouring significant DMPs, DISC1 and DUSP10 , have been previously shown to be differentially methylated in schizophrenia. Gene Ontology analysis revealed enrichment for terms relating to neuronal function and neurodevelopment among the genes harbouring the most significant DMPs. Differentially methylated region (DMR) analysis highlighted a number of genes from the MHC region, which has been implicated in psychiatric illness previously through genetic studies. We show that inheritance of a translocation linked to major mental illness is associated with differential DNA methylation at loci implicated in neuronal development/function and in psychiatric illness. As genomic rearrangements are over-represented in in iduals with psychiatric illness, such analyses may be valuable more widely in the study of these conditions.
Publisher: Springer Science and Business Media LLC
Date: 06-05-2009
DOI: 10.1007/S10519-009-9274-Z
Abstract: Cognitive ability has a substantial genetic component and more than 15 candidate genes have been identified over the past 8 years. One gene that has been associated with general cognitive ability is the cholinergic muscarinic 2 receptor (CHRM2). In an attempt to replicate this finding we typed marker rs8191992 (the originally reported CHRM2 SNP) in two population based cohorts-one Scottish aged over 50 years (N = 2,091) and the other English comprising non-demented elderly participants (N = 758)-and a family-based Australian adolescent s le (N = 1,537). An additional 29 SNPs in CHRM2 were typed in the Australian s le and a further seven in the English cohort. No significant association was found between CHRM2 and erse measures of cognitive ability in any of the s les. In conclusion, this study does not support a role for CHRM2 in cognitive ability.
Publisher: Cold Spring Harbor Laboratory
Date: 16-08-2022
DOI: 10.1101/2022.08.16.22278320
Abstract: The progressive nature of Crohn’s disease is highly variable and hard to predict. In addition, symptoms correlate poorly with mucosal inflammation. There is therefore an urgent need to better characterise the heterogeneity of disease trajectories in Crohn’s disease by utilising objective markers of inflammation. We aimed to better understand this heterogeneity by clustering Crohn’s disease patients with similar longitudinal faecal calprotectin profiles. Latent class mixed models were used to model faecal calprotectin trajectories within five years of diagnosis and to cluster subjects. Information criteria, alluvial plots, and cluster trajectories were used to decide the optimal number of clusters. Chi-squared, Fisher’s exact test, and ANOVA were used to test for associations with variables commonly assessed at diagnosis. Our study cohort comprised of 365 patients with newly diagnosed Crohn’s disease and 2856 faecal calprotectin measurements taken within five years of diagnosis (median 7 per subject). Four distinct clusters were identified by characteristic calprotectin profiles: a cluster with consistently high faecal calprotectin and three clusters characterised by different downward longitudinal trends. Cluster membership was significantly associated with smoking ( p = 0.015), upper gastrointestinal involvement ( p 0.001), and early biologic therapy ( p 0.001). Our analysis demonstrates a novel approach to characterising the heterogeneity of Crohn’s disease by using faecal calprotectin. The group profiles do not simply reflect different treatment regimes and do not mirror classical disease progression endpoints. We believe these profiles represent an entirely new way of classifying disease behaviour in Crohn’s disease.
Publisher: Cold Spring Harbor Laboratory
Date: 12-09-2022
DOI: 10.1101/2022.09.08.507115
Abstract: Epigenetic clocks can track both chronological age (cAge) and biological age (bAge). The latter is typically defined by physiological biomarkers and risk of adverse health outcomes, including all-cause mortality. As cohort s le sizes increase, estimates of cAge and bAge become more precise. Here, we aim to refine predictors and improve understanding of the epigenomic architecture of cAge and bAge. First, we perform large-scale (N = 18,413) epigenome-wide association studies (EWAS) of chronological age and all-cause mortality. Next, to improve cAge prediction, we use methylation data from 24,673 participants from the Generation Scotland (GS) study, the Lothian Birth Cohorts (LBC) of 1921 and 1936 and 8 publicly available datasets. Through the inclusion of linear and non-linear age-CpG associations from the EWAS, feature pre-selection/dimensionality reduction in advance of elastic net regression, and a leave-one-cohort-out (LOCO) cross validation framework, we arrive at an improved cAge predictor (median absolute error = 2.3 years across 10 cohorts). In addition, we train a predictor of bAge on 1,214 all-cause mortality events in GS, based on epigenetic surrogates for 109 plasma proteins and the 8 component parts of GrimAge, the current best epigenetic predictor of all-cause mortality. We test this predictor in four external cohorts (LBC1921, LBC1936, the Framingham Heart Study and the Women’s Health Initiative study) where it outperforms GrimAge in its association to survival (HR GrimAge = 1.47 [1.40, 1.54] with p = 1.08 × 10 −52 , and HR bAge = 1.52 [1.44, 1.59] with p = 2.20 × 10 −60 ). Finally, we introduce MethylBrowsR, an online tool to visualize epigenome-wide CpG-age associations.
Publisher: American Diabetes Association
Date: 03-12-2009
DOI: 10.2337/DB09-1163
Abstract: To determine whether circulating levels of the inflammatory markers C-reactive protein (CRP), interleukin (IL)-6, and tumor necrosis factor (TNF)-α are associated with cognitive ability and estimated lifetime cognitive decline in an elderly population with type 2 diabetes. A cross-sectional study of 1,066 men and women aged 60–75 years with type 2 diabetes and living in Lothian, Scotland (the Edinburgh Type 2 Diabetes Study), was performed. Seven cognitive tests were used to measure abilities in memory, nonverbal reasoning, information processing speed, executive function, and mental flexibility. The results were used to derive a general intelligence factor (g). A vocabulary–based test was administered as an estimate of peak prior cognitive ability. Results on the cognitive tests were assessed for statistical association with inflammatory markers measured in a venous blood s le at the time of cognitive testing. Higher IL-6 and TNF-α levels were associated with poorer age- and sex-adjusted scores on the majority of the in idual cognitive tests. They were also associated with g using standardized regression coefficients −0.074 to −0.173 (P & 0.05). After adjusting for vocabulary, education level, cardiovascular dysfunction, duration of diabetes, and glycemic control, IL-6 remained associated with three of the cognitive tests and with g. In this representative population of people with type 2 diabetes, elevated circulating levels of inflammatory markers were associated with poorer cognitive ability. IL-6 levels were also associated with estimated lifetime cognitive decline.
Publisher: Proceedings of the National Academy of Sciences
Date: 31-10-2016
Abstract: In iduals with more education tend to live longer. Genetic variants have been discovered that predict educational attainment. We tested whether a “polygenic score” based on these genetic variants could make predictions about people’s lifespan. We used data from three cohort studies (including ,000 participants) to examine the link between offspring polygenic score for education and parental longevity. Across the studies, we found that participants with more education-linked genetic variants had longer-living parents compared with those with the lowest genetic education scores, those with the highest scores had parents who lived on average 6 months longer. This finding suggests the hypothesis that part of the ultimate explanation for the extended longevity of better-educated people is an underlying, quantifiable, genetic propensity.
Publisher: Informa UK Limited
Date: 02-09-2018
Publisher: Springer Science and Business Media LLC
Date: 12-04-2016
DOI: 10.1038/MP.2016.49
Abstract: Neuroticism is a personality trait of fundamental importance for psychological well-being and public health. It is strongly associated with major depressive disorder (MDD) and several other psychiatric conditions. Although neuroticism is heritable, attempts to identify the alleles involved in previous studies have been limited by relatively small s le sizes. Here we report a combined meta-analysis of genome-wide association study (GWAS) of neuroticism that includes 91 370 participants from the UK Biobank cohort, 6659 participants from the Generation Scotland: Scottish Family Health Study (GS:SFHS) and 8687 participants from a QIMR (Queensland Institute of Medical Research) Berghofer Medical Research Institute (QIMR) cohort. All participants were assessed using the same neuroticism instrument, the Eysenck Personality Questionnaire-Revised (EPQ-R-S) Short Form’s Neuroticism scale. We found a single-nucleotide polymorphism-based heritability estimate for neuroticism of ∼15% (s.e.=0.7%). Meta-analysis identified nine novel loci associated with neuroticism. The strongest evidence for association was at a locus on chromosome 8 ( P =1.5 × 10 −15 ) spanning 4 Mb and containing at least 36 genes. Other associated loci included interesting candidate genes on chromosome 1 ( GRIK3 ( glutamate receptor ionotropic kainate 3 )), chromosome 4 ( KLHL2 ( Kelch-like protein 2 )), chromosome 17 ( CRHR1 ( corticotropin-releasing hormone receptor 1 ) and MAPT ( microtubule-associated protein Tau )) and on chromosome 18 ( CELF4 ( CUGBP elav-like family member 4 )). We found no evidence for genetic differences in the common allelic architecture of neuroticism by sex. By comparing our findings with those of the Psychiatric Genetics Consortia, we identified a strong genetic correlation between neuroticism and MDD and a less strong but significant genetic correlation with schizophrenia, although not with bipolar disorder. Polygenic risk scores derived from the primary UK Biobank s le captured ∼1% of the variance in neuroticism in the GS:SFHS and QIMR s les, although most of the genome-wide significant alleles identified within a UK Biobank-only GWAS of neuroticism were not independently replicated within these cohorts. The identification of nine novel neuroticism-associated loci will drive forward future work on the neurobiology of neuroticism and related phenotypes.
Publisher: Cambridge University Press (CUP)
Date: 02-10-2015
DOI: 10.1017/THG.2015.71
Abstract: Structural brain magnetic resonance imaging (MRI) traits share part of their genetic variance with cognitive traits. Here, we use genetic association results from large meta-analytic studies of genome-wide association (GWA) for brain infarcts (BI), white matter hyperintensities, intracranial, hippoc al, and total brain volumes to estimate polygenic scores for these traits in three Scottish s les: Generation Scotland: Scottish Family Health Study (GS:SFHS), and the Lothian Birth Cohorts of 1936 (LBC1936) and 1921 (LBC1921). These five brain MRI trait polygenic scores were then used to: (1) predict corresponding MRI traits in the LBC1936 (numbers ranged 573 to 630 across traits), and (2) predict cognitive traits in all three cohorts (in 8,115–8,250 persons). In the LBC1936, all MRI phenotypic traits were correlated with at least one cognitive measure, and polygenic prediction of MRI traits was observed for intracranial volume. Meta-analysis of the correlations between MRI polygenic scores and cognitive traits revealed a significant negative correlation (maximal r = 0.08) between the HV polygenic score and measures of global cognitive ability collected in childhood and in old age in the Lothian Birth Cohorts. The lack of association to a related general cognitive measure when including the GS:SFHS points to either type 1 error or the importance of using prediction s les that closely match the demographics of the GWA s les from which prediction is based. Ideally, these analyses should be repeated in larger s les with data on both MRI and cognition, and using MRI GWA results from even larger meta-analysis studies.
Publisher: Springer Science and Business Media LLC
Date: 13-03-2018
DOI: 10.1038/S41398-018-0111-0
Abstract: Lower performances in cognitive ability in in iduals with Major Depressive Disorder (MDD) have been observed on multiple occasions. Understanding cognitive performance in MDD could provide a wider insight in the aetiology of MDD as a whole. Using a large, well characterised cohort ( N = 7012), we tested for: differences in cognitive performance by MDD status and a gene (single SNP or polygenic score) by MDD interaction effect on cognitive performance. Linear regression was used to assess the association between cognitive performance and MDD status in a case-control, single-episode–recurrent MDD and control-recurrent MDD study design. Test scores on verbal declarative memory, executive functioning, vocabulary, and processing speed were examined. Cognitive performance measures showing a significant difference between groups were subsequently analysed for genetic associations. Those with recurrent MDD have lower processing speed versus controls and single-episode MDD ( β = − 2.44, p = 3.6 × 10 −04 β = - 2.86, p = 1.8 × 10 −03 , respectively). There were significantly higher vocabulary scores in MDD cases versus controls ( β = 0.79, p = 2.0 × 10 −06 ), and for recurrent MDD versus controls ( β = 0.95, p = 5.8 × 10 −05 ). Observed differences could not be linked to significant single-locus associations. Polygenic scores created from a processing speed meta-analysis GWAS explained 1% of variation in processing speed performance in the single-episode versus recurrent MDD study ( p = 1.7 × 10 −03 ) and 0.5% of variation in the control versus recurrent MDD study ( p = 1.6 × 10 −10 ). In iduals with recurrent MDD showed lower processing speed and executive function while showing higher vocabulary performance. Within MDD, persons with recurrent episodes show lower processing speed and executive function scores relative to in iduals experiencing a single episode.
Publisher: Impact Journals, LLC
Date: 12-2017
Publisher: Public Library of Science (PLoS)
Date: 30-10-2017
Publisher: Cold Spring Harbor Laboratory
Date: 25-07-2023
DOI: 10.1101/2023.07.21.550074
Abstract: Genome-wide association studies (GWAS) have proven a powerful tool for human geneticists to generate biological insights or hypotheses for drug discovery. Nevertheless, a dependency on sensitive in idual-level data together with ever-increasing cohort s le sizes, numbers of variants and phenotypes studied put a strain on existing algorithms, limiting the GWAS approach from maximising potential. Here we present in-silico GWAS (isGWAS), a uniquely scalable algorithm to infer regression parameters in case-control GWAS from cohort-level summary data. For any s le size, isGWAS computes a variant-disease association parameter in ∼1 millisecond, or ∼11m variants in UK-Biobank within ∼4 minutes (∼1500-fold faster than state-of-the-art). Extensive simulations and empirical tests demonstrate that isGWAS results are highly comparable to traditional regression-based approaches. We further introduce a heuristic re-s ling algorithm, leapfrog re-s ler (LRS), to extrapolate association results to semi-virtually enlarged cohorts. Owing to significant computational gains we anticipate a broad use of isGWAS and LRS which are customizable on a web interface.
Publisher: Springer Science and Business Media LLC
Date: 07-01-2014
DOI: 10.1038/TP.2013.114
Abstract: Differences in general cognitive ability (intelligence) account for approximately half of the variation in any large battery of cognitive tests and are predictive of important life events including health. Genome-wide analyses of common single-nucleotide polymorphisms indicate that they jointly tag between a quarter and a half of the variance in intelligence. However, no single polymorphism has been reliably associated with variation in intelligence. It remains possible that these many small effects might be aggregated in networks of functionally linked genes. Here, we tested a network of 1461 genes in the postsynaptic density and associated complexes for an enriched association with intelligence. These were ascertained in 3511 in iduals (the Cognitive Ageing Genetics in England and Scotland (CAGES) consortium) phenotyped for general cognitive ability, fluid cognitive ability, crystallised cognitive ability, memory and speed of processing. By analysing the results of a genome wide association study (GWAS) using Gene Set Enrichment Analysis, a significant enrichment was found for fluid cognitive ability for the proteins found in the complexes of N -methyl-D-aspartate receptor complex P =0.002. Replication was sought in two additional cohorts ( N =670 and 2062). A meta-analytic P -value of 0.003 was found when these were combined with the CAGES consortium. The results suggest that genetic variation in the macromolecular machines formed by membrane-associated guanylate kinase (MAGUK) scaffold proteins and their interaction partners contributes to variation in intelligence.
Publisher: Wiley
Date: 18-11-2018
DOI: 10.1111/ACEL.12877
Publisher: Springer Science and Business Media LLC
Date: 02-2015
DOI: 10.1038/MP.2014.188
Abstract: General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts ( N =53 949) in which the participants had undertaken multiple, erse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P =3.93 × 10 −9 , MIR2113 rs17522122, P =2.55 × 10 −8 , AKAP6 rs10119, P =5.67 × 10 −9 , APOE/TOMM40 ). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 ( P =1 × 10 −6 ). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study ( N =6617) and the Health and Retirement Study ( N =5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort ( N =5487 P =1.5 × 10 −17 ). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer’s disease: TOMM40 , APOE , ABCG1 and MEF2C .
Publisher: Cold Spring Harbor Laboratory
Date: 26-10-2023
Publisher: eLife Sciences Publications, Ltd
Date: 29-03-2022
DOI: 10.7554/ELIFE.75374
Abstract: Epigenetic clocks have been associated with cancer risk in several observational studies. Nevertheless, it is unclear whether they play a causal role in cancer risk or if they act as a non-causal biomarker. We conducted a two-s le Mendelian randomization (MR) study to examine the genetically predicted effects of epigenetic age acceleration as measured by HannumAge (nine single-nucleotide polymorphisms (SNPs)), Horvath Intrinsic Age (24 SNPs), PhenoAge (11 SNPs), and GrimAge (4 SNPs) on multiple cancers (i.e. breast, prostate, colorectal, ovarian and lung cancer). We obtained genome-wide association data for biological ageing from a meta-analysis (N = 34,710), and for cancer from the UK Biobank (N cases = 2671–13,879 N controls = 173,493–372,016), FinnGen (N cases = 719–8401 N controls = 74,685–174,006) and several international cancer genetic consortia (N cases = 11,348–122,977 N controls = 15,861–105,974). Main analyses were performed using multiplicative random effects inverse variance weighted (IVW) MR. In idual study estimates were pooled using fixed effect meta-analysis. Sensitivity analyses included MR-Egger, weighted median, weighted mode and Causal Analysis using Summary Effect Estimates (CAUSE) methods, which are robust to some of the assumptions of the IVW approach. Meta-analysed IVW MR findings suggested that higher GrimAge acceleration increased the risk of colorectal cancer (OR = 1.12 per year increase in GrimAge acceleration, 95% CI 1.04–1.20, p = 0.002). The direction of the genetically predicted effects was consistent across main and sensitivity MR analyses. Among subtypes, the genetically predicted effect of GrimAge acceleration was greater for colon cancer (IVW OR = 1.15, 95% CI 1.09–1.21, p = 0.006), than rectal cancer (IVW OR = 1.05, 95% CI 0.97–1.13, p = 0.24). Results were less consistent for associations between other epigenetic clocks and cancers. GrimAge acceleration may increase the risk of colorectal cancer. Findings for other clocks and cancers were inconsistent. Further work is required to investigate the potential mechanisms underlying the results. FMB was supported by a Wellcome Trust PhD studentship in Molecular, Genetic and Lifecourse Epidemiology (224982/Z/22/Z which is part of grant 218495/Z/19/Z). KKT was supported by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme) and by the Hellenic Republic’s Operational Programme ‘Competitiveness, Entrepreneurship & Innovation’ (OΠΣ 5047228). PH was supported by Cancer Research UK (C18281/A29019). RMM was supported by the NIHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol and by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). RMM is a National Institute for Health Research Senior Investigator (NIHR202411). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. GDS and CLR were supported by the Medical Research Council (MC_UU_00011/1 and MC_UU_00011/5, respectively) and by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). REM was supported by an Alzheimer’s Society project grant (AS-PG-19b-010) and NIH grant (U01 AG-18-018, PI: Steve Horvath). RCR is a de Pass Vice Chancellor’s Research Fellow at the University of Bristol.
Publisher: Cold Spring Harbor Laboratory
Date: 06-09-2021
DOI: 10.1101/2021.09.03.21263066
Abstract: Characterising associations between the methylome, proteome and phenome may provide insight into biological pathways governing brain health. Here, we report an integrated DNA methylation and phenotypic study of the circulating proteome in relation to brain health. Methylome-wide association studies of 4,058 plasma proteins are performed (N=774), identifying 2,928 CpG-protein associations after adjustment for multiple testing. These were independent of known genetic protein quantitative trait loci (pQTLs) and common lifestyle effects. Phenome-wide association studies of each protein are then performed in relation to 15 neurological traits (N=1,065), identifying 405 associations between the levels of 191 proteins and cognitive scores, brain imaging measures or APOE e4 status. We uncover 35 previously unreported DNA methylation signatures for 17 protein markers of brain health. The epigenetic and proteomic markers we identify are pertinent to understanding and stratifying brain health.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-12-2021
DOI: 10.1212/WNL.0000000000012997
Abstract: To investigate chronic inflammation in relation to cognitive aging by comparison of an epigenetic and serum biomarker of C-reactive protein and their associations with neuroimaging and cognitive outcomes. At baseline, participants (n = 521) were cognitively normal, around 73 years of age (mean 72.4, SD 0.716), and had inflammation, vascular risk (cardiovascular disease history, hypertension, diabetes, smoking, alcohol consumption, body mass index), and neuroimaging (structural and diffusion MRI) data available. Baseline inflammatory status was quantified by a traditional measure of peripheral inflammation—serum C-reactive protein (CRP)—and an epigenetic measure (DNA methylation [DNAm] signature of CRP). Linear models were used to examine the inflammation–brain health associations mediation analyses were performed to interrogate the relationship between chronic inflammation, brain structure, and cognitive functioning. We demonstrate that DNAm CRP shows significantly (on average 6.4-fold) stronger associations with brain health outcomes than serum CRP. DNAm CRP is associated with total brain volume (β = −0.197, 95% confidence interval [CI] −0.28 to −0.12, p FDR = 8.42 × 10 −6 ), gray matter volume (β = −0.200, 95% CI −0.28 to −0.12, p FDR = 1.66 × 10 −5 ), and white matter volume (β = −0.150, 95% CI −0.23 to −0.07, p FDR = 0.001) and regional brain atrophy. We also find that DNAm CRP has an inverse association with global and domain-specific (speed, visuospatial, and memory) cognitive functioning and that brain structure partially mediates this CRP–cognitive association (up to 29.7%), dependent on lifestyle and health factors. These results support the hypothesis that chronic inflammation may contribute to neurodegenerative brain changes that underlie differences in cognitive ability in later life and highlight the potential of DNAm proxies for indexing chronic inflammatory status. This study provides Class II evidence that a DNAm signature of CRP levels is more strongly associated with brain health outcomes than serum CRP levels.
Publisher: Springer Science and Business Media LLC
Date: 08-07-2020
Publisher: Cold Spring Harbor Laboratory
Date: 05-08-2021
DOI: 10.1101/2021.08.04.21261330
Abstract: Previous studies on the association between the long-term use of anticholinergic drugs and dementia report heterogenous results. This variability could be due to, among other factors, different anticholinergic scales used, and differential effects of distinct classes of anticholinergic drugs. Here, we use 171,775 participants of UK Biobank with linked GP prescription records to calculate the cumulative annual anticholinergic burden (ACB) and ascertain dementia diagnoses through GP- and inpatient records. We then compare 13 anticholinergic scales and anticholinergic burden (ACB) due to different classes of drugs in their association with dementia. We find dementia to be more strongly predicted by ACB than by polypharmacy across most anticholinergic scales (standardised ORs range: 1.027-1.125). Furthermore, not only the baseline ACB, but the slope of the longitudinal trajectory of ACB (HR=1.094 95% CI: 1.068-1.119) is predictive of dementia. However, the association between ACB and dementia holds only for some classes of drugs – especially antidepressants, antiepileptics, and high-ceiling antidiuretics. Moreover, we do not find a clear relationship between reported anticholinergic potency and dementia risk. The heterogeneity in findings on the association between ACB and dementia may in part be due to different effects for different classes of drugs. Future studies should establish such differences in more detail and further examine the practicality of using a general measure of anticholinergic potency as it relates to the risk of dementia.
Publisher: Springer Science and Business Media LLC
Date: 06-12-2023
Publisher: Springer Science and Business Media LLC
Date: 09-08-2022
DOI: 10.1038/S41467-022-32319-8
Abstract: Characterising associations between the methylome, proteome and phenome may provide insight into biological pathways governing brain health. Here, we report an integrated DNA methylation and phenotypic study of the circulating proteome in relation to brain health. Methylome-wide association studies of 4058 plasma proteins are performed ( N = 774), identifying 2928 CpG-protein associations after adjustment for multiple testing. These are independent of known genetic protein quantitative trait loci (pQTLs) and common lifestyle effects. Phenome-wide association studies of each protein are then performed in relation to 15 neurological traits ( N = 1,065), identifying 405 associations between the levels of 191 proteins and cognitive scores, brain imaging measures or APOE e4 status. We uncover 35 previously unreported DNA methylation signatures for 17 protein markers of brain health. The epigenetic and proteomic markers we identify are pertinent to understanding and stratifying brain health.
Publisher: Springer Science and Business Media LLC
Date: 20-11-2018
DOI: 10.1038/S41467-018-07400-W
Abstract: The original version of this Article contained an error in the spelling of the author Julia Sidorenko, which was incorrectly given as Julia Sirodenko. This has now been corrected in both the PDF and HTML versions of the Article. Further, the sixth sentence of the second paragraph of the Correspondence and the legend to Fig. 1 incorrectly omitted citation of work by Heilmann-Helmbach, S. et al. This has now been corrected in both the PDF and HTML versions of the Article.
Publisher: Elsevier BV
Date: 08-2018
Publisher: Cold Spring Harbor Laboratory
Date: 16-07-2023
DOI: 10.1101/2023.07.14.23292648
Abstract: PREVENT is a multi-centre prospective cohort study in the UK and Ireland that aims to examine mid-life risk factors for dementia, identify and describe the earliest indices of disease development. The PREVENT dementia programme is one of the original epidemiological initiatives targeting midlife as a critical window for intervention in neurodegenerative conditions. This paper provides an overview of the study protocol and presents the first summary results from the initial baseline data to describe the cohort. Participants in the PREVENT cohort provide demographic data, biological s les (blood, saliva, urine and optional cerebrospinal fluid), lifestyle and psychological questionnaires, undergo a comprehensive cognitive test battery, and are imaged using multi-modal 3T magnetic resonance imaging (MRI) scanning, with both structural and functional sequences. The PREVENT cohort governance structure is described, which includes a steering committee, a scientific advisory board and core patient and public involvement groups. A number of sub-studies which supplement the main PREVENT cohort are also described. The PREVENT cohort baseline data includes 700 participants recruited between 2014 and 2020 across five sites in the UK and Ireland (Cambridge, Dublin, Edinburgh, London and Oxford). At baseline, participants had a mean age of 51.2 years (range 40-59, SD ±5.47), with the majority female (n=433, 61.9%). There was a near equal distribution of participants with and without a parental history of dementia (51.4% vs 48.6%) and a relatively high prevalence of APOE⍰4 carriers (n=264, 38.0%). Participants were highly educated (16.7 ± 3.44 years of education), were mainly of European Ancestry (n=672, 95.9%) and were cognitively healthy as measured by the Addenbrookes Cognitive Examination-III (ACE-III) (Total score 95.6 ±4.06). Mean white matter hyperintensity (WMH) volume at recruitment was 2.26 ± 2.77 ml (median = 1.39ml), with hippoc al volume 8.15 ± 0.79ml. There was good representation of known dementia risk factors in the cohort. The PREVENT cohort offers a novel dataset to explore midlife risk factors and early signs of neurodegenerative disease. Data are available open access at no cost via the Alzheimer’s Disease Data Initiative (ADDI) platform and Dementia Platforms UK (DPUK) platform pending approval of the data access request from the PREVENT steering group committee.
Publisher: Springer Science and Business Media LLC
Date: 23-01-2011
DOI: 10.1007/S10519-011-9449-2
Abstract: There is increasing evidence to suggest that elevated plasma levels of fibrinogen are associated with late-life cognitive performance. This study tested the association of single nucleotide polymorphisms in the fibrinogen α (FGA) and β (FGB) genes with cognitive performance. Data were analysed from three community-dwelling populations of older persons (>50 years) in central Scotland: the Aspirin for Asymptomatic Atherosclerosis (AAA) Trial (n = 2,091), the Edinburgh Type 2 Diabetes Study (ET2DS, n = 1,066), and the Lothian Birth Cohort 1936 (LBC1936, n = 1,091). Cognition was assessed using a battery of five, seven, and four psychometric tests, respectively. This information was used to derive a general cognitive factor. Weakly significant associations were found between the rs4220 (FGB), and rs2227412 (FGB) SNPs and a single test of cognitive performance in the AAA Trial (p < 0.05). These findings did not replicate in the LBC1936 or ET2DS cohorts, except for the rs2227412 SNP, which was significantly associated with the general cognitive factor in the ET2DS (p = 3.3 × 10(-4)). A summary term that combined results from all three studies suggested that the rs2227412 genotype associated with reduced cognitive ability also associated with higher plasma fibrinogen levels. These findings suggest a tentative role for fibrinogen as a determinant of late-life cognitive performance and justify further attempts at replication in older persons.
Publisher: Public Library of Science (PLoS)
Date: 04-12-2014
Publisher: Springer Science and Business Media LLC
Date: 30-08-2018
Publisher: Oxford University Press (OUP)
Date: 20-03-2018
Publisher: Wiley
Date: 19-09-2022
DOI: 10.1111/BCP.15045
Abstract: The use of prescription drugs with anticholinergic properties has been associated with multiple negative health outcomes in older people. Moreover, recent evidence suggests that associated adverse effects may occur even decades after stopping anticholinergic use. Despite the implicated importance of examining longitudinal patterns of anticholinergic prescribing for different age groups, few such data are available. We performed an age-period-cohort (APC) analysis to study trends in an aggregate measure of anticholinergic burden between the years 1990 and 2015, utilising data from >220 000 UK Biobank participants with linked prescription data from primary care. Anticholinergic burden in the s le increased up to 9-fold over 25 years and was observed for both period and age effects across most classes of drugs. The greatest increase was seen in the prescribing of antidepressants. Female sex, lower education and greater deprivation were associated with greater anticholinergic burden. The increase in anticholinergic prescribing is mostly due to an increase in polypharmacy and is attributable to both ageing of participants and period-related changes in prescribing practices. Research is needed to clarify the implications of rising anticholinergic use for public health and to contextualise this rise in light of other relevant prescribing practices.
Publisher: Cold Spring Harbor Laboratory
Date: 21-11-2021
DOI: 10.1101/2021.11.19.21266469
Abstract: Type 2 diabetes mellitus (T2D) presents a major health and economic burden that could be alleviated with improved early prediction and intervention. While standard risk factors have shown good predictive performance, we show that the use of blood-based DNA methylation information leads to a significant improvement in the prediction of 10-year T2D incidence risk. Previous studies have been largely constrained by linear assumptions, the use of CpGs one-at-a-time, and binary outcomes. We present a flexible approach (via an R package, MethylPipeR ) based on a range of linear and tree-ensemble models that incorporate time-to-event data for prediction. Using the Generation Scotland cohort (training set n cases =374, n controls =9,461 test set n cases =252, n controls =4,526) our best-performing model (Area Under the Curve (AUC)=0.872, Precision Recall AUC (PRAUC)=0.302) showed notable improvement in 10-year onset prediction beyond standard risk factors (AUC=0.839, PRAUC=0.227). Replication was observed in the German-based KORA study (n=1,451, n cases = 142, p=1.6×10 -5 ).
Publisher: Springer Science and Business Media LLC
Date: 30-01-2015
Publisher: Oxford University Press (OUP)
Date: 02-03-2010
Abstract: the association between the rheological factors haematocrit and plasma viscosity and cognitive ability has not been extensively studied. It is possible that blood viscosity affects cerebral blood flow and cognitive function. This study tested the contemporaneous associations between these two markers of rheology and cognitive ability and estimated lifetime cognitive change in an elderly population with type 2 diabetes. a cross-sectional cohort of 1,066 men and women with type 2 diabetes (Edinburgh Type 2 Diabetes Study) was used for the analysis. Plasma viscosity and haematocrit were measured in venous blood s les at baseline. Contemporaneously, a battery of seven cognitive tests was administered to all participants. These data were used to derive a general intelligence factor, g. A vocabulary-based test was also administered as an estimate of prior intelligence, and adjustment for scores on this test was used to estimate lifetime cognitive decline. increased plasma viscosity was associated with poorer age- and sex-adjusted scores on the cognitive domains of processing speed, mental flexibility and general intelligence, g, with standardised regression coefficients -0.092 (P < 0.01), -0.077 (P < 0.05) and -0.093 (P < 0.01), respectively. After adjusting for vocabulary, education level, cardiovascular dysfunction, duration of diabetes and glycaemic control, the associations remained significant for the measure of processing speed and g, with standardised regression coefficients -0.059 (P < 0.05) and -0.051 (P < 0.05). Increased haematocrit was significantly associated with better age- and sex-adjusted cognitive scores on the majority of the tests and with g. However, significant associations were not retained after adjustments for additional covariates. increased plasma viscosity is associated with decreased cognitive ability and increased estimated lifetime cognitive decline. The relationship between haematocrit and cognitive ability requires further study.
Publisher: Springer Science and Business Media LLC
Date: 29-05-2018
DOI: 10.1038/S41467-018-04362-X
Abstract: General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486 age 16–102) and find 148 genome-wide significant independent loci ( P 5 × 10 −8 ) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent s les. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2009
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2016
DOI: 10.1161/CIRCGENETICS.116.001506
Abstract: DNA methylation leaves a long-term signature of smoking exposure and is one potential mechanism by which tobacco exposure predisposes to adverse health outcomes, such as cancers, osteoporosis, lung, and cardiovascular disorders. To comprehensively determine the association between cigarette smoking and DNA methylation, we conducted a meta-analysis of genome-wide DNA methylation assessed using the Illumina BeadChip 450K array on 15 907 blood-derived DNA s les from participants in 16 cohorts (including 2433 current, 6518 former, and 6956 never smokers). Comparing current versus never smokers, 2623 cytosine–phosphate–guanine sites (CpGs), annotated to 1405 genes, were statistically significantly differentially methylated at Bonferroni threshold of P ×10 −7 (18 760 CpGs at false discovery rate .05). Genes annotated to these CpGs were enriched for associations with several smoking-related traits in genome-wide studies including pulmonary function, cancers, inflammatory diseases, and heart disease. Comparing former versus never smokers, 185 of the CpGs that differed between current and never smokers were significant P ×10 −7 (2623 CpGs at false discovery rate .05), indicating a pattern of persistent altered methylation, with attenuation, after smoking cessation. Transcriptomic integration identified effects on gene expression at many differentially methylated CpGs. Cigarette smoking has a broad impact on genome-wide methylation that, at many loci, persists many years after smoking cessation. Many of the differentially methylated genes were novel genes with respect to biological effects of smoking and might represent therapeutic targets for prevention or treatment of tobacco-related diseases. Methylation at these sites could also serve as sensitive and stable biomarkers of lifetime exposure to tobacco smoke.
Publisher: Cold Spring Harbor Laboratory
Date: 30-06-2017
DOI: 10.1101/157776
Abstract: DNA methylation age is an accurate biomarker of chronological age and predicts lifespan, but its underlying molecular mechanisms are unknown. In this genome-wide association study of 9,907 in iduals, we found gene variants mapping to five loci associated with intrinsic epigenetic age acceleration (IEAA) and gene variants in 3 loci associated extrinsic epigenetic age acceleration (EEAA). Mendelian randomization analysis suggested causal influences of menarche and menopause on IEAA and lipid levels on IEAA and EEAA. Variants associated with longer leukocyte telomere length (LTL) in the telomerase reverse transcriptase gene ( TERT ) locus at 5p15.33 confer higher IEAA (P .7×10 -11 ). Causal modelling indicates TERT -specific and independent effects on LTL and IEAA. Experimental hTERT expression in primary human fibroblasts engenders a linear increase in DNA methylation age with cell population doubling number. Together, these findings indicate a critical role for hTERT in regulating the DNA methylation clock, in addition to its established role of compensating for cell replication-dependent telomere shortening.
Publisher: IOP Publishing
Date: 20-05-2019
Publisher: Cold Spring Harbor Laboratory
Date: 07-04-2019
DOI: 10.1101/600759
Abstract: Age-related clonal haemopoiesis (ARCH) in healthy in iduals was initially observed through an increased skewing in X chromosome inactivation. More recently, several groups reported that ARCH is driven by somatic mutations. The most prevalent ARCH mutations are in the DNMT3A and TET2 genes, previously described as drivers of myeloid malignancies. ARCH is associated with an increased risk for haematological cancers. ARCH also confers an increased risk for non-haematological diseases such as cardiovascular disease, atherosclerosis, and chronic ischemic heart failure, for which age is a main risk factor. Whether ARCH is linked to accelerated ageing has remained unexplored. The most accurate and commonly-used tools to measure age acceleration are epigenetic clocks. They are based on age-related methylation differences at specific CpG sites correlating chronological age accurately with epigenetic age. Deviations from chronological age towards an increased epigenetic age have been associated with increased risk of earlier mortality and age-related morbidities. Here we present evidence of accelerated epigenetic age in in iduals with ARCH.
Publisher: Elsevier BV
Date: 03-2016
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2016
DOI: 10.1161/CIRCGENETICS.116.001572
Abstract: The burden of subclinical atherosclerosis in asymptomatic in iduals is heritable and associated with elevated risk of developing clinical coronary heart disease. We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent coronary heart disease. We studied a total of 25 109 European ancestry and African ancestry participants with coronary artery calcification (CAC) measured by cardiac computed tomography and 52 869 participants with common carotid intima–media thickness measured by ultrasonography within the CHARGE Consortium (Cohorts for Heart and Aging Research in Genomic Epidemiology). Participants were genotyped for 247 870 DNA sequence variants (231 539 in exons) across the genome. A meta-analysis of exome-wide association studies was performed across cohorts for CAC and carotid intima–media thickness. APOB p.Arg3527Gln was associated with 4-fold excess CAC ( P =3×10 − 10 ). The APOE ε2 allele (p.Arg176Cys) was associated with both 22.3% reduced CAC ( P =1×10 − 12 ) and 1.4% reduced carotid intima–media thickness ( P =4×10 − 14 ) in carriers compared with noncarriers. In secondary analyses conditioning on low-density lipoprotein cholesterol concentration, the ε2 protective association with CAC, although attenuated, remained strongly significant. Additionally, the presence of ε2 was associated with reduced risk for coronary heart disease (odds ratio 0.77 P =1×10 − 11 ). Exome-wide association meta-analysis demonstrates that protein-coding variants in APOB and APOE associate with subclinical atherosclerosis. APOE ε2 represents the first significant association for multiple subclinical atherosclerosis traits across multiple ethnicities, as well as clinical coronary heart disease.
Publisher: Cold Spring Harbor Laboratory
Date: 10-06-2021
DOI: 10.1101/2021.06.07.21258457
Abstract: The levels of many blood proteins are associated with Alzheimer’s disease or its pathological hallmarks. Elucidating the molecular factors that control circulating levels of these proteins may help to identify proteins causally associated with the disease. Here, genome-wide and epigenome-wide studies (n in iduals ≤1,064) were performed on plasma levels of 281 Alzheimer’s disease-associated proteins, identified by a systematic review of the literature. We quantified the contributions of genetic and epigenetic variation towards inter-in idual variability in plasma protein levels. Sixty-one independent genetic and 32 epigenetic loci were associated with expression levels of 49 proteins eight and 24 of these respective findings are previously unreported. Novel findings included an association between plasma TREM2 levels and a polymorphism and CpG site within the MS4A4A locus. Through Mendelian randomisation analyses, causal associations were observed between higher plasma TBCA and TREM2 levels and lower Alzheimer’s disease risk. Our data inform the regulation of biomarker levels and their relationships with Alzheimer’s disease.
Publisher: Informa UK Limited
Date: 20-10-2020
Publisher: Cold Spring Harbor Laboratory
Date: 09-10-2018
DOI: 10.1101/433367
Abstract: Major depression is a debilitating psychiatric illness that is typically associated with low mood, anhedonia and a range of comorbidities. Depression has a heritable component that has remained difficult to elucidate with current s le sizes due to the polygenic nature of the disorder. To maximise s le size, we meta-analysed data on 807,553 in iduals (246,363 cases and 561,190 controls) from the three largest genome-wide association studies of depression. We identified 102 independent variants, 269 genes, and 15 gene-sets associated with depression, including both genes and gene-pathways associated with synaptic structure and neurotransmission. Further evidence of the importance of prefrontal brain regions in depression was provided by an enrichment analysis. In an independent replication s le of 1,306,354 in iduals (414,055 cases and 892,299 controls), 87 of the 102 associated variants were significant following multiple testing correction. Based on the putative genes associated with depression this work also highlights several potential drug repositioning opportunities. These findings advance our understanding of the complex genetic architecture of depression and provide several future avenues for understanding aetiology and developing new treatment approaches.
Publisher: Cambridge University Press (CUP)
Date: 06-03-2015
DOI: 10.1017/THG.2015.10
Abstract: Variation in human cognitive ability is of consequence to a large number of health and social outcomes and is substantially heritable. Genetic linkage, genome-wide association, and copy number variant studies have investigated the contribution of genetic variation to in idual differences in normal cognitive ability, but little research has considered the role of rare genetic variants. Exome sequencing studies have already met with success in discovering novel trait-gene associations for other complex traits. Here, we use exome sequencing to investigate the effects of rare variants on general cognitive ability. Unrelated Scottish in iduals were selected for high scores on a general component of intelligence ( g ). The frequency of rare genetic variants (in n = 146) was compared with those from Scottish controls (total n = 486) who scored in the lower to middle range of the g distribution or on a proxy measure of g . Biological pathway analysis highlighted enrichment of the mitochondrial inner membrane component and apical part of cell gene ontology terms. Global burden analysis showed a greater total number of rare variants carried by high g cases versus controls, which is inconsistent with a mutation load hypothesis whereby mutations negatively affect g . The general finding of greater non-synonymous (vs. synonymous) variant effects is in line with evolutionary hypotheses for g . Given that this first sequencing study of high g was small, promising results were found, suggesting that the study of rare variants in larger s les would be worthwhile.
Publisher: Elsevier BV
Date: 06-2015
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 22-12-2015
Publisher: IOP Publishing
Date: 29-03-2018
Publisher: Elsevier BV
Date: 07-2014
DOI: 10.1016/J.NEULET.2009.04.050
Abstract: We report on the association of KIBRA with memory in two s les of older in iduals assessed on either memory for semantically unrelated word stimuli (Rey Auditory Verbal Learning Test, n=2091), or a measure of semantically related material (the WAIS Logical Memory Test of prose-passage recall, n=542). SNP rs17070145 was associated with delayed recall of semantically unrelated items, but not with immediate recall for these stimuli, nor with either immediate or delayed recall for semantically related material. The pattern of results suggests a role for the T-->C substitution in intron 9 of KIBRA in a component of episodic memory involved in long-term storage but independent of processes shared with immediate recall such as rehearsal involved in acquisition and rehearsal or processes.
Publisher: Elsevier BV
Date: 11-2016
Publisher: Elsevier BV
Date: 11-2018
Publisher: Cold Spring Harbor Laboratory
Date: 10-05-2021
DOI: 10.1101/2021.05.06.21256747
Abstract: Genome-wide association studies (GWAS) of proxy-phenotypes using family history of disease (GWAX) substantially boost power for genetic discovery when combined with direct case-control GWAS, most prominently in the context of Alzheimer’s Disease (AD). However, despite twin study heritability estimates of approximately 60%, recent SNP-based estimates of common variant heritability of AD from meta-analyzed GWAS-GWAX data have been particularly low (2.5%), calling into question the prospects of continued progress in AD genetics. We demonstrate that commonly used approaches for combining GWAX and GWAS data produce dramatic underestimates of heritability, and we introduce a multivariate method for estimating in idual SNP effects and recovering unbiased estimates of SNP heritability when combining GWAS and GWAX summary data. We estimate the SNP heritability of Clinical AD diagnoses excluding the APOE region at ∼6-10%, with the corresponding estimate for biological AD (based on prevalence rate estimates from recently published molecular imaging data) as high as ∼20%. Common variant risk for AD appears to represent a very strong effect of APOE superimposed upon a relatively diffuse polygenic signal that is distributed across the genome.
Publisher: Springer Science and Business Media LLC
Date: 11-01-2018
Publisher: Springer Science and Business Media LLC
Date: 1
Publisher: Springer Science and Business Media LLC
Date: 18-05-2018
DOI: 10.1038/S41398-018-0150-6
Abstract: Alzheimer’s disease (AD) is a public health priority for the 21st century. Risk reduction currently revolves around lifestyle changes with much research trying to elucidate the biological underpinnings. We show that self-report of parental history of Alzheimer’s dementia for case ascertainment in a genome-wide association study of 314,278 participants from UK Biobank (27,696 maternal cases, 14,338 paternal cases) is a valid proxy for an AD genetic study. After meta-analysing with published consortium data ( n = 74,046 with 25,580 cases across the discovery and replication analyses), three new AD-associated loci ( P 5 × 10 −8 ) are identified. These contain genes relevant for AD and neurodegeneration: ADAM10 , BCKDK/KAT8 and ACE . Novel gene-based loci include drug targets such as VKORC1 (warfarin dose). We report evidence that the association of SNPs in the TOMM40 gene with AD is potentially mediated by both gene expression and DNA methylation in the prefrontal cortex. However, it is likely that multiple variants are affecting the trait and gene methylation/expression. Our discovered loci may help to elucidate the biological mechanisms underlying AD and, as they contain genes that are drug targets for other diseases and disorders, warrant further exploration for potential precision medicine applications.
Publisher: Springer Science and Business Media LLC
Date: 27-07-2020
DOI: 10.1186/S13148-020-00903-8
Abstract: Chronic systemic inflammation has been associated with incident dementia, but its association with age-related cognitive decline is less clear. The acute responses of many inflammatory biomarkers mean they may provide an unreliable picture of the chronicity of inflammation. Recently, a large-scale epigenome-wide association study identified DNA methylation correlates of C-reactive protein (CRP)—a widely used acute-phase inflammatory biomarker. DNA methylation is thought to be relatively stable in the short term, marking it as a potentially useful signature of exposure. We utilise a DNA methylation-based score for CRP and investigate its trajectories with age, and associations with cognitive ability in comparison with serum CRP and a genetic CRP score in a longitudinal study of older adults ( n = 889) and a large, cross-sectional cohort ( n = 7028). We identified no homogeneous trajectories of serum CRP with age across the cohorts, whereas the epigenetic CRP score was consistently found to increase with age (standardised β = 0.07 and 0.01) and to do so more rapidly in males compared to females. Additionally, the epigenetic CRP score had higher test-retest reliability compared to serum CRP, indicating its enhanced temporal stability. Higher serum CRP was not found to be associated with poorer cognitive ability (standardised β = − 0.08 and − 0.05) however, a consistent negative association was identified between cognitive ability and the epigenetic CRP score in both cohorts (standardised β = − 0.15 and − 0.08). An epigenetic proxy of CRP may provide a more reliable signature of chronic inflammation, allowing for more accurate stratification of in iduals, and thus clearer inference of associations with incident health outcomes.
Publisher: Springer Science and Business Media LLC
Date: 28-02-2014
Publisher: Elsevier BV
Date: 11-2018
Location: United States of America
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Start Date: Start date not available
End Date: End date not available
Funder: NIH Clinical Center
View Funded ActivityStart Date: 2017
End Date: 2020
Funder: Alzheimer’s Research UK
View Funded ActivityStart Date: 2016
End Date: 2019
Funder: Economic and Social Research Council
View Funded ActivityStart Date: 2015
End Date: 2018
Funder: Economic and Social Research Council
View Funded Activity