ORCID Profile
0000-0002-1733-263X
Current Organisations
Center for Stem Cell Research
,
The University of Edinburgh
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Publisher: Oxford University Press (OUP)
Date: 22-01-2015
DOI: 10.1093/IJE/DYU277
Publisher: Springer Science and Business Media LLC
Date: 02-2016
DOI: 10.1038/NN.4228
Publisher: Springer Science and Business Media LLC
Date: 09-08-2011
DOI: 10.1038/MP.2011.85
Publisher: Elsevier BV
Date: 07-2014
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: Springer Science and Business Media LLC
Date: 18-12-2017
Publisher: American Medical Association (AMA)
Date: 09-2018
Publisher: Springer Science and Business Media LLC
Date: 08-01-2014
Publisher: Springer Science and Business Media LLC
Date: 22-09-2020
DOI: 10.1038/S41467-020-18367-Y
Abstract: Cortical thickness, surface area and volumes vary with age and cognitive function, and in neurological and psychiatric diseases. Here we report heritability, genetic correlations and genome-wide associations of these cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery s le comprises 22,824 in iduals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank. We identify genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/β-catenin, TGF-β and sonic hedgehog pathways. There is enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging.
Publisher: F1000 Research Ltd
Date: 12-01-2018
DOI: 10.12688/WELLCOMEOPENRES.12583.1
Abstract: Background: Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. Methods: We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV 1 ), forced vital capacity (FVC) and the ratio of FEV 1 to FVC (FEV 1 /FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 in iduals of European ancestry from 23 studies, and 7,721 in iduals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent in iduals. Results: We identified significant (P ·8x10 -7 ) associations with six SNPs: a nonsynonymous variant in RPAP1 , which is predicted to be damaging, three intronic SNPs ( SEC24C, CASC17 and UQCC1 ) and two intergenic SNPs near to LY86 and FGF10. Expression quantitative trait loci analyses found evidence for regulation of gene expression at three signals and implicated several genes, including TYRO3 and PLAU . Conclusions: Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease.
Publisher: Springer Science and Business Media LLC
Date: 15-07-2017
Publisher: Springer Science and Business Media LLC
Date: 20-02-2014
Publisher: Oxford University Press (OUP)
Date: 22-09-2015
DOI: 10.1093/HMG/DDV378
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: Wiley
Date: 24-05-2012
DOI: 10.1002/AJMG.B.32072
Publisher: Wiley
Date: 12-06-2012
DOI: 10.1002/AJMG.B.32073
Abstract: The β-amyloid peptide may play a central role in Alzheimer's disease (AD) pathogenesis. We have evaluated variants in seven Aβ-degrading genes (ACE, ECE1, ECE2, IDE, MME, PLAU, and TF) for association with AD risk in the Genetic and Environmental Risk in Alzheimer's Disease Consortium 1 (GERAD1) cohort, and with three cognitive phenotypes in the Lothian Birth Cohort 1936 (LBC1936), using 128 and 121 SNPs, respectively. In GERAD1, we identified a significant association between a four-SNP intragenic ECE1 haplotype and risk of AD in in iduals that carried at least one APOE ε4 allele (P = 0.00035, odds ratio = 1.61). In LBC1936, we identified a significant association between a different two-SNP ECE1 intragenic haplotype and non-verbal reasoning in in iduals lacking the APOE ε4 allele (P = 0.00036, β = -0.19). Both results showed a trend towards significance after permutation (0.05 < P < 0.10). A follow-up cognitive genetic study evaluated the association of ECE1 SNPs in three additional cohorts of non-demented older people. Meta-analysis of the four cohorts identified the significant association (Z A (rs213045). We observed significantly less expression from the 338A variant in two human neuroblastoma cell lines and speculate that this promoter may be subject to tissue-specific regulation.
Publisher: Impact Journals, LLC
Date: 10-01-2017
Publisher: Springer Science and Business Media LLC
Date: 15-11-2021
Publisher: Springer Science and Business Media LLC
Date: 31-10-2016
DOI: 10.1038/NG.3698
Publisher: Springer Science and Business Media LLC
Date: 18-01-2012
DOI: 10.1038/NATURE10781
Abstract: Understanding the determinants of healthy mental ageing is a priority for society today. So far, we know that intelligence differences show high stability from childhood to old age and there are estimates of the genetic contribution to intelligence at different ages. However, attempts to discover whether genetic causes contribute to differences in cognitive ageing have been relatively uninformative. Here we provide an estimate of the genetic and environmental contributions to stability and change in intelligence across most of the human lifetime. We used genome-wide single nucleotide polymorphism (SNP) data from 1,940 unrelated in iduals whose intelligence was measured in childhood (age 11 years) and again in old age (age 65, 70 or 79 years). We use a statistical method that allows genetic (co)variance to be estimated from SNP data on unrelated in iduals. We estimate that causal genetic variants in linkage disequilibrium with common SNPs account for 0.24 of the variation in cognitive ability change from childhood to old age. Using bivariate analysis, we estimate a genetic correlation between intelligence at age 11 years and in old age of 0.62. These estimates, derived from rarely available data on lifetime cognitive measures, warrant the search for genetic causes of cognitive stability and change.
Publisher: Springer Science and Business Media LLC
Date: 21-01-2015
DOI: 10.1038/NATURE14101
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: 03-08-2018
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: Springer Science and Business Media LLC
Date: 14-04-2015
DOI: 10.1038/MP.2015.37
Publisher: Elsevier BV
Date: 09-2017
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: Wiley
Date: 16-12-2010
DOI: 10.1002/AJMG.B.31149
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: 12-2016
Publisher: Cold Spring Harbor Laboratory
Date: 12-03-0044
DOI: 10.1101/2021.03.10.21253201
Abstract: The environment and events that we are exposed to in utero, during birth and in early childhood influence our future physical and mental health. The underlying mechanisms that lead to these outcomes in adulthood are unclear, but long-term changes in epigenetic marks, such as DNA methylation, could act as a mediating factor or biomarker. DNA methylation data was assayed at 713,522 CpG sites from 9,537 participants of the Generation Scotland: Scottish Family Health Study, a family-based cohort with extensive data on genetic, medical, family history and lifestyle information. Methylome-wide association studies of eight early life environment phenotypes and two adult mental health phenotypes were conducted using DNA methylation data collected from adult whole blood s les. Two genes involved with different developmental pathways (PRICKLE2 and ABI1) were annotated to CpG sites associated with preterm birth (P 1.27 × 10 −9 ). A further two genes important to the development of sensory pathways (SOBP and RPGRIP1) were annotated to sites associated with low birth weight (P 4.35 × 10 −8 ). Genes and gene-sets annotated from associated CpGs sites and methylation profile scores were then used to quantify any overlap between the early life environment and mental health traits. However, there was no evidence of any overlap after applying a correction for multiple testing. Time of year of birth was found to be associated with a significant difference in estimated lymphocyte and neutrophil counts. Early life environments influence the risk of developing mental health disorders later in life however, this study provides no evidence that this is mediated by stable changes to the methylome detectable in peripheral blood.
Publisher: Public Library of Science (PLoS)
Date: 14-02-2017
Publisher: American Medical Association (AMA)
Date: 06-2018
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: Impact Journals, LLC
Date: 28-09-2016
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: Proceedings of the National Academy of Sciences
Date: 08-01-2015
Publisher: Impact Journals, LLC
Date: 07-07-2017
Publisher: American Thoracic Society
Date: 10-2012
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: 25-04-2017
DOI: 10.1038/MP.2017.62
Publisher: Springer Science and Business Media LLC
Date: 02-2017
DOI: 10.1038/NATURE21039
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: Wiley
Date: 19-10-2016
DOI: 10.1002/ANA.24780
Abstract: In observational epidemiologic studies, higher plasma high‐density lipoprotein cholesterol (HDL‐C) has been associated with increased risk of intracerebral hemorrhage (ICH). DNA sequence variants that decrease cholesteryl ester transfer protein ( CETP ) gene activity increase plasma HDL‐C as such, medicines that inhibit CETP and raise HDL‐C are in clinical development. Here, we test the hypothesis that CETP DNA sequence variants associated with higher HDL‐C also increase risk for ICH. We performed 2 candidate‐gene analyses of CETP . First, we tested in idual CETP variants in a discovery cohort of 1,149 ICH cases and 1,238 controls from 3 studies, followed by replication in 1,625 cases and 1,845 controls from 5 studies. Second, we constructed a genetic risk score comprised of 7 independent variants at the CETP locus and tested this score for association with HDL‐C as well as ICH risk. Twelve variants within CETP demonstrated nominal association with ICH, with the strongest association at the rs173539 locus (odds ratio [OR] = 1.25, standard error [SE] = 0.06, p = 6.0 × 10 −4 ) with no heterogeneity across studies ( I 2 = 0%). This association was replicated in patients of European ancestry ( p = 0.03). A genetic score of CETP variants found to increase HDL‐C by ∼2.85mg/dl in the Global Lipids Genetics Consortium was strongly associated with ICH risk (OR = 1.86, SE = 0.13, p = 1.39 × 10 −6 ). Genetic variants in CETP associated with increased HDL‐C raise the risk of ICH. Given ongoing therapeutic development in CETP inhibition and other HDL‐raising strategies, further exploration of potential adverse cerebrovascular outcomes may be warranted. Ann Neurol 2016 :730–740
Publisher: Springer Science and Business Media LLC
Date: 15-04-2012
DOI: 10.1038/NG.2237
Publisher: Springer Science and Business Media LLC
Date: 21-12-2010
DOI: 10.1038/MP.2010.128
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: 08-01-2018
Publisher: Elsevier BV
Date: 04-2014
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: 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: eLife Sciences Publications, Ltd
Date: 11-02-2022
DOI: 10.7554/ELIFE.65421
Abstract: Naturally occurring point mutations in the HBG promoter switch hemoglobin synthesis from defective adult beta-globin to fetal gamma-globin in sickle cell patients with hereditary persistence of fetal hemoglobin (HPFH) and ameliorate the clinical severity. Inspired by this natural phenomenon, we tiled the highly homologous HBG proximal promoters using adenine and cytosine base editors that avoid the generation of large deletions and identified novel regulatory regions including a cluster at the –123 region. Base editing at –123 and –124 bp of HBG promoter induced fetal hemoglobin (HbF) to a higher level than disruption of well-known BCL11A binding site in erythroblasts derived from human CD34+ hematopoietic stem and progenitor cells (HSPC). We further demonstrated in vitro that the introduction of –123T C and –124T C HPFH-like mutations drives gamma-globin expression by creating a de novo binding site for KLF1. Overall, our findings shed light on so far unknown regulatory elements within the HBG promoter and identified additional targets for therapeutic upregulation of fetal hemoglobin.
Publisher: Wiley
Date: 12-06-2011
Publisher: Proceedings of the National Academy of Sciences
Date: 15-05-2018
Abstract: Left–right asymmetry is a key feature of the human brain's structure and function. It remains unclear which cortical regions are asymmetrical on average in the population and how biological factors such as age, sex, and genetic variation affect these asymmetries. Here, we describe by far the largest-ever study of cerebral cortical asymmetry, based on data from 17,141 participants. We found a global anterior–posterior “torque” pattern in cortical thickness, together with various regional asymmetries at the population level, which have not been previously described, as well as effects of age, sex, and heritability estimates. From these data, we have created an online resource that will serve future studies of human brain anatomy in health and disease.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2018
DOI: 10.1161/STROKEAHA.118.020689
Abstract: White matter hyperintensities (WMH) on brain magnetic resonance imaging are typical signs of cerebral small vessel disease and may indicate various preclinical, age-related neurological disorders, such as stroke. Though WMH are highly heritable, known common variants explain a small proportion of the WMH variance. The contribution of low-frequency/rare coding variants to WMH burden has not been explored. In the discovery s le we recruited 20 719 stroke/dementia-free adults from 13 population-based cohort studies within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, among which 17 790 were of European ancestry and 2929 of African ancestry. We genotyped these participants at ≈250 000 mostly exonic variants with Illumina HumanExome BeadChip arrays. We performed ethnicity-specific linear regression on rank-normalized WMH in each study separately, which were then combined in meta-analyses to test for association with single variants and genes aggregating the effects of putatively functional low-frequency/rare variants. We then sought replication of the top findings in 1192 adults (European ancestry) with whole exome/genome sequencing data from 2 independent studies. At 17q25, we confirmed the association of multiple common variants in TRIM65 , FBF1 , and ACOX1 ( P ×10 −7 ). We also identified a novel association with 2 low-frequency nonsynonymous variants in MRPL38 (lead, rs34136221 P EA =4.5×10 −8 ) partially independent of known common signal ( P EA(conditional) =1.4×10 −3 ). We further identified a locus at 2q33 containing common variants in NBEAL1 , CARF , and WDR12 (lead, rs2351524 P all =1.9×10 −10 ). Although our novel findings were not replicated because of limited power and possible differences in study design, meta-analysis of the discovery and replication s les yielded stronger association for the 2 low-frequency MRPL38 variants ( P rs34136221 =2.8×10 −8 ). Both common and low-frequency/rare functional variants influence WMH. Larger replication and experimental follow-up are essential to confirm our findings and uncover the biological causal mechanisms of age-related WMH.
Publisher: Elsevier BV
Date: 05-2015
Publisher: Springer Science and Business Media LLC
Date: 29-11-2016
DOI: 10.1038/NG1216-1587B
Publisher: Oxford University Press (OUP)
Date: 12-01-2017
DOI: 10.1093/IJE/DYW318
Publisher: Springer Science and Business Media LLC
Date: 18-01-2017
DOI: 10.1038/NCOMMS13624
Abstract: The hippoc al formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippoc al volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippoc al structure here we perform a genome-wide association study (GWAS) of 33,536 in iduals and discover six independent loci significantly associated with hippoc al volume, four of them novel. Of the novel loci, three lie within genes ( ASTN2 , DPP4 and MAST4 ) and one is found 200 kb upstream of SHH . A hippoc al subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippoc al volume are also associated with increased risk for Alzheimer’s disease ( r g =−0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippoc al volume and risk for neuropsychiatric illness.
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: Springer Science and Business Media LLC
Date: 15-11-2016
DOI: 10.1038/MP.2016.192
Publisher: Research Square Platform LLC
Date: 10-03-2022
DOI: 10.21203/RS.3.RS-1409164/V1
Abstract: Hypertension is a leading cause of premature death affecting more than a billion in iduals worldwide. Here we report on the genetic determinants of blood pressure (BP) traits (systolic, diastolic, and pulse pressure) in the largest single-stage genome-wide analysis to date (N = 1,028,980 European-descent in iduals). We identified 2,103 independent genetic signals (P 5x10 − 8 ) for BP traits, including 113 novel loci. These associations explain ~ 40% of common SNP heritability of systolic and diastolic BP. Comparison of top versus bottom deciles of polygenic risk scores (PRS) based on these results reveal clinically meaningful differences in BP (12.9 mm Hg for systolic BP, 95% CI 11.5–14.2 mm Hg, p = 9.08×10 − 73 ) and hypertension risk (OR 5.41 95% CI 4.12 to 7.10 P = 9.71×10 − 33 ) in an independent dataset. Compared with the area under the curve (AUC) for hypertension discrimination for a model with sex, age, BMI, and genetic ancestry, adding systolic and diastolic BP PRS increased discrimination from 0.791 (95% CI = 0.781–0.801) to 0.814 (95% CI = 0.805–0.824, ∆AUC = 0.023, P = 2.27x10 − 22 ). Our transcriptome-wide association study detected 2,793 BP colocalized associations with genetically-predicted expression of 1,070 genes in five cardiovascular tissues, of which 500 are previously unreported for BP traits. These findings represent an advance in our understanding of hypertension and highlight the role of increasingly large genomic studies for development of more accurate PRS, which may inform precision health research.
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: 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: Oxford University Press (OUP)
Date: 04-2016
DOI: 10.1093/IJE/DYW041
Publisher: Wiley
Date: 27-12-2011
DOI: 10.1002/AJMG.B.32013
Publisher: Springer Science and Business Media LLC
Date: 18-04-2016
DOI: 10.1038/NG.3552
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: Springer Science and Business Media LLC
Date: 23-12-2012
DOI: 10.1038/NG.2500
Publisher: Wiley
Date: 04-2010
Publisher: Springer Science and Business Media LLC
Date: 11-05-2016
DOI: 10.1038/NATURE17671
Publisher: Elsevier BV
Date: 02-2017
Publisher: Springer Science and Business Media LLC
Date: 25-06-2018
Publisher: Springer Science and Business Media LLC
Date: 07-2015
DOI: 10.1038/NATURE14618
Publisher: Elsevier BV
Date: 02-2014
Publisher: Springer Science and Business Media LLC
Date: 05-04-2016
DOI: 10.1038/MP.2016.45
Publisher: Springer Science and Business Media LLC
Date: 18-10-2011
DOI: 10.1038/TP.2011.45
Publisher: Oxford University Press (OUP)
Date: 27-11-2016
DOI: 10.1093/IJE/DYX233
Publisher: Elsevier BV
Date: 2011
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: Elsevier BV
Date: 10-2017
Publisher: Public Library of Science (PLoS)
Date: 29-04-2011
Publisher: Springer Science and Business Media LLC
Date: 08-01-2018
Publisher: Public Library of Science (PLoS)
Date: 31-07-2014
Publisher: Springer Science and Business Media LLC
Date: 04-08-2015
DOI: 10.1038/NCOMMS8756
Abstract: More than 100 loci have been identified for age at menarche by genome-wide association studies however, collectively these explain only ∼3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency protein-coding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1 / LAMB2 / TNRC6A/TACR3/PRKAG1 ) are associated with age at menarche (minor allele frequencies 0.08–4.6% effect sizes 0.08–1.25 years per allele P × 10 −8 ). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P =9.4 × 10 −13 ) and FAAH2 (rs5914101, P =4.9 × 10 −10 ). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche ( P =2.8 × 10 −11 ), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain ∼0.5% variance, indicating that these overlooked sources of variation do not substantially explain the ‘missing heritability’ of this complex trait.
Publisher: Springer Science and Business Media LLC
Date: 27-05-2012
DOI: 10.1038/NG.2293
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: Elsevier BV
Date: 04-2015
Publisher: Public Library of Science (PLoS)
Date: 07-02-2013
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: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2015
Publisher: Cambridge University Press (CUP)
Date: 21-10-2015
DOI: 10.1016/J.EURPSY.2015.08.006
Abstract: This study investigated differences in cognitive performance between middle-aged adults with and without a lifetime history of mood disorder features, adjusting for a range of potential confounders. Cross-sectional analysis of baseline data from the UK Biobank cohort. Adults aged 40–69 ( n = 143,828) were assessed using measures of reasoning, reaction time and memory. Self-reported data on lifetime features of major depression and bipolar disorder were used to construct groups for comparison against controls. Regression models examined the association between mood disorder classification and cognitive performance, adjusting for sociodemographic, lifestyle and clinical confounders. Inverse associations between lifetime history of bipolar or severe recurrent depression features and cognitive performance were attenuated or reversed after adjusting for confounders, including psychotropic medication use and current depressive symptoms. Participants with a lifetime history of single episode or moderate recurrent depression features outperformed controls to a small (but statistically significant) degree, independent of adjustment for confounders. There was a significant interaction between use of psychotropic medication and lifetime mood disorder features, with reduced cognitive performance observed in participants taking psychotropic medication. In this general population s le of adults in middle age, lifetime features of recurrent depression or bipolar disorder were only associated with cognitive impairment within unadjusted analyses. These findings underscore the importance of adjusting for potential confounders when investigating mood disorder-related cognitive function.
Publisher: Elsevier BV
Date: 05-2014
Publisher: Springer Science and Business Media LLC
Date: 11-02-2015
DOI: 10.1038/NATURE14177
Publisher: Springer Science and Business Media LLC
Date: 06-02-2017
DOI: 10.1038/NG.3787
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: 23-07-2018
Publisher: Springer Science and Business Media LLC
Date: 12-2012
DOI: 10.1038/NATURE11677
Publisher: Portland Press Ltd.
Date: 22-03-2010
DOI: 10.1042/BST0380445
Abstract: Understanding how cognitive processes including learning, memory, decision making and ideation are encoded by the genome is a key question in biology. Identification of sets of genes underlying human mental disorders is a path towards this objective. Schizophrenia is a common disease with cognitive symptoms, high heritability and complex genetics. We have identified genes involved with schizophrenia by measuring differences in DNA copy number across the entire genome in 91 schizophrenia cases and 92 controls in the Scottish population. Our data reproduce rare and common variants observed in public domain data from & schizophrenia cases, confirming known disease loci as well as identifying novel loci. We found copy number variants in PDE10A (phosphodiesterase 10A), CYFIP1 [cytoplasmic FMR1 (Fragile X mental retardation 1)-interacting protein 1], K+ channel genes KCNE1 and KCNE2, the Down's syndrome critical region 1 gene RCAN1 (regulator of calcineurin 1), cell-recognition protein CHL1 (cell adhesion molecule with homology with L1CAM), the transcription factor SP4 (specificity protein 4) and histone deacetylase HDAC9, among others (see www.genes2cognition.org/SCZ-CNV). Integrating the function of these many genes into a coherent model of schizophrenia and cognition is a major unanswered challenge.
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: 14-08-2018
Publisher: Springer Science and Business Media LLC
Date: 15-06-2014
DOI: 10.1038/NG.3011
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: 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: Springer Science and Business Media LLC
Date: 10-11-2017
DOI: 10.1038/S41598-017-11852-3
Abstract: Hair cortisol concentration (HCC) is a promising measure of long-term hypothalamus-pituitary-adrenal (HPA) axis activity. Previous research has suggested an association between HCC and psychological variables, and initial studies of inter-in idual variance in HCC have implicated genetic factors. However, whether HCC and psychological variables share genetic risk factors remains unclear. The aims of the present twin study were to: (i) assess the heritability of HCC (ii) estimate the phenotypic and genetic correlation between HPA axis activity and the psychological variables perceived stress, depressive symptoms, and neuroticism using formal genetic twin models and molecular genetic methods, i.e. polygenic risk scores (PRS). HCC was measured in 671 adolescents and young adults. These included 115 monozygotic and 183 dizygotic twin-pairs. For 432 subjects PRS scores for plasma cortisol, major depression, and neuroticism were calculated using data from large genome wide association studies. The twin model revealed a heritability for HCC of 72%. No significant phenotypic or genetic correlation was found between HCC and the three psychological variables of interest. PRS did not explain variance in HCC. The present data suggest that HCC is highly heritable. However, the data do not support a strong biological link between HCC and any of the investigated psychological variables.
Publisher: Springer Science and Business Media LLC
Date: 10-03-2015
DOI: 10.1038/MP.2015.12
Publisher: Elsevier BV
Date: 06-2013
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: 26-04-2018
Publisher: Springer Science and Business Media LLC
Date: 03-10-2016
DOI: 10.1038/NN.4398
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: Springer Science and Business Media LLC
Date: 13-10-2016
Publisher: Public Library of Science (PLoS)
Date: 30-10-2017
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: 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: Elsevier BV
Date: 2017
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2017
DOI: 10.1161/HYPERTENSIONAHA.117.09438
Abstract: Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project–based imputation in 150 134 European ancestry in iduals and sought significant evidence for independent replication in a further 228 245 in iduals. We report 6 new signals of association in or near HSPB7 , TNXB , LRP12 , LOC283335 , SEPT9 , and AKT2 , and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA . Combining large whole-blood gene expression resources totaling 12 607 in iduals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.
Publisher: Springer Science and Business Media LLC
Date: 30-01-2017
DOI: 10.1038/NG.3768
Publisher: Springer Science and Business Media LLC
Date: 17-04-2012
DOI: 10.1038/TP.2012.27
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: Springer Science and Business Media LLC
Date: 30-08-2018
Publisher: Springer Science and Business Media LLC
Date: 29-01-2014
DOI: 10.1038/MP.2012.184
Publisher: Oxford University Press (OUP)
Date: 20-03-2018
Publisher: Public Library of Science (PLoS)
Date: 19-07-2012
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: Elsevier BV
Date: 03-2011
Publisher: Wiley
Date: 21-06-2016
DOI: 10.1111/ACEL.12468
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: 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: Springer Science and Business Media LLC
Date: 15-06-2012
DOI: 10.1007/S10519-012-9549-7
Abstract: The genetic influence on the association between contemporaneously measured intelligence and academic achievement in childhood was examined in nationally representative cohorts from England and The Netherlands using a whole population indirect twin design, including singleton data. We identified 1,056 same-sex (SS) and 495 opposite-sex (OS) twin pairs among 174,098 British 11 year-olds with test scores from 2004, and, 785 SS and 327 OS twin pairs among 120,995 Dutch schoolchildren, aged 8, 10 or 12 years, with assessments from 1994 to 2002. The estimate of intelligence heritability was large in both cohorts, consistent with previous studies (h (2) = 0.70 ± 0.14, England h (2) = 0.43 ± 0.28-0.67 ± 0.31, The Netherlands), as was the heritability of academic achievement variables (h (2) = 0.51 ± 0.16-0.81 ± 0.16, England h (2) = 0.36 ± 0.27-0.74 ± 0.27, The Netherlands). Additive genetic covariance explained the large majority of the phenotypic correlations between intelligence and academic achievement scores in England, when standardised to a bivariate heritability (Biv h (2) = 0.76 ± 0.15-0.88 ± 0.16), and less consistent but often large proportions of the phenotypic correlations in The Netherlands (Biv h (2) = 0.33 ± 0.52-1.00 ± 0.43). In the British cohort both nonverbal and verbal reasoning showed very high additive genetic covariance with achievement scores (Biv h (2) = 0.94-0.98 Biv h (2) = 0.77-1.00 respectively). In The Netherlands, covariance estimates were consistent across age groups. The heritability of intelligence-academic achievement associations in two population cohorts of elementary schoolchildren, using a twin pair extraction method, is at the high end of estimates reported by studies of largely preselected twin s les.
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: 22-08-2016
DOI: 10.1017/THG.2016.65
Abstract: Approximately half of the variation in wellbeing measures overlaps with variation in personality traits. Studies of non-human primate pedigrees and human twins suggest that this is due to common genetic influences. We tested whether personality polygenic scores for the NEO Five-Factor Inventory (NEO-FFI) domains and for item response theory (IRT) derived extraversion and neuroticism scores predict variance in wellbeing measures. Polygenic scores were based on published genome-wide association (GWA) results in over 17,000 in iduals for the NEO-FFI and in over 63,000 for the IRT extraversion and neuroticism traits. The NEO-FFI polygenic scores were used to predict life satisfaction in 7 cohorts, positive affect in 12 cohorts, and general wellbeing in 1 cohort (maximal N = 46,508). Meta-analysis of these results showed no significant association between NEO-FFI personality polygenic scores and the wellbeing measures. IRT extraversion and neuroticism polygenic scores were used to predict life satisfaction and positive affect in almost 37,000 in iduals from UK Biobank. Significant positive associations (effect sizes .05%) were observed between the extraversion polygenic score and wellbeing measures, and a negative association was observed between the polygenic neuroticism score and life satisfaction. Furthermore, using GWA data, genetic correlations of -0.49 and -0.55 were estimated between neuroticism with life satisfaction and positive affect, respectively. The moderate genetic correlation between neuroticism and wellbeing is in line with twin research showing that genetic influences on wellbeing are also shared with other independent personality domains.
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: Elsevier BV
Date: 12-2014
Publisher: Cambridge University Press (CUP)
Date: 02-10-2019
DOI: 10.1017/S0033291719002629
Abstract: Major depressive disorder and neuroticism (Neu) share a large genetic basis. We sought to determine whether this shared basis could be decomposed to identify genetic factors that are specific to depression. We analysed summary statistics from genome-wide association studies (GWAS) of depression (from the Psychiatric Genomics Consortium, 23andMe and UK Biobank) and compared them with GWAS of Neu (from UK Biobank). First, we used a pairwise GWAS analysis to classify variants as associated with only depression, with only Neu or with both. Second, we estimated partial genetic correlations to test whether the depression's genetic link with other phenotypes was explained by shared overlap with Neu. We found evidence that most genomic regions (25/37) associated with depression are likely to be shared with Neu. The overlapping common genetic variance of depression and Neu was genetically correlated primarily with psychiatric disorders. We found that the genetic contributions to depression, that were not shared with Neu, were positively correlated with metabolic phenotypes and cardiovascular disease, and negatively correlated with the personality trait conscientiousness. After removing shared genetic overlap with Neu, depression still had a specific association with schizophrenia, bipolar disorder, coronary artery disease and age of first birth. Independent of depression, Neu had specific genetic correlates in ulcerative colitis, pubertal growth, anorexia and education. Our findings demonstrate that, while genetic risk factors for depression are largely shared with Neu, there are also non-Neu-related features of depression that may be useful for further patient or phenotypic stratification.
Publisher: Springer Science and Business Media LLC
Date: 28-09-2020
Publisher: Elsevier BV
Date: 11-2016
Publisher: Elsevier BV
Date: 2016
Publisher: Public Library of Science (PLoS)
Date: 10-04-2015
Publisher: Public Library of Science (PLoS)
Date: 22-08-2013
Publisher: F1000 Research Ltd
Date: 07-08-2018
DOI: 10.12688/WELLCOMEOPENRES.12583.3
Abstract: Background: Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. Methods: We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV 1 ), forced vital capacity (FVC) and the ratio of FEV 1 to FVC (FEV 1 /FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 in iduals of European ancestry from 23 studies, and 7,721 in iduals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent in iduals. Results: We identified significant (P ·8x10 -7 ) associations with six SNPs: a nonsynonymous variant in RPAP1 , which is predicted to be damaging, three intronic SNPs ( SEC24C, CASC17 and UQCC1 ) and two intergenic SNPs near to LY86 and FGF10. Expression quantitative trait loci analyses found evidence for regulation of gene expression at three signals and implicated several genes, including TYRO3 and PLAU . Conclusions: Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease.
Publisher: Springer Science and Business Media LLC
Date: 15-04-2012
DOI: 10.1038/NG.2250
Publisher: F1000 Research Ltd
Date: 21-06-2018
DOI: 10.12688/WELLCOMEOPENRES.12583.2
Abstract: Background: Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. Methods: We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV 1 ), forced vital capacity (FVC) and the ratio of FEV 1 to FVC (FEV 1 /FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 in iduals of European ancestry from 23 studies, and 7,721 in iduals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent in iduals. Results: We identified significant (P ·8x10 -7 ) associations with six SNPs: a nonsynonymous variant in RPAP1 , which is predicted to be damaging, three intronic SNPs ( SEC24C, CASC17 and UQCC1 ) and two intergenic SNPs near to LY86 and FGF10. Expression quantitative trait loci analyses found evidence for regulation of gene expression at three signals and implicated several genes, including TYRO3 and PLAU . Conclusions: Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease.
Publisher: Oxford University Press (OUP)
Date: 19-12-2013
DOI: 10.1093/HMG/DDT620
Publisher: Springer Science and Business Media LLC
Date: 22-12-2017
Publisher: Springer Science and Business Media LLC
Date: 11-01-2018
Publisher: Wiley
Date: 08-2016
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: 22-09-2016
DOI: 10.1038/MP.2015.120
Publisher: Springer Science and Business Media LLC
Date: 11-02-2015
DOI: 10.1038/NATURE14132
Publisher: Springer Science and Business Media LLC
Date: 29-05-2012
DOI: 10.1038/TP.2012.49
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Ian Deary.