ORCID Profile
0000-0002-0198-4588
Current Organisations
Royal College of Psychiatrists
,
The University of Edinburgh
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Publisher: Springer Science and Business Media LLC
Date: 21-11-2016
DOI: 10.1038/NG.3725
Publisher: Springer Science and Business Media LLC
Date: 02-2016
DOI: 10.1038/NN.4228
Publisher: Elsevier BV
Date: 07-2014
Publisher: Cold Spring Harbor Laboratory
Date: 11-04-2020
DOI: 10.1101/2020.04.06.20055517
Abstract: Dementia pathogenesis begins years before clinical symptom onset, necessitating the understanding of premorbid risk mechanisms. Here, we investigated potential pathogenic mechanisms by assessing DNA methylation associations with dementia risk factors in Alzheimer’s disease (AD)-free participants. Associations between dementia risk measures (family history, genetic risk score (GRS), and dementia risk scores (combining lifestyle, demographic and genetic factors) and whole-blood DNA methylation were assessed in discovery and replication s les (n=∼400 – ∼5,000) from Generation Scotland. AD genetic risk and two risk scores were associated with differential methylation. The GRS predominantly associated with methylation differences in cis but also identified a genomic region implicated in Parkinson’s disease. Loci associated with the risk scores were enriched for those previously associated with body mass index and alcohol consumption. Dementia risk measures show widespread association with blood-based methylation, which indicates differences in the processes affected by genetic and demographic/lifestyle risk factors.
Publisher: Center for Open Science
Date: 14-10-2019
Abstract: A key objective in the field of translational psychiatry over the past few decades has been to identify the brain correlates common to in iduals with major depressive disorder (MDD). Identifying measurable indicators of brain processes associated with MDD could facilitate the detection of in iduals at risk, and the development of novel treatments, the monitoring of treatment effects, and predicting who might benefit most from treatments that target specific brain mechanisms. However, despite intensive neuroimaging research towards this effort, underpowered studies and a lack of reproducible findings have hindered progress. Here we discuss the work of the ENIGMA Major Depressive Disorder (MDD) Consortium, which was established to address issues of poor replication, unreliable results, and overestimation of effect sizes in previous studies. The ENIGMA MDD Consortium currently includes data from 45 MDD study cohorts from 14 countries across 6 continents. The primary aim of ENIGMA MDD is to identify structural and functional brain alterations associated with MDD that can be reliably detected and replicated across cohorts worldwide. A secondary goal is to investigate how demographic, genetic, clinical, psychological, and environmental factors affect these associations. In this review, we summarize findings of the ENIGMA-MDD disease working group to date and discuss future directions. We also highlight the challenges and benefits of large-scale data-sharing for mental health research.
Publisher: Springer Science and Business Media LLC
Date: 18-12-2017
Publisher: Springer Science and Business Media LLC
Date: 29-06-2017
DOI: 10.1038/S41598-017-03054-8
Abstract: Obesity is a genetically heterogeneous disorder. Using targeted and whole-exome sequencing, we studied 32 human and 87 rodent obesity genes in 2,548 severely obese children and 1,117 controls. We identified 52 variants contributing to obesity in 2% of cases including multiple novel variants in GNAS , which were sometimes found with accelerated growth rather than short stature as described previously. Nominally significant associations were found for rare functional variants in BBS1 , BBS9 , GNAS , MKKS , CLOCK and ANGPTL6 . The p.S284X variant in ANGPTL6 drives the association signal (rs201622589, MAF~0.1%, odds ratio = 10.13, p-value = 0.042) and results in complete loss of secretion in cells. Further analysis including additional case-control studies and population controls (N = 260,642) did not support association of this variant with obesity (odds ratio = 2.34, p-value = 2.59 × 10 −3 ), highlighting the challenges of testing rare variant associations and the need for very large s le sizes. Further validation in cohorts with severe obesity and engineering the variants in model organisms will be needed to explore whether human variants in ANGPTL6 and other genes that lead to obesity when deleted in mice, do contribute to obesity. Such studies may yield druggable targets for weight loss therapies.
Publisher: American Medical Association (AMA)
Date: 09-2018
Publisher: Wiley
Date: 16-02-2020
DOI: 10.1111/ADB.12880
Publisher: Springer Science and Business Media LLC
Date: 08-01-2014
Publisher: Cold Spring Harbor Laboratory
Date: 11-01-2023
DOI: 10.1101/2023.01.10.23284387
Abstract: Blood DNA methylation can inform us about the biological mechanisms that underlie common disease states. Previous epigenome-wide analyses of common diseases often focus solely on the prevalence or incidence of in idual conditions and rely on small s le sizes, which may limit power to discover disease-associated loci. We conduct blood-based epigenome-wide association studies on the prevalence of 14 common disease states in Generation Scotland (n in iduals ≤18,413, n CpGs =752,722). We also utilise health record linkage to perform epigenome-wide analyses on the incidence of 19 disease states. We present a structured literature review on existing epigenome-wide analyses for all 19 disease states to assess the degree of replication within the existing literature and the novelty of the present findings. We identify 69 associations between CpGs and the prevalence of four disease states at baseline, of which 58 are novel. We also uncover 64 CpGs that associate with the incidence of two disease states (COPD and type 2 diabetes), of which 56 are novel. These associations were independent from common lifestyle risk factors. We highlight poor replication across the existing literature. Here, replication was defined by the reporting of at least one common gene in studies examining the same disease state. Existing blood-based epigenome-wide analyses showed evidence of replication for only 4/19 disease states (with up-to-15% of unique genes replicated for lung cancer). Our summary data and structured review of the literature provide an important platform to guide future studies that examine the role of blood DNA methylation in complex disease states.
Publisher: Wiley
Date: 23-11-2019
DOI: 10.1111/BDI.12868
Publisher: Springer Science and Business Media LLC
Date: 26-02-2018
Publisher: Elsevier BV
Date: 03-2013
Publisher: Elsevier BV
Date: 06-2018
Publisher: Public Library of Science (PLoS)
Date: 02-09-2021
DOI: 10.1371/JOURNAL.PONE.0248254
Abstract: Anxiety and depression are common mental health disorders and have a higher prevalence in females. They are modestly heritable, share genetic liability with other psychiatric disorders, and are highly heterogeneous. There is evidence that genetic liability to neurodevelopmental disorders, such as attention deficit hyperactivity disorder (ADHD) is associated with anxiety and depression, particularly in females. We investigated sex differences in family history for neurodevelopmental and psychiatric disorders and neurodevelopmental genetic risk burden (indexed by ADHD polygenic risk scores (PRS) and rare copy number variants CNVs) in in iduals with anxiety and depression, also taking into account age at onset. We used two complementary datasets: 1) participants with a self-reported diagnosis of anxiety or depression (N = 4,178, 65.5% female mean age = 41.5 years N = 1,315 with genetic data) from the National Centre for Mental Health (NCMH) cohort and 2) a clinical s le of 13,273 (67.6% female mean age = 45.2 years) patients with major depressive disorder (MDD) from the Psychiatric Genomics Consortium (PGC). We tested for sex differences in family history of psychiatric problems and presence of rare CNVs (neurodevelopmental and kb loci) in NCMH only and for sex differences in ADHD PRS in both datasets. In the NCMH cohort, females were more likely to report family history of neurodevelopmental and psychiatric disorders, but there were no robust sex differences in ADHD PRS or presence of rare CNVs. There was weak evidence of higher ADHD PRS in females compared to males in the PGC MDD s le, particularly in those with an early onset of MDD. These results do not provide strong evidence of sex differences in neurodevelopmental genetic risk burden in adults with anxiety and depression. This indicates that sex may not be a major index of neurodevelopmental genetic heterogeneity, that is captured by ADHD PRS and rare CNV burden, in adults with anxiety and depression.
Publisher: Cold Spring Harbor Laboratory
Date: 31-03-2022
DOI: 10.1101/2022.03.27.22273017
Abstract: Based on observational studies and small-scale randomized controlled trials, it is uncertain whether cholesterol-lowering statins have any beneficial or adverse effects on depressive symptoms. In this study we investigate this question using a genomics approach. To compare the pharmacological effects of statin and antidepressant exposure and identify commonly perturbed biological pathways, we interrogated Connectivity Map (CMap), a database of gene expression signatures from drug-treated human cell lines. We used Mendelian randomization, a statistical genomics approach, to investigate the potential causal on-target (HMGCR inhibition) and off-target effects of statin exposure on depression, depressive symptoms, and traits related to the shared pathways identified from CMap analysis. Compounds inducing highly similar gene expression responses to statins (as indicated by an average CMap connectivity score with statins 90) were enriched for antidepressants (12 out of 38 antidepressants p 1E-05). Genes perturbed in the same direction by both statins and antidepressants were significantly enriched for erse cellular and metabolic pathways, and various immune activation, development and response processes. Genetically proxied HMGCR inhibition was significantly associated with monocyte and platelet-related metrics. Our study is the first to directly compare gene expression responses to statins and antidepressants, demonstrating perturbation of shared immune pathways. We further show that statin exposure is strongly associated with alterations in monocyte and platelet measures, both of which have previously been implicated in depression. Our findings warrant further investigation into the use of statins for treating depression, particularly in patients with raised blood biomarkers of inflammation.
Publisher: Springer Science and Business Media LLC
Date: 28-05-2020
DOI: 10.1038/S41380-020-0774-9
Abstract: Emerging evidence suggests that obesity impacts brain physiology at multiple levels. Here we aimed to clarify the relationship between obesity and brain structure using structural MRI ( n = 6420) and genetic data ( n = 3907) from the ENIGMA Major Depressive Disorder (MDD) working group. Obesity (BMI 30) was significantly associated with cortical and subcortical abnormalities in both mass-univariate and multivariate pattern recognition analyses independent of MDD diagnosis. The most pronounced effects were found for associations between obesity and lower temporo-frontal cortical thickness (maximum Cohen´s d (left fusiform gyrus) = −0.33). The observed regional distribution and effect size of cortical thickness reductions in obesity revealed considerable similarities with corresponding patterns of lower cortical thickness in previously published studies of neuropsychiatric disorders. A higher polygenic risk score for obesity significantly correlated with lower occipital surface area. In addition, a significant age-by-obesity interaction on cortical thickness emerged driven by lower thickness in older participants. Our findings suggest a neurobiological interaction between obesity and brain structure under physiological and pathological brain conditions.
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: Cold Spring Harbor Laboratory
Date: 17-02-2020
DOI: 10.1101/2020.02.17.952010
Abstract: For many traits, males show greater variability than females, with possible implications for understanding sex differences in health and disease. Here, the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Consortium presents the largest-ever mega-analysis of sex differences in variability of brain structure, based on international data spanning nine decades of life. Subcortical volumes, cortical surface area and cortical thickness were assessed in MRI data of 16,683 healthy in iduals 1-90 years old (47% females). We observed significant patterns of greater male than female between-subject variance for all subcortical volumetric measures, all cortical surface area measures, and 60% of cortical thickness measures. This pattern was stable across the lifespan for 50% of the subcortical structures, 70% of the regional area measures, and nearly all regions for thickness. Our findings that these sex differences are present in childhood implicate early life genetic or gene-environment interaction mechanisms. The findings highlight the importance of in idual differences within the sexes, that may underpin sex-specific vulnerability to disorders.
Publisher: Springer Science and Business Media LLC
Date: 02-05-2017
DOI: 10.1038/MP.2017.73
Publisher: Springer Science and Business Media LLC
Date: 15-11-2021
Publisher: Springer Science and Business Media LLC
Date: 21-08-2019
Publisher: Springer Science and Business Media LLC
Date: 30-08-2019
Publisher: Springer Science and Business Media LLC
Date: 02-02-2015
DOI: 10.1038/NG.3211
Publisher: Elsevier BV
Date: 07-2011
DOI: 10.1016/J.BIOPSYCH.2011.01.032
Abstract: It is well established that schizophrenia is associated with structural brain abnormalities, but whether these are static or progress over time remains controversial. A systematic review of longitudinal volumetric studies using region-of-interest structural magnetic resonance imaging in patients with schizophrenia and healthy control subjects. The percentage change in volume between scans for each brain region of interest was obtained, and data were combined using random effects meta-analysis. Twenty-seven studies were included in the meta-analysis, with 928 patients and 867 control subjects, and 32 different brain regions of interest. Subjects with schizophrenia showed significantly greater decreases over time in whole brain volume, whole brain gray matter, frontal gray and white matter, parietal white matter, and temporal white matter volume, as well as larger increases in lateral ventricular volume, than healthy control subjects. The time between baseline and follow-up magnetic resonance imaging scans ranged from 1 to 10 years. The differences between patients and control subjects in annualized percentage volume change were -.07% for whole brain volume, -.59% for whole brain gray matter, -.32% for frontal white matter, -.32% for parietal white matter, -.39% for temporal white matter, and +.36% for bilateral lateral ventricles. These findings suggest that schizophrenia is associated with progressive structural brain abnormalities, affecting both gray and white matter. We found no evidence to suggest progressive medial temporal lobe involvement but did find evidence that this may be partly explained by heterogeneity between studies in patient age and illness duration. The causes and clinical correlates of these progressive brain changes should now be the focus of investigation.
Publisher: Springer Science and Business Media LLC
Date: 21-01-2019
DOI: 10.1038/S41467-018-07863-X
Abstract: Cranial growth and development is a complex process which affects the closely related traits of head circumference (HC) and intracranial volume (ICV). The underlying genetic influences shaping these traits during the transition from childhood to adulthood are little understood, but might include both age-specific genetic factors and low-frequency genetic variation. Here, we model the developmental genetic architecture of HC, showing this is genetically stable and correlated with genetic determinants of ICV. Investigating up to 46,000 children and adults of European descent, we identify association with final HC and/or final ICV + HC at 9 novel common and low-frequency loci, illustrating that genetic variation from a wide allele frequency spectrum contributes to cranial growth. The largest effects are reported for low-frequency variants within TP53 , with 0.5 cm wider heads in increaser-allele carriers versus non-carriers during mid-childhood, suggesting a previously unrecognized role of TP53 transcripts in human cranial development.
Publisher: Springer Science and Business Media LLC
Date: 21-01-2015
DOI: 10.1038/NATURE14101
Publisher: Springer Science and Business Media LLC
Date: 03-06-2019
DOI: 10.1038/S41588-019-0450-7
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Publisher: Elsevier BV
Date: 09-2017
Publisher: Public Library of Science (PLoS)
Date: 06-07-2023
DOI: 10.1371/JOURNAL.PMED.1004247
Abstract: DNA methylation is a dynamic epigenetic mechanism that occurs at cytosine-phosphate-guanine dinucleotide (CpG) sites. Epigenome-wide association studies (EWAS) investigate the strength of association between methylation at in idual CpG sites and health outcomes. Although blood methylation may act as a peripheral marker of common disease states, previous EWAS have typically focused only on in idual conditions and have had limited power to discover disease-associated loci. This study examined the association of blood DNA methylation with the prevalence of 14 disease states and the incidence of 19 disease states in a single population of over 18,000 Scottish in iduals. DNA methylation was assayed at 752,722 CpG sites in whole-blood s les from 18,413 volunteers in the family-structured, population-based cohort study Generation Scotland (age range 18 to 99 years). EWAS tested for cross-sectional associations between baseline CpG methylation and 14 prevalent disease states, and for longitudinal associations between baseline CpG methylation and 19 incident disease states. Prevalent cases were self-reported on health questionnaires at the baseline. Incident cases were identified using linkage to Scottish primary (Read 2) and secondary (ICD-10) care records, and the censoring date was set to October 2020. The mean time-to-diagnosis ranged from 5.0 years (for chronic pain) to 11.7 years (for Coronavirus Disease 2019 (COVID-19) hospitalisation). The 19 disease states considered in this study were selected if they were present on the World Health Organisation’s 10 leading causes of death and disease burden or included in baseline self-report questionnaires. EWAS models were adjusted for age at methylation typing, sex, estimated white blood cell composition, population structure, and 5 common lifestyle risk factors. A structured literature review was also conducted to identify existing EWAS for all 19 disease states tested. The MEDLINE, Embase, Web of Science, and preprint servers were searched to retrieve relevant articles indexed as of March 27, 2023. Fifty-four of approximately 2,000 indexed articles met our inclusion criteria: assayed blood-based DNA methylation, had in iduals in each comparison group, and examined one of the 19 conditions considered. First, we assessed whether the associations identified in our study were reported in previous studies. We identified 69 associations between CpGs and the prevalence of 4 conditions, of which 58 were newly described. The conditions were breast cancer, chronic kidney disease, ischemic heart disease, and type 2 diabetes mellitus. We also uncovered 64 CpGs that associated with the incidence of 2 disease states (COPD and type 2 diabetes), of which 56 were not reported in the surveyed literature. Second, we assessed replication across existing studies, which was defined as the reporting of at least 1 common site in studies that examined the same condition. Only 6/19 disease states had evidence of such replication. The limitations of this study include the nonconsideration of medication data and a potential lack of generalizability to in iduals that are not of Scottish and European ancestry. We discovered over 100 associations between blood methylation sites and common disease states, independently of major confounding risk factors, and a need for greater standardisation among EWAS on human disease.
Publisher: Springer Science and Business Media LLC
Date: 17-10-2017
DOI: 10.1038/MP.2017.170
Publisher: Wiley
Date: 2018
Publisher: Springer Science and Business Media LLC
Date: 31-12-2019
DOI: 10.1186/S13073-019-0693-Z
Abstract: Advanced age is associated with cognitive and physical decline and is a major risk factor for a multitude of disorders. There is also a gap in life expectancy between males and females. DNA methylation differences have been shown to be associated with both age and sex. Here, we investigate age-by-sex differences in blood-based DNA methylation in an unrelated cohort of 2586 in iduals between the ages of 18 and 87 years, with replication in a further 4450 in iduals between the ages of 18 and 93 years. Linear regression models were applied, with stringent genome-wide significance thresholds ( p 3.6 × 10 −8 ) used in both the discovery and replication data. A second, highly conservative mixed linear model method that better controls the false-positive rate was also applied, using the same genome-wide significance thresholds. Using the linear regression method, 52 autosomal and 597 X-linked CpG sites, mapping to 251 unique genes, replicated with concordant effect size directions in the age-by-sex interaction analysis. The site with the greatest difference mapped to GAGE10 , an X-linked gene. Here, DNA methylation levels remained stable across the male adult age range (DNA methylation by age r = 0.02) but decreased across female adult age range (DNA methylation by age r = − 0.61). One site (cg23722529) with a significant age-by-sex interaction also had a quantitative trait locus (rs17321482) that is a genome-wide significant variant for prostate cancer. The mixed linear model method identified 11 CpG sites associated with the age-by-sex interaction. The majority of differences in age-associated DNA methylation trajectories between sexes are present on the X chromosome. Several of these differences occur within genes that have been implicated in sexually dimorphic traits.
Publisher: Springer Science and Business Media LLC
Date: 23-02-2016
DOI: 10.1038/MP.2016.9
Publisher: Elsevier BV
Date: 11-2013
Publisher: Springer Science and Business Media LLC
Date: 05-07-2018
DOI: 10.1038/S41598-018-28160-Z
Abstract: Previous studies have shown an increased risk for mental health problems in children born to both younger and older parents compared to children of average-aged parents. We previously used a novel design to reveal a latent mechanism of genetic association between schizophrenia and age at first birth in women (AFB). Here, we use independent data from the UK Biobank (N = 38,892) to replicate the finding of an association between predicted genetic risk of schizophrenia and AFB in women, and to estimate the genetic correlation between schizophrenia and AFB in women stratified into younger and older groups. We find evidence for an association between predicted genetic risk of schizophrenia and AFB in women (P-value = 1.12E-05), and we show genetic heterogeneity between younger and older AFB groups (P-value = 3.45E-03). The genetic correlation between schizophrenia and AFB in the younger AFB group is −0.16 (SE = 0.04) while that between schizophrenia and AFB in the older AFB group is 0.14 (SE = 0.08). Our results suggest that early, and perhaps also late, age at first birth in women is associated with increased genetic risk for schizophrenia in the UK Biobank s le. These findings contribute new insights into factors contributing to the complex bio-social risk architecture underpinning the association between parental age and offspring mental health.
Publisher: Royal College of Psychiatrists
Date: 15-08-2018
DOI: 10.1192/BJO.2018.47
Publisher: Springer Science and Business Media LLC
Date: 25-03-2019
Publisher: Cold Spring Harbor Laboratory
Date: 21-01-2020
DOI: 10.1101/2020.01.20.913228
Abstract: Common types of musculoskeletal conditions include pain in the neck and shoulder areas. This study seeks to identify the genetic variants associated with neck or shoulder pain based on a genome-wide association approach using 203,309 subjects from the UK Biobank cohort and look for replication evidence from the Generation Scotland: Scottish Family Health Study (GS:SFHS) and TwinsUK. Cases in the UK Biobank were determined by a question which asked the participants if they had experienced pain in the neck or shoulder in the previous month influencing daily activities. Controls were the UK Biobank participants who reported no pain anywhere in the last month. A genome-wide association study was performed adjusting for age, sex, BMI and 9 population principal components. Significant and independent genetic variants were then sent to GS:SFHS and TwinsUK for replication. We identified 3 genetic loci that were associated with neck or shoulder pain in the UK Biobank s les. The most significant locus was in an intergenic region in chromosome 17, rs12453010, having P = 1.66 × 10 -11 . The second most significant locus was located in the FOXP2 gene in chromosome 7 with P = 2.38 × 10 -10 for rs34291892. The third locus was located in the LINC01572 gene in chromosome 16 with P = 4.50 × 10 -8 for rs62053992. In the replication stage, among 4 significant and independent genetic variants, rs2049604 in the FOXP2 gene and rs62053992 in the LINC01572 gene were weakly replicated in GS:SFHS ( P = 0.0240 and P = 0.0202, respectively). None of the single nucleotide polymorphisms (SNPs) were replicated in the TwinsUK cohort ( P 0.05). We have identified 3 loci associated with neck or shoulder pain in the UK Biobank cohort, two of which were weakly supported in a replication cohort. Further evidence is needed to confirm their roles in neck or shoulder pain. This is the first genome-wide association study on neck or shoulder pain. We have identified 3 genetic loci (an intergenic region in chromosome 17, the FOXP2 gene in chromosome 7, and the LINC01572 gene in chromosome 16) that are associated with neck or shoulder pain using the UK Biobank cohort, among which the FOXP2 gene and the LINC01572 gene were weakly replicated by the Generation Scotland: Scottish Family Health Study ( P 0.05). The SNP heritability was 0.11, indicating neck or shoulder pain is a heritable trait. The tissue expression analysis suggested that neck or shoulder pain was related to multiple brain tissues, indicating the involvement of neuron function. The results will inform further research in the characterisation of the mechanisms of neck or shoulder pain.
Publisher: Springer Science and Business Media LLC
Date: 26-11-2018
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: Springer Science and Business Media LLC
Date: 29-05-2020
DOI: 10.1038/S41398-020-0842-6
Abstract: A key objective in the field of translational psychiatry over the past few decades has been to identify the brain correlates of major depressive disorder (MDD). Identifying measurable indicators of brain processes associated with MDD could facilitate the detection of in iduals at risk, and the development of novel treatments, the monitoring of treatment effects, and predicting who might benefit most from treatments that target specific brain mechanisms. However, despite intensive neuroimaging research towards this effort, underpowered studies and a lack of reproducible findings have hindered progress. Here, we discuss the work of the ENIGMA Major Depressive Disorder (MDD) Consortium, which was established to address issues of poor replication, unreliable results, and overestimation of effect sizes in previous studies. The ENIGMA MDD Consortium currently includes data from 45 MDD study cohorts from 14 countries across six continents. The primary aim of ENIGMA MDD is to identify structural and functional brain alterations associated with MDD that can be reliably detected and replicated across cohorts worldwide. A secondary goal is to investigate how demographic, genetic, clinical, psychological, and environmental factors affect these associations. In this review, we summarize findings of the ENIGMA MDD disease working group to date and discuss future directions. We also highlight the challenges and benefits of large-scale data sharing for mental health research.
Publisher: BMJ
Date: 18-03-2000
Publisher: Springer Science and Business Media LLC
Date: 09-02-2016
DOI: 10.1038/MP.2015.227
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: 06-03-2019
Publisher: Public Library of Science (PLoS)
Date: 24-08-2015
Publisher: Springer Science and Business Media LLC
Date: 09-10-2020
DOI: 10.1038/S41467-020-19099-9
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Publisher: Springer Science and Business Media LLC
Date: 27-09-2018
Publisher: Springer Science and Business Media LLC
Date: 12-2018
Publisher: Cold Spring Harbor Laboratory
Date: 02-03-2021
DOI: 10.1101/2021.02.28.21251786
Abstract: Our group developed a transcriptome-based polygenic risk score (T-PRS) that uses common genetic variants to capture ‘depression-like’ shifts in cortical gene expression. Here, we mapped T-PRS onto diagnosis and symptom severity in major depressive disorder (MDD) cases and controls from the Psychiatric Genomics Consortium (PGC). To evaluate potential mechanisms, we further mapped T-PRS onto discrete measures of brain morphology and broad depression risk in healthy young adults. Genetic, self-report, and/or neuroimaging data were available in 29,340 PGC participants (59% women 12,923 MDD cases, 16,417 controls) and 482 participants in the Duke Neurogenetics Study (DNS: 53% women aged 19.8±1.2 years). T-PRS was computed from SNP data using PrediXcan to impute cortical expression levels of MDD-related genes from a previous post-mortem transcriptome meta-analysis. Sex-specific regressions were used to test effects of T-PRS on depression diagnosis, symptom severity, and Freesurfer-derived subcortical volume, cortical thickness, surface area, and local gyrification index in the PGC and DNS s les, respectively. T-PRS did not predict depression diagnosis (OR=1.007, 95%CI=[0.997-1.018]) however, it correlated with symptom severity in men (rho=0.175, p=7.957×10 −4 ) in one large PGC cohort (N=762, 48% men). In DNS, T-PRS was associated with smaller amygdala volume in women (β=-0.186, t=-3.478, p=.001) and less prefrontal gyrification (max≤-2.970, p≤.006) in both sexes. In men, prefrontal gyrification mediated an indirect effect of T-PRS on broad depression risk (b=.005, p=.029), indexed using self-reported family history of depression. Depression-like shifts in cortical gene expression predict symptom severity in men and may contribute to disease vulnerability through their effect on cortical gyrification.
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: Cold Spring Harbor Laboratory
Date: 12-07-2022
DOI: 10.1101/2022.07.12.22277553
Abstract: Schizophrenia is a heritable psychiatric disorder with a polygenic architecture. Genome-wide association studies (GWAS) have reported an increasing number of risk-associated variants and polygenic risk scores (PRS) now explain 17% of the variance in the disorder. There exists substantial heterogeneity in the effect of these variants and aggregating them based on biologically relevant functions may provide mechanistic insight into the disorder. Using the largest schizophrenia GWAS to date, we calculated PRS based on 5 gene-sets previously found to contribute to the pathophysiology of schizophrenia: the postsynaptic density of excitatory synapses, postsynaptic membrane, dendritic spine, axon, and histone H3-K4 methylation gene-sets. We associated each PRS, along with respective whole-genome PRS (excluding single nucleotide polymorphisms in each gene-set), with neuroimaging (N ,000 cortical, subcortical, and white matter microstructure) and clinical (N ,000 psychotic-like experiences including conspiracies, communications, voices, visions, and distress) variables in healthy subjects in UK Biobank. A number of clinical and neuroimaging variables were significantly associated with the axon gene-set (psychotic-like communications: β=0.0916, p FDR =0.04, parahippoc al gyrus volume: β=0.0156, p FDR =0.03, FA thalamic radiations: β=-0.014, p FDR =0.036, FA posterior thalamic radiations: β=-0.016, p FDR =0.048), postsynaptic density gene-set (distress due to psychotic-like experiences: β=0.0588, p FDR =0.02, global surface area: β=-0.012, p FDR =0.034, and cingulate lobe surface area: β=-0.014, p FDR =0.04), and histone gene-set (entorhinal surface area: β=-0.016, p FDR =0.035). In the associations above, whole-genome PRS were significantly associated with psychotic-like communications (β=0.2218, p FDR =1.34×10 −7 ), distress (β=0.1943, p FDR =7.28×10 −16 ), and FA thalamic radiations (β=-0.0143, p FDR =0.036). Permutation analysis carried out for these associations revealed that they were not due to chance. Our results indicate that genetic variation in 3 gene-sets relevant to schizophrenia (axon, postsynaptic density, histone) may confer risk for the disorder through effects on a number of neuroimaging variables that have previously been implicated in schizophrenia. As neuroimaging associations were stronger for gene-set PRS than whole-genome PRS, findings here highlight that selection of biologically relevant variants may address the heterogeneity of the disorder by providing further mechanistic insight into schizophrenia.
Publisher: Springer Science and Business Media LLC
Date: 05-2019
Publisher: Cold Spring Harbor Laboratory
Date: 23-10-2019
DOI: 10.1101/815035
Abstract: The Apolipoprotein E ( APOE ) ε4 allele is the strongest genetic risk factor for late onset Alzheimer’s disease, while the ε2 allele confers protection. Previous studies report differential DNA methylation of APOE between ε4 and ε2 carriers, but associations with epigenome-wide methylation have not previously been characterised. Using the EPIC array, we investigated epigenome-wide differences in whole blood DNA methylation patterns between Alzheimer’s disease-free APOE ε4 (n=2469) and ε2 (n=1118) carriers from the two largest single-cohort DNA methylation s les profiled to date. Using a discovery, replication and meta-analysis study design, methylation differences were identified using epigenome-wide association analysis and differentially methylated region (DMR) approaches. Results were explored using pathway and methylation quantitative trait loci (meQTL) analyses. We obtained replicated evidence for DNA methylation differences in a ~ 169kb region, which encompasses part of APOE and several upstream genes. Meta-analytic approaches identified DNA methylation differences outside of APOE: differentially methylated positions were identified in DHCR24, LDLR and ABCG1 (2.59 x 10 −100 ≤ P ≤2.44 x 10 −8 ) and DMRs were identified in SREBF2 and LDLR (1.63 x 10 −4 ≤ P ≤3.01 x 10 −2 ). Pathway and meQTL analyses implicated lipid-related processes and high density lipoprotein cholesterol was identified as a partial mediator of the methylation differences in ABCG1 and DHCR24 . APOE ε4 vs. ε2 carrier status is associated with epigenome-wide methylation differences in the blood. The loci identified are located in trans as well as cis to APOE and implicate genes involved in lipid homeostasis.
Publisher: Wiley
Date: 18-07-2020
DOI: 10.1002/AJMG.B.32807
Publisher: Springer Science and Business Media LLC
Date: 06-03-2019
DOI: 10.1038/S41380-019-0388-2
Abstract: Autosomal variants have successfully been associated with trait neuroticism in genome-wide analysis of adequately powered s les. But such studies have so far excluded the X chromosome from analysis. Here, we report genetic association analyses of X chromosome and XY pseudoautosomal single nucleotide polymorphisms (SNPs) and trait neuroticism using UK Biobank s les ( N = 405,274). Significant association was found with neuroticism on the X chromosome for 204 markers found within three independent loci (a further 783 were suggestive). Most of the lead neuroticism-related X chromosome variants were located in intergenic regions ( n = 397). Involvement of HS6ST2 , which has been previously associated with sociability behaviour in the dog, was supported by single SNP and gene-based tests. We found that the amino acid and nucleotide sequences are highly conserved between dogs and humans. From the suggestive X chromosome variants, there were 19 nearby genes which could be linked to gene ontology information. Molecular function was primarily related to binding and catalytic activity notable biological processes were cellular and metabolic, and nucleic acid binding and transcription factor protein classes were most commonly involved. X-variant heritability of neuroticism was estimated at 0.22% (SE = 0.05) from a full dosage compensation model. A polygenic X-variant score created in an independent s le (maximum N ≈ 7,300) did not predict significant variance in neuroticism, psychological distress, or depressive disorder. We conclude that the X chromosome harbours significant variants influencing neuroticism, and might prove important for other quantitative traits and complex disorders.
Publisher: Springer Science and Business Media LLC
Date: 20-06-2017
DOI: 10.1038/TP.2017.115
Abstract: Borderline personality disorder (BOR) is determined by environmental and genetic factors, and characterized by affective instability and impulsivity, diagnostic symptoms also observed in manic phases of bipolar disorder (BIP). Up to 20% of BIP patients show comorbidity with BOR. This report describes the first case–control genome-wide association study (GWAS) of BOR, performed in one of the largest BOR patient s les worldwide. The focus of our analysis was (i) to detect genes and gene sets involved in BOR and (ii) to investigate the genetic overlap with BIP. As there is considerable genetic overlap between BIP, major depression (MDD) and schizophrenia (SCZ) and a high comorbidity of BOR and MDD, we also analyzed the genetic overlap of BOR with SCZ and MDD. GWAS, gene-based tests and gene-set analyses were performed in 998 BOR patients and 1545 controls. Linkage disequilibrium score regression was used to detect the genetic overlap between BOR and these disorders. Single marker analysis revealed no significant association after correction for multiple testing. Gene-based analysis yielded two significant genes: DPYD ( P =4.42 × 10 −7 ) and PKP4 ( P =8.67 × 10 −7 ) and gene-set analysis yielded a significant finding for exocytosis (GO:0006887, P FDR =0.019 FDR, false discovery rate). Prior studies have implicated DPYD , PKP4 and exocytosis in BIP and SCZ. The most notable finding of the present study was the genetic overlap of BOR with BIP ( r g =0.28 [ P =2.99 × 10 −3 ]), SCZ ( r g =0.34 [ P =4.37 × 10 −5 ]) and MDD ( r g =0.57 [ P =1.04 × 10 −3 ]). We believe our study is the first to demonstrate that BOR overlaps with BIP, MDD and SCZ on the genetic level. Whether this is confined to transdiagnostic clinical symptoms should be examined in future studies.
Publisher: Elsevier BV
Date: 05-2015
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: Cold Spring Harbor Laboratory
Date: 21-09-2021
DOI: 10.1101/2021.09.15.21263562
Abstract: A major limitation of current suicide research is the lack of power to identify robust correlates of suicidal thoughts or behaviour. Variation in suicide risk assessment instruments used across cohorts may represent a limitation to pooling data in international consortia. Here, we examine this issue through two approaches: (i) an extensive literature search on the reliability and concurrent validity of the most commonly used instruments and (ii) by pooling data (N∼6,000 participants) from cohorts from the ENIGMA-Major Depressive Disorder (ENIGMA-MDD) and ENIGMA-Suicidal Thoughts and Behaviour (ENIGMA-STB) working groups, to assess the concurrent validity of instruments currently used for assessing suicidal thoughts or behaviour. Our results suggested a pattern of moderate-to-high correlations between instruments, consistent with the wide range of correlations, r=0.22-0.97, reported in the literature. Two common complex instruments, the Columbia Suicide Severity Rating Scale (C-SSRS) and the Beck Scale for Suicidal Ideation (SSI), were highly correlated with each other (r=0.83), as were suicidal ideation items from common depression severity questionnaires. Our findings suggest that multi-item instruments provide valuable information on different aspects of suicidal thoughts or behaviour, but share a core factor with single suicidal ideation items found in depression severity questionnaires. Multi-site collaborations including cohorts that used distinct instruments for suicide risk assessment should be feasible provided that they harmonise across instruments or focus on specific constructs of suicidal thoughts or behaviours. Question: To inform future suicide research in multi-site international consortia, it is important to examine how different suicide measures relate to each other and whether they can be used interchangeably. Findings: Findings suggest detailed instruments (such as the Columbia Suicide Severity Rating Scale and Beck Scale for Suicidal Ideation) provide valuable information on suicidal thoughts and behaviour, and share a core factor with items on suicidal ideation from depression severity rating scale (such as the Hamilton Depression Rating Scale or the Beck Depression Inventory). Importance: Results from international collaborations can mitigate biases by harmonising distinct suicide risk assessment instruments. Next steps: Pooling data within international suicide research consortia may reveal novel clinical, biological and cognitive correlates of suicidal thoughts and/or behaviour.
Publisher: Wiley
Date: 12-10-2020
DOI: 10.1002/HBM.25204
Abstract: For many traits, males show greater variability than females, with possible implications for understanding sex differences in health and disease. Here, the ENIGMA (Enhancing Neuro Imaging Genetics through Meta‐Analysis) Consortium presents the largest‐ever mega‐analysis of sex differences in variability of brain structure, based on international data spanning nine decades of life. Subcortical volumes, cortical surface area and cortical thickness were assessed in MRI data of 16,683 healthy in iduals 1‐90 years old (47% females). We observed significant patterns of greater male than female between‐subject variance for all subcortical volumetric measures, all cortical surface area measures, and 60% of cortical thickness measures. This pattern was stable across the lifespan for 50% of the subcortical structures, 70% of the regional area measures, and nearly all regions for thickness. Our findings that these sex differences are present in childhood implicate early life genetic or gene‐environment interaction mechanisms. The findings highlight the importance of in idual differences within the sexes, that may underpin sex‐specific vulnerability to disorders.
Publisher: Royal College of Psychiatrists
Date: 06-02-2020
DOI: 10.1192/BJO.2019.100
Abstract: UK Biobank is a well-characterised cohort of over 500 000 participants including genetics, environmental data and imaging. An online mental health questionnaire was designed for UK Biobank participants to expand its potential. Describe the development, implementation and results of this questionnaire. An expert working group designed the questionnaire, using established measures where possible, and consulting a patient group. Operational criteria were agreed for defining likely disorder and risk states, including lifetime depression, mania/hypomania, generalised anxiety disorder, unusual experiences and self-harm, and current post-traumatic stress and hazardous/harmful alcohol use. A total of 157 366 completed online questionnaires were available by August 2017. Participants were aged 45–82 (53% were ≥65 years) and 57% women. Comparison of self-reported diagnosed mental disorder with a contemporary study shows a similar prevalence, despite respondents being of higher average socioeconomic status. Lifetime depression was a common finding, with 24% (37 434) of participants meeting criteria and current hazardous/harmful alcohol use criteria were met by 21% (32 602), whereas other criteria were met by less than 8% of the participants. There was extensive comorbidity among the syndromes. Mental disorders were associated with a high neuroticism score, adverse life events and long-term illness addiction and bipolar affective disorder in particular were associated with measures of deprivation. The UK Biobank questionnaire represents a very large mental health survey in itself, and the results presented here show high face validity, although caution is needed because of selection bias. Built into UK Biobank, these data intersect with other health data to offer unparalleled potential for crosscutting biomedical research involving mental health.
Publisher: Springer Science and Business Media LLC
Date: 21-10-2019
Publisher: Springer Science and Business Media LLC
Date: 18-05-2020
Publisher: Springer Science and Business Media LLC
Date: 06-03-2015
DOI: 10.1038/NCOMMS6681
Abstract: Normal thyroid function is essential for health, but its genetic architecture remains poorly understood. Here, for the heritable thyroid traits thyrotropin (TSH) and free thyroxine (FT4), we analyse whole-genome sequence data from the UK10K project ( N =2,287). Using additional whole-genome sequence and deeply imputed data sets, we report meta-analysis results for common variants (MAF≥1%) associated with TSH and FT4 ( N =16,335). For TSH, we identify a novel variant in SYN2 (MAF=23.5%, P =6.15 × 10 −9 ) and a new independent variant in PDE8B (MAF=10.4%, P =5.94 × 10 −14 ). For FT4, we report a low-frequency variant near B4GALT6/SLC25A52 (MAF=3.2%, P =1.27 × 10 −9 ) tagging a rare TTR variant (MAF=0.4%, P =2.14 × 10 −11 ). All common variants explain ≥20% of the variance in TSH and FT4. Analysis of rare variants (MAF %) using sequence kernel association testing reveals a novel association with FT4 in NRG1. Our results demonstrate that increased coverage in whole-genome sequence association studies identifies novel variants associated with thyroid function.
Publisher: F1000 Research Ltd
Date: 14-02-2018
DOI: 10.12688/WELLCOMEOPENRES.13893.1
Abstract: Background: Stressful life events (SLEs) and neuroticism are risk factors for major depressive disorder (MDD). However, SLEs and neuroticism are heritable and genetic risk for SLEs is correlated with risk for MDD. We sought to investigate the genetic and environmental contributions to SLEs in a family-based s le, and quantify genetic overlap with MDD and neuroticism. Methods: A subset of Generation Scotland: the Scottish Family Health Study (GS), consisting of 9618 in iduals with information on MDD, past 6 month SLEs, neuroticism and genome-wide genotype data was used in the present study. We estimated the heritability of SLEs using GCTA software. The environmental contribution to SLEs was assessed by modelling familial, couple and sibling components. Using polygenic risk scores (PRS) and LD score regression (LDSC) we analysed the genetic overlap between MDD, neuroticism and SLEs. Results: Past 6-month life events were positively correlated with lifetime MDD status (β=0.21, r 2 =1.1%, p=2.5 x 10 -25 ) and neuroticism (β =0.13, r 2 =1.9%, p=1.04 x 10 -37 ) at the phenotypic level. Common SNPs explained 8% of the phenotypic variance in personal life events (those directly affecting the in idual) (S.E.=0.03, p= 9 x 10 -4 ). A significant effect of couple environment was detected accounting for 13% (S.E.=0.03, p=0.016) of the phenotypic variation in SLEs. PRS analyses found that reporting more SLEs was associated with a higher polygenic risk for MDD (β =0.05, r 2 =0.3%, p=3 x 10 -5 ), but not a higher polygenic risk for neuroticism. LDSC showed a significant genetic correlation between SLEs and both MDD (r G =0.33, S.E.=0.08 ) and neuroticism (r G =0.15, S.E.=0.07). Conclusions: These findings suggest that SLEs should not be regarded solely as environmental risk factors for MDD as they are partially heritable and this heritability is shared with risk for MDD and neuroticism. Further work is needed to determine the causal direction and source of these associations.
Publisher: Public Library of Science (PLoS)
Date: 22-06-2012
Publisher: Springer Science and Business Media LLC
Date: 05-2019
DOI: 10.1038/S41467-019-10160-W
Abstract: Christina M. Lill, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this article. This has now been corrected in both the PDF and HTML versions of the article.
Publisher: Elsevier BV
Date: 06-2018
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: Springer Science and Business Media LLC
Date: 14-09-2015
DOI: 10.1038/NATURE14962
Publisher: Springer Science and Business Media LLC
Date: 07-2014
DOI: 10.1038/NATURE13595
Publisher: Cold Spring Harbor Laboratory
Date: 07-07-2023
DOI: 10.1101/2023.07.05.23292214
Abstract: Diagnostic criteria for major depressive disorder allow for heterogeneous symptom profiles but genetic analysis of major depressive symptoms has the potential to identify clinical and aetiological subtypes. There are several challenges to integrating symptom data from genetically-informative cohorts, such as s le size differences between clinical and community cohorts and various patterns of missing data. We conducted genome-wide association studies of major depressive symptoms in three clinical cohorts that were enriched for affected participants (Psychiatric Genomics Consortium, Australian Genetics of Depression Study, Generation Scotland) and three community cohorts (Avon Longitudinal Study of Parents and Children, Estonian Biobank, and UK Biobank). We fit a series of confirmatory factor models with factors that accounted for how symptom data was s led and then compared alternative models with different symptom factors. The best fitting model had a distinct factor for Appetite/Weight symptoms and an additional measurement factor that accounted for missing data patterns in the community cohorts (use of Depression and Anhedonia as gating symptoms). The results show the importance of assessing the directionality of symptoms (such as hypersomnia versus insomnia) and of accounting for study and measurement design when meta-analysing genetic association data.
Publisher: Cold Spring Harbor Laboratory
Date: 12-01-2018
DOI: 10.1101/247353
Abstract: Depression is more frequently observed among in iduals exposed to traumatic events. The relationship between trauma exposure and depression, including the role of genetic variation, is complex and poorly understood. The UK Biobank concurrently assessed depression and reported trauma exposure in 126,522 genotyped in iduals of European ancestry. We compared the shared aetiology of depression and a range of phenotypes, contrasting in iduals reporting trauma exposure with those who did not (final s le size range: 24,094-92,957). Depression was heritable in participants reporting trauma exposure and in unexposed in iduals, and the genetic correlation between the groups was substantial and not significantly different from 1. Genetic correlations between depression and psychiatric traits were strong regardless of reported trauma exposure, whereas genetic correlations between depression and body mass index (and related phenotypes) were observed only in trauma exposed in iduals. The narrower range of genetic correlations in trauma unexposed depression and the lack of correlation with BMI echoes earlier ideas of endogenous depression.
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: 25-08-2013
DOI: 10.1038/NG.2742
Publisher: Elsevier BV
Date: 02-2017
Publisher: Cambridge University Press (CUP)
Date: 21-09-2022
DOI: 10.1017/S0033291722002720
Abstract: Major depressive disorder (MDD) was previously associated with negative affective biases. Evidence from larger population-based studies, however, is lacking, including whether biases normalise with remission. We investigated associations between affective bias measures and depressive symptom severity across a large community-based s le, followed by examining differences between remitted in iduals and controls. Participants from Generation Scotland ( N = 1109) completed the: (i) Bristol Emotion Recognition Task (BERT), (ii) Face Affective Go/No-go (FAGN), and (iii) Cambridge Gambling Task (CGT). In iduals were classified as MDD-current ( n = 43), MDD-remitted ( n = 282), or controls ( n = 784). Analyses included using affective bias summary measures (primary analyses), followed by detailed emotion/condition analyses of BERT and FAGN (secondary analyses). For summary measures, the only significant finding was an association between greater symptoms and lower risk adjustment for CGT across the s le (in iduals with greater symptoms were less likely to bet more, despite increasingly favourable conditions). This was no longer significant when controlling for non-affective cognition. No differences were found for remitted-MDD v. controls. Detailed analysis of BERT and FAGN indicated subtle negative biases across multiple measures of affective cognition with increasing symptom severity, that were independent of non-effective cognition [e.g. greater tendency to rate faces as angry (BERT), and lower accuracy for happy/neutral conditions (FAGN)]. Results for remitted-MDD were inconsistent. This suggests the presence of subtle negative affective biases at the level of emotion/condition in association with depressive symptoms across the s le, over and above those accounted for by non-affective cognition, with no evidence for affective biases in remitted in iduals.
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: 08-12-2020
DOI: 10.1038/S41398-020-01109-5
Abstract: It has been difficult to find robust brain structural correlates of the overall severity of major depressive disorder (MDD). We hypothesized that specific symptoms may better reveal correlates and investigated this for the severity of insomnia, both a key symptom and a modifiable major risk factor of MDD. Cortical thickness, surface area and subcortical volumes were assessed from T1-weighted brain magnetic resonance imaging (MRI) scans of 1053 MDD patients (age range 13-79 years) from 15 cohorts within the ENIGMA MDD Working Group. Insomnia severity was measured by summing the insomnia items of the Hamilton Depression Rating Scale (HDRS). Symptom specificity was evaluated with correlates of overall depression severity. Disease specificity was evaluated in two independent s les comprising 2108 healthy controls, and in 260 clinical controls with bipolar disorder. Results showed that MDD patients with more severe insomnia had a smaller cortical surface area, mostly driven by the right insula, left inferior frontal gyrus pars triangularis, left frontal pole, right superior parietal cortex, right medial orbitofrontal cortex, and right supramarginal gyrus. Associations were specific for insomnia severity, and were not found for overall depression severity. Associations were also specific to MDD healthy controls and clinical controls showed differential insomnia severity association profiles. The findings indicate that MDD patients with more severe insomnia show smaller surfaces in several frontoparietal cortical areas. While explained variance remains small, symptom-specific associations could bring us closer to clues on underlying biological phenomena of MDD.
Publisher: Springer Science and Business Media LLC
Date: 16-03-2200
DOI: 10.1038/S41380-020-0689-5
Abstract: Lithium is a first-line medication for bipolar disorder (BD), but only one in three patients respond optimally to the drug. Since evidence shows a strong clinical and genetic overlap between depression and bipolar disorder, we investigated whether a polygenic susceptibility to major depression is associated with response to lithium treatment in patients with BD. Weighted polygenic scores (PGSs) were computed for major depression (MD) at different GWAS p value thresholds using genetic data obtained from 2586 bipolar patients who received lithium treatment and took part in the Consortium on Lithium Genetics (ConLi
Publisher: Springer Science and Business Media LLC
Date: 25-02-2019
Publisher: Cambridge University Press (CUP)
Date: 15-02-2013
DOI: 10.1017/S0033291713000196
Abstract: Schizophrenia is associated with lower pre-morbid intelligence (IQ) in addition to (pre-morbid) cognitive decline. Both schizophrenia and IQ are highly heritable traits. Therefore, we hypothesized that genetic variants associated with schizophrenia, including copy number variants (CNVs) and a polygenic schizophrenia (risk) score (PSS), may influence intelligence. IQ was estimated with the Wechsler Adult Intelligence Scale (WAIS). CNVs were determined from single nucleotide polymorphism (SNP) data using the QuantiSNP and PennCNV algorithms. For the PSS, odds ratios for genome-wide SNP data were calculated in a s le collected by the Psychiatric Genome-Wide Association Study (GWAS) Consortium (8690 schizophrenia patients and 11 831 controls). These were used to calculate in idual PSSs in our independent s le of 350 schizophrenia patients and 322 healthy controls. Although significantly more genes were disrupted by deletions in schizophrenia patients compared to controls ( p = 0.009), there was no effect of CNV measures on IQ. The PSS was associated with disease status ( R 2 = 0.055, p = 2.1 × 10 −7 ) and with IQ in the entire s le ( R 2 = 0.018, p = 0.0008) but the effect on IQ disappeared after correction for disease status. Our data suggest that rare and common schizophrenia-associated variants do not explain the variation in IQ in healthy subjects or in schizophrenia patients. Thus, reductions in IQ in schizophrenia patients may be secondary to other processes related to schizophrenia risk.
Publisher: Frontiers Media SA
Date: 09-05-2019
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: 16-09-2019
DOI: 10.1038/S41386-019-0521-6
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Publisher: Springer Science and Business Media LLC
Date: 05-06-2015
DOI: 10.1038/NCOMMS8074
Abstract: The analysis of in iduals with ciliary chondrodysplasias can shed light on sensitive mechanisms controlling ciliogenesis and cell signalling that are essential to embryonic development and survival. Here we identify TCTEX1D2 mutations causing Jeune asphyxiating thoracic dystrophy with partially penetrant inheritance. Loss of TCTEX1D2 impairs retrograde intraflagellar transport (IFT) in humans and the protist Chlamydomonas , accompanied by destabilization of the retrograde IFT dynein motor. We thus define TCTEX1D2 as an integral component of the evolutionarily conserved retrograde IFT machinery. In complex with several IFT dynein light chains, it is required for correct vertebrate skeletal formation but may be functionally redundant under certain conditions.
Publisher: Elsevier BV
Date: 08-2021
Publisher: Royal College of Psychiatrists
Date: 19-04-2018
DOI: 10.1192/BJO.2018.19
Publisher: Cold Spring Harbor Laboratory
Date: 16-04-2021
DOI: 10.1101/2021.04.16.21251163
Abstract: Studying the phenotypic and genetic characteristics of age and polarity at onset (AAO, PAO) in bipolar disorder (BD) can provide new insights into disease pathology and facilitate the development of screening tools. To examine the genetic architecture of AAO and PAO and their association with BD disease characteristics. Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (N=12977) and PAO (N=6773) were conducted in BD patients of 34 cohorts and a replication s le (N=2237). The association of onset with disease characteristics was investigated in two of these cohorts. Earlier AAO was associated with an increased risk of psychotic symptoms, suicidality, and fewer episodes. A depressive onset correlated with lifetime suicidality and a manic onset with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in SNV-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased polygenic scores for autism spectrum disorder (β=-0.34 years, SE=0.08), major depression (β=-0.34 years, SE=0.08), schizophrenia (β=-0.39 years, SE=0.08), and educational attainment (β=-0.31 years, SE=0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO. AAO and PAO are associated with indicators of BD severity. In iduals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents, and phenotype definitions introduce significant heterogeneity, affecting analyses. In the largest study to systematically characterize age at onset (N=12977) and polarity at onset (N=6773) in bipolar disorder, we describe an association between illness onset characteristics and indicators of severity, confirming their clinical relevance. Our study shows that that early illness onset is associated with genetic liability for a broad range of psychiatric disorders. However, we also highlight systematic differences in age at onset across cohorts, continents, and phenotype definitions. This heterogeneity results in reduced heritability and affects genetic analyses, underscoring the need for the development of standardized phenotype definitions.
Publisher: Springer Science and Business Media LLC
Date: 29-07-2019
Publisher: Cambridge University Press (CUP)
Date: 29-11-2017
DOI: 10.1017/S0033291717003415
Abstract: Polygenic risk scores (PRS) for depression correlate with depression status and chronicity, and provide causal anchors to identify depressive mechanisms. Neuroticism is phenotypically and genetically positively associated with depression, whereas psychological resilience demonstrates negative phenotypic associations. Whether increased neuroticism and reduced resilience are downstream mediators of genetic risk for depression, and whether they contribute independently to risk remains unknown. Moderating and mediating relationships between depression PRS, neuroticism, resilience and both clinical and self-reported depression were examined in a large, population-based cohort, Generation Scotland: Scottish Family Health Study ( N = 4166), using linear regression and structural equation modelling. Neuroticism and resilience were measured by the Eysenck Personality Scale Short Form Revised and the Brief Resilience Scale, respectively. PRS for depression was associated with increased likelihood of self-reported and clinical depression. No interaction was found between PRS and neuroticism, or between PRS and resilience. Neuroticism was associated with increased likelihood of self-reported and clinical depression, whereas resilience was associated with reduced risk. Structural equation modelling suggested the association between PRS and self-reported and clinical depression was mediated by neuroticism (43–57%), while resilience mediated the association in the opposite direction (37–40%). For both self-reported and clinical diagnoses, the genetic risk for depression was independently mediated by neuroticism and resilience. Findings suggest polygenic risk for depression increases vulnerability for self-reported and clinical depression through independent effects on increased neuroticism and reduced psychological resilience. In addition, two partially independent mechanisms – neuroticism and resilience – may form part of the pathway of vulnerability to depression.
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: Springer Science and Business Media LLC
Date: 31-07-2020
DOI: 10.1186/S13148-020-00905-6
Abstract: In iduals of the same chronological age display different rates of biological ageing. A number of measures of biological age have been proposed which harness age-related changes in DNA methylation profiles. These measures include five ‘epigenetic clocks’ which provide an index of how much an in idual’s biological age differs from their chronological age at the time of measurement. The five clocks encompass methylation-based predictors of chronological age (HorvathAge, HannumAge), all-cause mortality (DNAm PhenoAge, DNAm GrimAge) and telomere length (DNAm Telomere Length). A sixth epigenetic measure of ageing differs from these clocks in that it acts as a speedometer providing a single time-point measurement of the pace of an in idual’s biological ageing. This measure of ageing is termed DunedinPoAm. In this study, we test the association between these six epigenetic measures of ageing and the prevalence and incidence of the leading causes of disease burden and mortality in high-income countries ( n ≤ 9537, Generation Scotland: Scottish Family Health Study). DNAm GrimAge predicted incidence of clinically diagnosed chronic obstructive pulmonary disease (COPD), type 2 diabetes and ischemic heart disease after 13 years of follow-up (hazard ratios = 2.22, 1.52 and 1.41, respectively). DunedinPoAm predicted the incidence of COPD and lung cancer (hazard ratios = 2.02 and 1.45, respectively). DNAm PhenoAge predicted incidence of type 2 diabetes (hazard ratio = 1.54). DNAm Telomere Length associated with the incidence of ischemic heart disease (hazard ratio = 0.80). DNAm GrimAge associated with all-cause mortality, the prevalence of COPD and spirometry measures at the study baseline. These associations were present after adjusting for possible confounding risk factors including alcohol consumption, body mass index, deprivation, education and tobacco smoking and surpassed stringent Bonferroni-corrected significance thresholds. Our data suggest that epigenetic measures of ageing may have utility in clinical settings to complement gold-standard methods for disease assessment and management.
Publisher: Springer Science and Business Media LLC
Date: 23-08-2019
Publisher: Springer Science and Business Media LLC
Date: 06-09-2019
DOI: 10.1038/S41380-019-0463-8
Abstract: Based on the discovery by the Resilience Project (Chen R. et al. Nat Biotechnol 34:531–538, 2016) of rare variants that confer resistance to Mendelian disease, and protective alleles for some complex diseases, we posited the existence of genetic variants that promote resilience to highly heritable polygenic disorders1,0 such as schizophrenia. Resilience has been traditionally viewed as a psychological construct, although our use of the term resilience refers to a different construct that directly relates to the Resilience Project, namely: heritable variation that promotes resistance to disease by reducing the penetrance of risk loci, wherein resilience and risk loci operate orthogonal to one another. In this study, we established a procedure to identify unaffected in iduals with relatively high polygenic risk for schizophrenia, and contrasted them with risk-matched schizophrenia cases to generate the first known “polygenic resilience score” that represents the additive contributions to SZ resistance by variants that are distinct from risk loci. The resilience score was derived from data compiled by the Psychiatric Genomics Consortium, and replicated in three independent s les. This work establishes a generalizable framework for finding resilience variants for any complex, heritable disorder.
Publisher: Springer Science and Business Media LLC
Date: 22-06-2021
Publisher: Springer Science and Business Media LLC
Date: 30-06-2015
DOI: 10.1038/MP.2015.69
Publisher: Springer Science and Business Media LLC
Date: 11-05-2020
Publisher: Springer Science and Business Media LLC
Date: 11-11-2019
DOI: 10.1038/S41380-019-0558-2
Abstract: Multiplex families with a high prevalence of a psychiatric disorder are often examined to identify rare genetic variants with large effect sizes. In the present study, we analysed whether the risk for bipolar disorder (BD) in BD multiplex families is influenced by common genetic variants. Furthermore, we investigated whether this risk is conferred mainly by BD-specific risk variants or by variants also associated with the susceptibility to schizophrenia or major depression. In total, 395 in iduals from 33 Andalusian BD multiplex families (166 BD, 78 major depressive disorder, 151 unaffected) as well as 438 subjects from an independent, BD case/control cohort (161 unrelated BD, 277 unrelated controls) were analysed. Polygenic risk scores (PRS) for BD, schizophrenia (SCZ), and major depression were calculated and compared between the cohorts. Both the familial BD cases and unaffected family members had higher PRS for all three psychiatric disorders than the independent controls, with BD and SCZ being significant after correction for multiple testing, suggesting a high baseline risk for several psychiatric disorders in the families. Moreover, familial BD cases showed significantly higher BD PRS than unaffected family members and unrelated BD cases. A plausible hypothesis is that, in multiplex families with a general increase in risk for psychiatric disease, BD development is attributable to a high burden of common variants that confer a specific risk for BD. The present analyses demonstrated that common genetic risk variants for psychiatric disorders are likely to contribute to the high incidence of affective psychiatric disorders in the multiplex families. However, the PRS explained only part of the observed phenotypic variance, and rare variants might have also contributed to disease development.
Publisher: Springer Science and Business Media LLC
Date: 06-04-2023
Publisher: Springer Science and Business Media LLC
Date: 28-03-2017
DOI: 10.1038/TP.2016.292
Abstract: Major depressive disorder (MDD) is a common, complex psychiatric disorder and a leading cause of disability worldwide. Despite twin studies indicating its modest heritability (~30–40%), extensive heterogeneity and a complex genetic architecture have complicated efforts to detect associated genetic risk variants. We combined single-nucleotide polymorphism (SNP) summary statistics from the CONVERGE and PGC studies of MDD, representing 10 502 Chinese (5282 cases and 5220 controls) and 18 663 European (9447 cases and 9215 controls) subjects. We determined the fraction of SNPs displaying consistent directions of effect, assessed the significance of polygenic risk scores and estimated the genetic correlation of MDD across ancestries. Subsequent trans-ancestry meta-analyses combined SNP-level evidence of association. Sign tests and polygenic score profiling weakly support an overlap of SNP effects between East Asian and European populations. We estimated the trans-ancestry genetic correlation of lifetime MDD as 0.33 female-only and recurrent MDD yielded estimates of 0.40 and 0.41, respectively. Common variants downstream of GPHN achieved genome-wide significance by Bayesian trans-ancestry meta-analysis (rs9323497 log 10 Bayes Factor=8.08) but failed to replicate in an independent European s le ( P =0.911). Gene-set enrichment analyses indicate enrichment of genes involved in neuronal development and axonal trafficking. We successfully demonstrate a partially shared polygenic basis of MDD in East Asian and European populations. Taken together, these findings support a complex etiology for MDD and possible population differences in predisposing genetic factors, with important implications for future genetic studies.
Publisher: Springer Science and Business Media LLC
Date: 06-10-2022
DOI: 10.1038/S43856-022-00189-2
Abstract: Newborn heel prick blood spots are routinely used to screen for inborn errors of metabolism and life-limiting inherited disorders. The potential value of secondary data from newborn blood spot archives merits ethical consideration and assessment of feasibility for public benefit. Early life exposures and behaviours set health trajectories in childhood and later life. The newborn blood spot is potentially well placed to create an unbiased and cost-effective population-level retrospective birth cohort study. Scotland has retained newborn blood spots for all children born since 1965, around 3 million in total. However, a moratorium on research access is currently in place, pending public consultation. We conducted a Citizens’ Jury as a first step to explore whether research use of newborn blood spots was in the public interest. We also assessed the feasibility and value of extracting research data from dried blood spots for predictive medicine. Jurors delivered an agreed verdict that conditional research access to the newborn blood spots was in the public interest. The Chief Medical Officer for Scotland authorised restricted lifting of the current research moratorium to allow a feasibility study. Newborn blood spots from consented Generation Scotland volunteers were retrieved and their potential for both epidemiological and biological research demonstrated. Through the Citizens’ Jury, we have begun to identify under what conditions, if any, should researchers in Scotland be granted access to the archive. Through the feasibility study, we have demonstrated the potential value of research access for health data science and predictive medicine.
Publisher: Royal College of Psychiatrists
Date: 03-04-2018
DOI: 10.1192/BJO.2018.12
Abstract: UK Biobank is a well-characterised cohort of over 500 000 participants that offers unique opportunities to investigate multiple diseases and risk factors. An online mental health questionnaire completed by UK Biobank participants was expected to expand the potential for research into mental disorders. An expert working group designed the questionnaire, using established measures where possible, and consulting with a patient group regarding acceptability. Case definitions were defined using operational criteria for lifetime depression, mania, anxiety disorder, psychotic-like experiences and self-harm, as well as current post-traumatic stress and alcohol use disorders. 157 366 completed online questionnaires were available by August 2017. Comparison of self-reported diagnosed mental disorder with a contemporary study shows a similar prevalence, despite respondents being of higher average socioeconomic status than the general population across a range of indicators. Thirty-five per cent (55 750) of participants had at least one defined syndrome, of which lifetime depression was the most common at 24% (37 434). There was extensive comorbidity among the syndromes. Mental disorders were associated with high neuroticism score, adverse life events and long-term illness addiction and bipolar affective disorder in particular were associated with measures of deprivation. The questionnaire represents a very large mental health survey in itself, and the results presented here show high face validity, although caution is needed owing to selection bias. Built into UK Biobank, these data intersect with other health data to offer unparalleled potential for crosscutting biomedical research involving mental health. G.B. received grants from the National Institute for Health Research during the study and support from Illumina Ltd. and the European Commission outside the submitted work. B.C. received grants from the Scottish Executive Chief Scientist Office and from The Dr Mortimer and Theresa Sackler Foundation during the study. C.S. received grants from the Medical Research Council and Wellcome Trust during the study, and is the Chief Scientist for UK Biobank. M.H. received grants from the Innovative Medicines Initiative via the RADAR-CNS programme and personal fees as an expert witness outside the submitted work.
Publisher: Springer Science and Business Media LLC
Date: 19-03-2018
DOI: 10.1038/S41537-018-0047-7
Abstract: Recent work has highlighted a possible role for altered epigenetic modifications, including differential DNA methylation, in susceptibility to psychiatric illness. Here, we investigate blood-based DNA methylation in a large family where a balanced translocation between chromosomes 1 and 11 shows genome-wide significant linkage to psychiatric illness. Genome-wide DNA methylation was profiled in whole-blood-derived DNA from 41 in iduals using the Infinium HumanMethylation450 BeadChip (Illumina Inc., San Diego, CA). We found significant differences in DNA methylation when translocation carriers ( n = 17) were compared to related non-carriers ( n = 24) at 13 loci. All but one of the 13 significant differentially methylated positions (DMPs) mapped to the regions surrounding the translocation breakpoints. Methylation levels of five DMPs were associated with genotype at SNPs in linkage disequilibrium with the translocation. Two of the five genes harbouring significant DMPs, DISC1 and DUSP10 , have been previously shown to be differentially methylated in schizophrenia. Gene Ontology analysis revealed enrichment for terms relating to neuronal function and neurodevelopment among the genes harbouring the most significant DMPs. Differentially methylated region (DMR) analysis highlighted a number of genes from the MHC region, which has been implicated in psychiatric illness previously through genetic studies. We show that inheritance of a translocation linked to major mental illness is associated with differential DNA methylation at loci implicated in neuronal development/function and in psychiatric illness. As genomic rearrangements are over-represented in in iduals with psychiatric illness, such analyses may be valuable more widely in the study of these conditions.
Publisher: Springer Science and Business Media LLC
Date: 08-05-2020
DOI: 10.1038/S41467-020-16022-0
Abstract: Depression is a leading cause of worldwide disability but there remains considerable uncertainty regarding its neural and behavioural associations. Here, using non-overlapping Psychiatric Genomics Consortium (PGC) datasets as a reference, we estimate polygenic risk scores for depression (depression-PRS) in a discovery ( N = 10,674) and replication ( N = 11,214) imaging s le from UK Biobank. We report 77 traits that are significantly associated with depression-PRS, in both discovery and replication analyses. Mendelian Randomisation analysis supports a potential causal effect of liability to depression on brain white matter microstructure ( β : 0.125 to 0.868, p FDR 0.043). Several behavioural traits are also associated with depression-PRS ( β : 0.014 to 0.180, p FDR : 0.049 to 1.28 × 10 −14 ) and we find a significant and positive interaction between depression-PRS and adverse environmental exposures on mental health outcomes. This study reveals replicable associations between depression-PRS and white matter microstructure. Our results indicate that white matter microstructure differences may be a causal consequence of liability to depression.
Publisher: Elsevier BV
Date: 12-2019
Publisher: Cold Spring Harbor Laboratory
Date: 12-09-2022
DOI: 10.1101/2022.09.08.507115
Abstract: Epigenetic clocks can track both chronological age (cAge) and biological age (bAge). The latter is typically defined by physiological biomarkers and risk of adverse health outcomes, including all-cause mortality. As cohort s le sizes increase, estimates of cAge and bAge become more precise. Here, we aim to refine predictors and improve understanding of the epigenomic architecture of cAge and bAge. First, we perform large-scale (N = 18,413) epigenome-wide association studies (EWAS) of chronological age and all-cause mortality. Next, to improve cAge prediction, we use methylation data from 24,673 participants from the Generation Scotland (GS) study, the Lothian Birth Cohorts (LBC) of 1921 and 1936 and 8 publicly available datasets. Through the inclusion of linear and non-linear age-CpG associations from the EWAS, feature pre-selection/dimensionality reduction in advance of elastic net regression, and a leave-one-cohort-out (LOCO) cross validation framework, we arrive at an improved cAge predictor (median absolute error = 2.3 years across 10 cohorts). In addition, we train a predictor of bAge on 1,214 all-cause mortality events in GS, based on epigenetic surrogates for 109 plasma proteins and the 8 component parts of GrimAge, the current best epigenetic predictor of all-cause mortality. We test this predictor in four external cohorts (LBC1921, LBC1936, the Framingham Heart Study and the Women’s Health Initiative study) where it outperforms GrimAge in its association to survival (HR GrimAge = 1.47 [1.40, 1.54] with p = 1.08 × 10 −52 , and HR bAge = 1.52 [1.44, 1.59] with p = 2.20 × 10 −60 ). Finally, we introduce MethylBrowsR, an online tool to visualize epigenome-wide CpG-age associations.
Publisher: Springer Science and Business Media LLC
Date: 04-02-2019
Publisher: Cold Spring Harbor Laboratory
Date: 03-06-2019
DOI: 10.1101/657163
Abstract: Although the underlying neurobiology of major mental illness (MMI) remains unknown, emerging evidence implicates a role for oligodendrocyte-myelin abnormalities. Here, we took advantage of a large family carrying a balanced t(1 ) translocation, which substantially increases risk of MMI, to undertake both diffusion tensor imaging (DTI) and cellular studies to evaluate the consequences of the t(1 ) translocation on white matter structural integrity and oligodendrocyte-myelin biology. This translocation disrupts among others the DISC1 gene which plays a crucial role in brain development. We show that translocation-carrying patients display significant disruption in white matter integrity compared to familial controls. At a cellular level, we observe dysregulation of key pathways controlling oligodendrocyte development and morphogenesis in induced pluripotent stem cell (iPSC) case derived oligodendrocytes. This is associated with reduced proliferation and a stunted morphology in vitro . Further, myelin internodes in a humanized mouse model that recapitulates the human translocation as well as after transplantation of t(1 ) oligodendrocyte progenitors were significantly reduced compared to controls. Thus we provide evidence that the t(1 ) translocation has biological effects at both the systems and cellular level that together suggest oligodendrocyte-myelin dysfunction.
Publisher: Royal College of Psychiatrists
Date: 25-08-2021
DOI: 10.1192/BJP.2021.102
Abstract: Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools. To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics. Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO ( n = 12 977) and PAO ( n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication s le ( n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts. Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO. AAO and PAO are associated with indicators of bipolar disorder severity. In iduals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.
Publisher: Springer Science and Business Media LLC
Date: 29-09-2021
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: 18-01-2019
DOI: 10.1038/S41398-018-0356-7
Abstract: Depression has well-established influences from genetic and environmental risk factors. This has led to the diathesis-stress theory, which assumes a multiplicative gene-by-environment interaction (GxE) effect on risk. Recently, Colodro-Conde et al . empirically tested this theory, using the polygenic risk score for major depressive disorder (PRS, genes) and stressful life events (SLE, environment) effects on depressive symptoms, identifying significant GxE effects with an additive contribution to liability. We have tested the diathesis-stress theory on an independent s le of 4919 in iduals. We identified nominally significant positive GxE effects in the full cohort ( R 2 = 0.08%, p = 0.049) and in women ( R 2 = 0.19%, p = 0.017), but not in men ( R 2 = 0.15%, p = 0.07). GxE effects were nominally significant, but only in women, when SLE were split into those in which the respondent plays an active or passive role ( R 2 = 0.15%, p = 0.038 R 2 = 0.16%, p = 0.033, respectively). High PRS increased the risk of depression in participants reporting high numbers of SLE ( p = 2.86 × 10 −4 ). However, in those participants who reported no recent SLE, a higher PRS appeared to increase the risk of depressive symptoms in men ( β = 0.082, p = 0.016) but had a protective effect in women ( β = −0.061, p = 0.037). This difference was nominally significant ( p = 0.017). Our study reinforces the evidence of additional risk in the aetiology of depression due to GxE effects. However, larger s le sizes are required to robustly validate these findings.
Publisher: Springer Science and Business Media LLC
Date: 09-01-2019
Publisher: Wiley
Date: 02-2019
DOI: 10.1002/AJMG.B.32713
Publisher: Springer Science and Business Media LLC
Date: 10-03-2015
DOI: 10.1038/MP.2015.12
Publisher: Springer Science and Business Media LLC
Date: 18-09-2011
DOI: 10.1038/NG.940
Publisher: Springer Science and Business Media LLC
Date: 23-10-2019
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: Wiley
Date: 23-02-2019
DOI: 10.1002/AJMG.B.32716
Publisher: Springer Science and Business Media LLC
Date: 04-04-2023
DOI: 10.1038/S41398-023-02403-8
Abstract: Observational studies and randomized controlled trials presented inconsistent findings on the effects of cholesterol-lowering statins on depression. It therefore remains unclear whether statins have any beneficial effects on depression, and if so, what the underlying molecular mechanisms are. Here, we aimed to use genomic approaches to investigate this further. Using Connectivity Map (CMap), we first investigated whether statins and antidepressants shared pharmacological effects by interrogating gene expression responses to drug exposure in human cell lines. Second, using Mendelian randomization analysis, we investigated both on-target (through HMGCR inhibition) and potential off-target (through ITGAL and HDAC2 inhibition) causal effects of statins on depression risk and depressive symptoms, and traits related to the shared biological pathways identified from CMap analysis. Compounds inducing highly similar gene expression responses to statins in HA1E cells (indicated by an average connectivity score with statins 90) were found to be enriched for antidepressants (12 out of 38 antidepressants p = 9E-08). Genes perturbed in the same direction by both statins and antidepressants were significantly enriched for erse cellular and metabolic pathways, and various immune activation, development and response processes. MR analysis did not identify any significant associations between statin exposure and depression risk or symptoms after multiple testing correction. However, genetically proxied HMGCR inhibition was strongly associated with alterations in platelets (a prominent serotonin reservoir) and monocyte percentage, which have previously been implicated in depression. Genetically proxied ITGAL inhibition was strongly associated with basophil, monocyte and neutrophil counts. We identified biological pathways that are commonly perturbed by both statins and antidepressants, and haematological biomarkers genetically associated with statin targets. Our findings warrant pre-clinical investigation of the causal role of these shared pathways in depression and potential as therapeutic targets, and investigation of whether blood biomarkers may be important considerations in clinical trials investigating effects of statins on depression.
Publisher: Springer Science and Business Media LLC
Date: 03-05-2016
DOI: 10.1038/MP.2016.60
Publisher: Springer Science and Business Media LLC
Date: 28-11-2019
DOI: 10.1038/S41398-019-0657-5
Abstract: The identification of biomarkers that discriminate in idual ageing trajectories is a principal target of ageing research. Some of the most promising predictors of biological ageing have been developed using DNA methylation. One recent candidate, which tracks age-related phenotypes in addition to chronological age, is ‘DNAm PhenoAge’. Here, we performed a phenome-wide association analysis of this biomarker in a cohort of older adults to assess its relationship with a comprehensive set of both historical, and contemporaneously-measured, phenotypes. Higher than expected DNAm PhenoAge compared with chronological age, known as epigenetic age acceleration, was found to associate with a number of blood, cognitive, physical fitness and lifestyle variables, and with mortality. Notably, DNAm PhenoAge, assessed at age 70, was associated with cognitive ability at age 11, and with educational attainment. Adjusting for age 11 cognitive ability attenuated the majority of the cross-sectional later-life associations between DNAm PhenoAge and health outcomes. These results highlight the importance of early life factors on healthy older ageing.
Publisher: Springer Science and Business Media LLC
Date: 03-09-2019
Publisher: Springer Science and Business Media LLC
Date: 24-05-2020
DOI: 10.1038/S41398-020-0848-0
Abstract: Depression is a common and clinically heterogeneous mental health disorder that is frequently comorbid with other diseases and conditions. Stratification of depression may align sub-diagnoses more closely with their underling aetiology and provide more tractable targets for research and effective treatment. In the current study, we investigated whether genetic data could be used to identify subgroups within people with depression using the UK Biobank. Examination of cross-locus correlations were used to test for evidence of subgroups using genetic data from seven other complex traits and disorders that were genetically correlated with depression and had sufficient power ( .6) for detection. We found no evidence for subgroups within depression for schizophrenia, bipolar disorder, attention deficit/hyperactivity disorder, autism spectrum disorder, anorexia nervosa, inflammatory bowel disease or obesity. This suggests that for these traits, genetic correlations with depression were driven by pleiotropic genetic variants carried by everyone rather than by a specific subgroup.
Publisher: Elsevier BV
Date: 09-2017
Publisher: Springer Science and Business Media LLC
Date: 21-03-2017
DOI: 10.1038/NCOMMS14774
Abstract: We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique in iduals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05–21.6 P =1 × 10 −4 ) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS ( P =8.4 × 10 −7 ). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08–1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.
Publisher: Cold Spring Harbor Laboratory
Date: 05-08-2019
DOI: 10.1101/19001214
Abstract: This paper corrects and updates a paper published in BJPsych Open 2018 “Mental Health in UK Biobank” ( 0.1192/bjo.2018.12 ) that was voluntarily retracted following the finding of errors in the coding of the variable for alcohol use disorder. Notably, the percentage of participants reaching threshold for alcohol use disorder on the Alcohol Use Disorder Identification Tool increased from 7% to 21%. UK Biobank is a well-characterised cohort of over 500,000 participants that offers unique opportunities to investigate multiple diseases and risk factors. An online mental health questionnaire completed by UK Biobank participants expands the potential for research into mental disorders. An expert working group designed the questionnaire, using established measures where possible, and consulting with a service user group regarding acceptability. Operational criteria were agreed for defining likely disorder and risk states, including lifetime depression, mania/hypomania, generalised anxiety disorder, unusual experiences and self-harm, and current post-traumatic stress and alcohol use disorders. 157,366 completed online questionnaires were available by August 2017. Comparison of self-reported diagnosed mental disorder with a contemporary study shows a similar prevalence, despite respondents being of higher average socioeconomic status. Lifetime depression was the most common finding in 24% of participants (37,434), with current alcohol use disorder criteria met by 21% (32,602), while other criteria were met by less than 8% of the participants. There was extensive comorbidity among the syndromes. Mental disorders were associated with a high neuroticism score, adverse life events and long-term illness addiction and bipolar affective disorder in particular were associated with measures of deprivation. The questionnaire represents a very large mental health survey in itself, and the results presented here show high face validity, although caution is needed due to selection bias. Built into UK Biobank, these data intersect with other health data to offer unparalleled potential for crosscutting biomedical research involving mental health.
Publisher: Cold Spring Harbor Laboratory
Date: 06-09-2021
DOI: 10.1101/2021.09.03.21263066
Abstract: Characterising associations between the methylome, proteome and phenome may provide insight into biological pathways governing brain health. Here, we report an integrated DNA methylation and phenotypic study of the circulating proteome in relation to brain health. Methylome-wide association studies of 4,058 plasma proteins are performed (N=774), identifying 2,928 CpG-protein associations after adjustment for multiple testing. These were independent of known genetic protein quantitative trait loci (pQTLs) and common lifestyle effects. Phenome-wide association studies of each protein are then performed in relation to 15 neurological traits (N=1,065), identifying 405 associations between the levels of 191 proteins and cognitive scores, brain imaging measures or APOE e4 status. We uncover 35 previously unreported DNA methylation signatures for 17 protein markers of brain health. The epigenetic and proteomic markers we identify are pertinent to understanding and stratifying brain health.
Publisher: Springer Science and Business Media LLC
Date: 11-08-2202
DOI: 10.1038/NG.2711
Publisher: Springer Science and Business Media LLC
Date: 09-08-2022
DOI: 10.1038/S41467-022-32319-8
Abstract: Characterising associations between the methylome, proteome and phenome may provide insight into biological pathways governing brain health. Here, we report an integrated DNA methylation and phenotypic study of the circulating proteome in relation to brain health. Methylome-wide association studies of 4058 plasma proteins are performed ( N = 774), identifying 2928 CpG-protein associations after adjustment for multiple testing. These are independent of known genetic protein quantitative trait loci (pQTLs) and common lifestyle effects. Phenome-wide association studies of each protein are then performed in relation to 15 neurological traits ( N = 1,065), identifying 405 associations between the levels of 191 proteins and cognitive scores, brain imaging measures or APOE e4 status. We uncover 35 previously unreported DNA methylation signatures for 17 protein markers of brain health. The epigenetic and proteomic markers we identify are pertinent to understanding and stratifying brain health.
Publisher: Elsevier BV
Date: 12-2020
Publisher: Springer Science and Business Media LLC
Date: 24-05-2016
DOI: 10.1038/MP.2016.72
Publisher: Cold Spring Harbor Laboratory
Date: 09-08-2016
DOI: 10.1101/068593
Abstract: Schizophrenia is a debilitating psychiatric condition often associated with poor quality of life and decreased life expectancy. Lack of progress in improving treatment outcomes has been attributed to limited knowledge of the underlying biology, although large-scale genomic studies have begun to provide such insight. We report the largest single cohort genome-wide association study of schizophrenia (11,260 cases and 24,542 controls) and through meta-analysis with existing data we identify 50 novel GWAS loci. Using gene-wide association statistics we implicate an additional set of 22 novel associations that map onto a single gene. We show for the first time that the common variant association signal is highly enriched among genes that are intolerant to loss of function mutations and that variants in these genes persist in the population despite the low fecundity associated with the disorder through the process of background selection. Associations point to novel areas of biology (e.g. metabotropic GABA-B signalling and acetyl cholinesterase), reinforce those implicated in earlier GWAS studies (e.g. calcium channel function), converge with earlier rare variants studies (e.g. NRXN1, GABAergic signalling), identify novel overlaps with autism (e.g. RBFOX1, FOXP1, FOXG1), and support early controversial candidate gene hypotheses (e.g. ERBB4 implicating neuregulin signalling). We also demonstrate the involvement of six independent central nervous system functional gene sets in schizophrenia pathophysiology. These findings provide novel insights into the biology and genetic architecture of schizophrenia, highlight the importance of mutation intolerant genes and suggest a mechanism by which common risk variants are maintained in the population.
Publisher: Springer Science and Business Media LLC
Date: 30-08-2018
Publisher: Elsevier BV
Date: 11-2018
Publisher: Cold Spring Harbor Laboratory
Date: 21-11-2021
DOI: 10.1101/2021.11.19.21266469
Abstract: Type 2 diabetes mellitus (T2D) presents a major health and economic burden that could be alleviated with improved early prediction and intervention. While standard risk factors have shown good predictive performance, we show that the use of blood-based DNA methylation information leads to a significant improvement in the prediction of 10-year T2D incidence risk. Previous studies have been largely constrained by linear assumptions, the use of CpGs one-at-a-time, and binary outcomes. We present a flexible approach (via an R package, MethylPipeR ) based on a range of linear and tree-ensemble models that incorporate time-to-event data for prediction. Using the Generation Scotland cohort (training set n cases =374, n controls =9,461 test set n cases =252, n controls =4,526) our best-performing model (Area Under the Curve (AUC)=0.872, Precision Recall AUC (PRAUC)=0.302) showed notable improvement in 10-year onset prediction beyond standard risk factors (AUC=0.839, PRAUC=0.227). Replication was observed in the German-based KORA study (n=1,451, n cases = 142, p=1.6×10 -5 ).
Publisher: Public Library of Science (PLoS)
Date: 12-04-2012
Publisher: Elsevier BV
Date: 07-2020
Publisher: Elsevier BV
Date: 03-2020
Publisher: Public Library of Science (PLoS)
Date: 28-10-2016
Publisher: Wiley
Date: 19-10-2020
DOI: 10.1002/HBM.25249
Abstract: The hippoc us consists of anatomically and functionally distinct subfields that may be differentially involved in the pathophysiology of bipolar disorder (BD). Here we, the Enhancing NeuroImaging Genetics through Meta‐Analysis Bipolar Disorder workinggroup, study hippoc al subfield volumetry in BD. T1‐weighted magnetic resonance imaging scans from 4,698 in iduals (BD = 1,472, healthy controls [HC] = 3,226) from 23 sites worldwide were processed with FreeSurfer. We used linear mixed‐effects models and mega‐analysis to investigate differences in hippoc al subfield volumes between BD and HC, followed by analyses of clinical characteristics and medication use. BD showed significantly smaller volumes of the whole hippoc us (Cohen's d = −0.20), cornu ammonis (CA)1 ( d = −0.18), CA2/3 ( d = −0.11), CA4 ( d = −0.19), molecular layer ( d = −0.21), granule cell layer of dentate gyrus ( d = −0.21), hippoc al tail ( d = −0.10), subiculum ( d = −0.15), presubiculum ( d = −0.18), and hippoc al amygdala transition area ( d = −0.17) compared to HC. Lithium users did not show volume differences compared to HC, while non‐users did. Antipsychotics or antiepileptic use was associated with smaller volumes. In this largest study of hippoc al subfields in BD to date, we show widespread reductions in nine of 12 subfields studied. The associations were modulated by medication use and specifically the lack of differences between lithium users and HC supports a possible protective role of lithium in BD.
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: F1000 Research Ltd
Date: 16-07-2021
DOI: 10.12688/WELLCOMEOPENRES.15538.2
Abstract: STratifying Resilience and Depression Longitudinally (STRADL) is a population-based study built on the Generation Scotland: Scottish Family Health Study (GS:SFHS) resource. The aim of STRADL is to subtype major depressive disorder (MDD) on the basis of its aetiology, using detailed clinical, cognitive, and brain imaging assessments. The GS:SFHS provides an important opportunity to study complex gene-environment interactions, incorporating linkage to existing datasets and inclusion of early-life variables for two longitudinal birth cohorts. Specifically, data collection in STRADL included: socio-economic and lifestyle variables physical measures questionnaire data that assesses resilience, early-life adversity, personality, psychological health, and lifetime history of mood disorder laboratory s les cognitive tests and brain magnetic resonance imaging. Some of the questionnaire and cognitive data were first assessed at the GS:SFHS baseline assessment between 2006-2011, thus providing longitudinal measures relevant to the study of depression, psychological resilience, and cognition. In addition, routinely collected historic NHS data and early-life variables are linked to STRADL data, further providing opportunities for longitudinal analysis. Recruitment has been completed and we consented and tested 1,188 participants.
Publisher: American Medical Association (AMA)
Date: 04-2019
DOI: 10.1001/JAMAPSYCHIATRY.2018.4175
Abstract: Increasing evidence shows that physical activity is associated with reduced risk for depression, pointing to a potential modifiable target for prevention. However, the causality and direction of this association are not clear physical activity may protect against depression, and/or depression may result in decreased physical activity. To examine bidirectional relationships between physical activity and depression using a genetically informed method for assessing potential causal inference. This 2-s le mendelian randomization (MR) used independent top genetic variants associated with 2 physical activity phenotypes—self-reported (n = 377 234) and objective accelerometer-based (n = 91 084)—and with major depressive disorder (MDD) (n = 143 265) as genetic instruments from the largest available, nonoverlapping genome-wide association studies (GWAS). GWAS were previously conducted in erse observational cohorts, including the UK Biobank (for physical activity) and participating studies in the Psychiatric Genomics Consortium (for MDD) among adults of European ancestry. Mendelian randomization estimates from each genetic instrument were combined using inverse variance weighted meta-analysis, with alternate methods (eg, weighted median, MR Egger, MR–Pleiotropy Residual Sum and Outlier [PRESSO]) and multiple sensitivity analyses to assess horizontal pleiotropy and remove outliers. Data were analyzed from May 10 through July 31, 2018. MDD and physical activity. GWAS summary data were available for a combined s le size of 611 583 adult participants. Mendelian randomization evidence suggested a protective relationship between accelerometer-based activity and MDD (odds ratio [OR], 0.74 for MDD per 1-SD increase in mean acceleration 95% CI, 0.59-0.92 P = .006). In contrast, there was no statistically significant relationship between MDD and accelerometer-based activity (β = −0.08 in mean acceleration per MDD vs control status 95% CI, −0.47 to 0.32 P = .70). Furthermore, there was no significant relationship between self-reported activity and MDD (OR, 1.28 for MDD per 1-SD increase in metabolic-equivalent minutes of reported moderate-to-vigorous activity 95% CI, 0.57-3.37 P = .48), or between MDD and self-reported activity (β = 0.02 per MDD in standardized metabolic-equivalent minutes of reported moderate-to-vigorous activity per MDD vs control status 95% CI, −0.008 to 0.05 P = .15). Using genetic instruments identified from large-scale GWAS, robust evidence supports a protective relationship between objectively assessed—but not self-reported—physical activity and the risk for MDD. Findings point to the importance of objective measurement of physical activity in epidemiologic studies of mental health and support the hypothesis that enhancing physical activity may be an effective prevention strategy for depression.
Publisher: American Medical Association (AMA)
Date: 07-2014
Publisher: Springer Science and Business Media LLC
Date: 11-06-2019
DOI: 10.1038/S41467-019-10461-0
Abstract: Epigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function. While many studies have investigated either environmental or genetic contributions to DNAm, few have assessed their integrated effects. Here we examine the relative contributions of prenatal environmental factors and genotype on DNA methylation in neonatal blood at variably methylated regions (VMRs) in 4 independent cohorts (overall n = 2365). We use Akaike’s information criterion to test which factors best explain variability of methylation in the cohort-specific VMRs: several prenatal environmental factors (E), genotypes in cis (G), or their additive (G + E) or interaction (GxE) effects. Genetic and environmental factors in combination best explain DNAm at the majority of VMRs. The CpGs best explained by either G, G + E or GxE are functionally distinct. The enrichment of genetic variants from GxE models in GWAS for complex disorders supports their importance for disease risk.
Publisher: Springer Science and Business Media LLC
Date: 08-06-2020
DOI: 10.1038/S41467-020-16520-1
Abstract: Linking epigenetic marks to clinical outcomes improves insight into molecular processes, disease prediction, and therapeutic target identification. Here, a statistical approach is presented to infer the epigenetic architecture of complex disease, determine the variation captured by epigenetic effects, and estimate phenotype-epigenetic probe associations jointly. Implicitly adjusting for probe correlations, data structure (cell-count or relatedness), and single-nucleotide polymorphism (SNP) marker effects, improves association estimates and in 9,448 in iduals, 75.7% (95% CI 71.70–79.3) of body mass index (BMI) variation and 45.6% (95% CI 37.3–51.9) of cigarette consumption variation was captured by whole blood methylation array data. Pathway-linked probes of blood cholesterol, lipid transport and sterol metabolism for BMI, and xenobiotic stimuli response for smoking, showed .5 times larger associations with % posterior inclusion probability. Prediction accuracy improved by 28.7% for BMI and 10.2% for smoking over a LASSO model, with age-, and tissue-specificity, implying associations are a phenotypic consequence rather than causal.
Publisher: Springer Science and Business Media LLC
Date: 28-06-2019
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: Cold Spring Harbor Laboratory
Date: 28-10-2023
Publisher: Oxford University Press (OUP)
Date: 18-08-2015
DOI: 10.1093/IJE/DYV136
Publisher: Public Library of Science (PLoS)
Date: 20-12-2018
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: Elsevier BV
Date: 04-2019
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: 08-10-2018
DOI: 10.1038/S42003-018-0155-Y
Abstract: Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree ( n ~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected in iduals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders.
Publisher: Springer Science and Business Media LLC
Date: 18-05-2020
DOI: 10.1038/S41380-020-0754-0
Abstract: Major depressive disorder (MDD) is associated with an increased risk of brain atrophy, aging-related diseases, and mortality. We examined potential advanced brain aging in adult MDD patients, and whether this process is associated with clinical characteristics in a large multicenter international dataset. We performed a mega-analysis by pooling brain measures derived from T1-weighted MRI scans from 19 s les worldwide. Healthy brain aging was estimated by predicting chronological age (18–75 years) from 7 subcortical volumes, 34 cortical thickness and 34 surface area, lateral ventricles and total intracranial volume measures separately in 952 male and 1236 female controls from the ENIGMA MDD working group. The learned model coefficients were applied to 927 male controls and 986 depressed males, and 1199 female controls and 1689 depressed females to obtain independent unbiased brain-based age predictions. The difference between predicted “brain age” and chronological age was calculated to indicate brain-predicted age difference (brain-PAD). On average, MDD patients showed a higher brain-PAD of +1.08 (SE 0.22) years (Cohen’s d = 0.14, 95% CI: 0.08–0.20) compared with controls. However, this difference did not seem to be driven by specific clinical characteristics (recurrent status, remission status, antidepressant medication use, age of onset, or symptom severity). This highly powered collaborative effort showed subtle patterns of age-related structural brain abnormalities in MDD. Substantial within-group variance and overlap between groups were observed. Longitudinal studies of MDD and somatic health outcomes are needed to further assess the clinical value of these brain-PAD estimates.
Publisher: Elsevier BV
Date: 11-2016
Publisher: Springer Science and Business Media LLC
Date: 09-2021
Publisher: Elsevier BV
Date: 11-2018
Publisher: American Medical Association (AMA)
Date: 05-2019
Publisher: Springer Science and Business Media LLC
Date: 15-04-2012
DOI: 10.1038/NG.2250
Publisher: American Association for the Advancement of Science (AAAS)
Date: 22-06-2018
Abstract: Consistent classification of neuropsychiatric diseases is problematic because it can lead to misunderstanding of etiology. The Brainstorm Consortium examined multiple genome-wide association studies drawn from more than 200,000 patients for 25 brain-associated disorders and 17 phenotypes. Broadly, it appears that psychiatric and neurologic disorders share relatively little common genetic risk. However, different and independent pathways can result in similar clinical manifestations (e.g., psychosis, which occurs in both schizophrenia and Alzheimer's disease). Schizophrenia correlated with many psychiatric disorders, whereas the immunopathological affliction Crohn's disease did not, and posttraumatic stress syndrome was also largely independent of underlying traits. Essentially, the earlier the onset of a disorder, the more inheritable it appeared to be. Science , this issue p. eaap8757
Publisher: Springer Science and Business Media LLC
Date: 11-01-2018
Publisher: Cold Spring Harbor Laboratory
Date: 05-05-2017
DOI: 10.1101/134601
Abstract: Depression is a common and clinically heterogeneous mental health disorder that is frequently comorbid with other diseases and conditions. Stratification of depression may align sub-diagnoses more closely with their underling aetiology and provide more tractable targets for research and effective treatment. In the current study, we investigated whether genetic data could be used to identify subgroups within people with depression using the UK Biobank. Examination of cross-locus correlations was used to test for evidence of subgroups by examining whether there was clustering of independent genetic variants associated with eleven other complex traits and disorders in people with depression. We found evidence of a subgroup within depression using age of natural menopause variants ( P = 1.69 × 10 −3 ) and this effect remained significant in females ( P = 1.18 × 10 −3 ), but not males ( P = 0.186). However, no evidence for this subgroup ( P 0.05) was found in Generation Scotland, iPSYCH, a UK Biobank replication cohort or the GERA cohort. In the UK Biobank, having depression was also associated with a later age of menopause (beta = 0.34, standard error = 0.06, P = 9.92 × 10 −8 ). A potential age of natural menopause subgroup within depression and the association between depression and a later age of menopause suggests that they partially share a developmental pathway.
Publisher: Springer Science and Business Media LLC
Date: 27-07-2020
DOI: 10.1186/S13148-020-00903-8
Abstract: Chronic systemic inflammation has been associated with incident dementia, but its association with age-related cognitive decline is less clear. The acute responses of many inflammatory biomarkers mean they may provide an unreliable picture of the chronicity of inflammation. Recently, a large-scale epigenome-wide association study identified DNA methylation correlates of C-reactive protein (CRP)—a widely used acute-phase inflammatory biomarker. DNA methylation is thought to be relatively stable in the short term, marking it as a potentially useful signature of exposure. We utilise a DNA methylation-based score for CRP and investigate its trajectories with age, and associations with cognitive ability in comparison with serum CRP and a genetic CRP score in a longitudinal study of older adults ( n = 889) and a large, cross-sectional cohort ( n = 7028). We identified no homogeneous trajectories of serum CRP with age across the cohorts, whereas the epigenetic CRP score was consistently found to increase with age (standardised β = 0.07 and 0.01) and to do so more rapidly in males compared to females. Additionally, the epigenetic CRP score had higher test-retest reliability compared to serum CRP, indicating its enhanced temporal stability. Higher serum CRP was not found to be associated with poorer cognitive ability (standardised β = − 0.08 and − 0.05) however, a consistent negative association was identified between cognitive ability and the epigenetic CRP score in both cohorts (standardised β = − 0.15 and − 0.08). An epigenetic proxy of CRP may provide a more reliable signature of chronic inflammation, allowing for more accurate stratification of in iduals, and thus clearer inference of associations with incident health outcomes.
Publisher: American Psychiatric Association Publishing
Date: 12-2019
DOI: 10.1176/APPI.AJP.2019.18101144
Abstract: Asymmetry is a subtle but pervasive aspect of the human brain, and it may be altered in several psychiatric conditions. MRI studies have shown subtle differences of brain anatomy between people with major depressive disorder and healthy control subjects, but few studies have specifically examined brain anatomical asymmetry in relation to this disorder, and results from those studies have remained inconclusive. At the functional level, some electroencephalography studies have indicated left fronto-cortical hypoactivity and right parietal hypoactivity in depressive disorders, so aspects of lateralized anatomy may also be affected. The authors used pooled in idual-level data from data sets collected around the world to investigate differences in laterality in measures of cortical thickness, cortical surface area, and subcortical volume between in iduals with major depression and healthy control subjects. The authors investigated differences in the laterality of thickness and surface area measures of 34 cerebral cortical regions in 2,256 in iduals with major depression and 3,504 control subjects from 31 separate data sets, and they investigated volume asymmetries of eight subcortical structures in 2,540 in iduals with major depression and 4,230 control subjects from 32 data sets. T The largest effect size (Cohen's d) of major depression diagnosis was 0.085 for the thickness asymmetry of the superior temporal cortex, which was not significant after adjustment for multiple testing. Asymmetry measures were not significantly associated with medication use, acute compared with remitted status, first episode compared with recurrent status, or age at onset. Altered brain macro-anatomical asymmetry may be of little relevance to major depression etiology in most cases.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Start Date: 2015
End Date: 2019
Funder: Wellcome Trust
View Funded ActivityStart Date: 2020
End Date: 2024
Funder: European Commission
View Funded Activity