ORCID Profile
0000-0002-6759-0944
Current Organisations
King's College London
,
Auckland City Hospital
,
The University of Auckland
,
NIHR Maudsley Biomedical Research Centre
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Springer Science and Business Media LLC
Date: 15-07-2019
Publisher: Informa UK Limited
Date: 21-02-2017
DOI: 10.1080/09537104.2017.1280149
Abstract: GluN1 is a mandatory component of N-methyl-D-aspartate receptors (NMDARs) best known for their roles in the brain, but with increasing evidence for relevance in peripheral tissues, including platelets. Certain anti-GluN1 antibodies reduce brain infarcts in rodent models of ischaemic stroke. There is also evidence that human anti-GluN1 autoantibodies reduce neuronal damage in stroke patients, but the underlying mechanism is unclear. This study investigated whether anti-GluN1-mediated neuroprotection involves inhibition of platelet function. Four commercial anti-GluN1 antibodies were screened for their abilities to inhibit human platelet aggregation. Haematological parameters were examined in rats vaccinated with GluN1. Platelet effects of a mouse monoclonal antibody targeting the glycine-binding region of GluN1 (GluN1-S2) were tested in assays of platelet activation, aggregation and thrombus formation. The epitope of anti-GluN1-S2 was mapped and the mechanism of antibody action modelled using crystal structures of GluN1. Our work found that rats vaccinated with GluN1 had a mildly prolonged bleeding time and carried antibodies targeting mostly GluN1-S2. The monoclonal anti-GluN1-S2 antibody (from BD Biosciences) inhibited activation and aggregation of human platelets in the presence of adrenaline, adenosine diphosphate, collagen, thrombin and a protease-activated receptor 1-activating peptide. When human blood was flowed over collagen-coated surfaces, anti-GluN1-S2 impaired thrombus growth and stability. The epitope of anti-GluN1-S2 was mapped to α-helix H located within the glycine-binding clamshell of GluN1, where the antibody binding was computationally predicted to impair opening of the NMDAR channel. Our results indicate that anti-GluN1-S2 inhibits function of human platelets, including dense granule release and thrombus growth. Findings add to the evidence that platelet NMDARs regulate thrombus formation and suggest a novel mechanism by which anti-GluN1 autoantibodies limit stroke-induced neuronal damage.
Publisher: American Society of Hematology
Date: 26-04-2023
DOI: 10.1182/BLOODADVANCES.2022008457
Abstract: Extracellular protein disulfide isomerases (PDIs), including PDI, endoplasmic reticulum protein 57 (ERp57), ERp72, ERp46, and ERp5, are required for in vivo thrombus formation in mice. Platelets secrete PDIs upon activation, which regulate platelet aggregation. However, platelets secrete only ∼10% of their PDI content extracellularly. The intracellular role of PDIs in platelet function is unknown. Here, we aim to characterize the role of ERp5 (gene Pdia6) using platelet conditional knockout mice, platelet factor 4 (Pf4) Cre+/ERp5floxed (fl)/fl. Pf4Cre+/ERp5fl/fl mice developed mild macrothrombocytopenia. Platelets deficient in ERp5 showed marked dysregulation of their ER, indicated by a twofold upregulation of ER proteins, including PDI, ERp57, ERp72, ERp46, 78 kilodalton glucose-regulated protein (GRP78), and calreticulin. ERp5-deficient platelets showed an enhanced ER stress response to ex vivo and in vivo ER stress inducers, with enhanced phosphorylation of eukaryotic translation initiation factor 2A and inositol-requiring enzyme 1 (IRE1). ERp5 deficiency was associated with increased secretion of PDIs, an enhanced response to thromboxane A2 receptor activation, and increased thrombus formation in vivo. Our results support that ERp5 acts as a negative regulator of ER stress responses in platelets and highlight the importance of a disulfide isomerase in platelet ER homeostasis. The results also indicate a previously unanticipated role of platelet ER stress in platelet secretion and thrombosis. This may have important implications for the therapeutic applications of ER stress inhibitors in thrombosis.
Publisher: Frontiers Media SA
Date: 23-06-2021
DOI: 10.3389/FNINS.2021.678503
Abstract: Growing research suggests that posttraumatic stress disorder (PTSD) may be a risk factor for poor cardiovascular health, and yet our understanding of who might be at greatest risk of adverse cardiovascular outcomes after trauma is limited. In this study, we conducted the first examination of the in idual and synergistic contributions of PTSD symptoms and blood pressure genetics to continuous blood pressure levels. We harnessed the power of the Psychiatric Genomics Consortium-PTSD Physical Health Working Group and investigated these associations across 11 studies of 72,224 trauma-exposed in iduals of European ( n = 70,870) and African ( n = 1,354) ancestry. Genetic contributions to blood pressure were modeled via polygenic scores (PGS) for systolic blood pressure (SBP) and diastolic blood pressure (DBP) that were derived from a prior trans-ethnic blood pressure genome-wide association study (GWAS). Results of trans-ethnic meta-analyses revealed significant main effects of the PGS on blood pressure levels [SBP: β = 2.83, standard error (SE) = 0.06, p & 1E-20 DBP: β = 1.32, SE = 0.04, p & 1E-20]. Significant main effects of PTSD symptoms were also detected for SBP and DBP in trans-ethnic meta-analyses, though there was significant heterogeneity in these results. When including data from the largest contributing study – United Kingdom Biobank – PTSD symptoms were negatively associated with SBP levels (β = −1.46, SE = 0.44, p = 9.8E-4) and positively associated with DBP levels (β = 0.70, SE = 0.26, p = 8.1E-3). However, when excluding the United Kingdom Biobank cohort in trans-ethnic meta-analyses, there was a nominally significant positive association between PTSD symptoms and SBP levels (β = 2.81, SE = 1.13, p = 0.01) no significant association was observed for DBP (β = 0.43, SE = 0.78, p = 0.58). Blood pressure PGS did not significantly moderate the associations between PTSD symptoms and blood pressure levels in meta-analyses. Additional research is needed to better understand the extent to which PTSD is associated with high blood pressure and how genetic as well as contextual factors may play a role in influencing cardiovascular risk.
Publisher: Wiley
Date: 16-02-2020
DOI: 10.1111/ADB.12880
Publisher: Springer Science and Business Media LLC
Date: 18-12-2019
DOI: 10.1038/S41467-019-13544-0
Abstract: Body composition is often altered in psychiatric disorders. Using genome-wide common genetic variation data, we calculate sex-specific genetic correlations amongst body fat %, fat mass, fat-free mass, physical activity, glycemic traits and 17 psychiatric traits (up to N = 217,568). Two patterns emerge: (1) anorexia nervosa, schizophrenia, obsessive-compulsive disorder, and education years are negatively genetically correlated with body fat % and fat-free mass, whereas (2) attention-deficit/hyperactivity disorder (ADHD), alcohol dependence, insomnia, and heavy smoking are positively correlated. Anorexia nervosa shows a stronger genetic correlation with body fat % in females, whereas education years is more strongly correlated with fat mass in males. Education years and ADHD show genetic overlap with childhood obesity. Mendelian randomization identifies schizophrenia, anorexia nervosa, and higher education as causal for decreased fat mass, with higher body fat % possibly being a causal risk factor for ADHD and heavy smoking. These results suggest new possibilities for targeted preventive strategies.
Publisher: Cold Spring Harbor Laboratory
Date: 04-12-2020
DOI: 10.1101/2020.12.01.20241281
Abstract: Suicide is a leading cause of death worldwide and non-fatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both are known to have a substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium and conditioned the results on psychiatric disorders using GWAS summary statistics, to investigate their shared and ergent genetic architectures. Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, which remained associated after conditioning and has previously been implicated in risk-taking, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, lower socioeconomic status, pain, lower educational attainment, reproductive traits, risk-taking, sleep disturbances, and poorer overall general health. After conditioning, the genetic correlations between SA and psychiatric disorders decreased, whereas those with non-psychiatric traits remained largely unchanged. Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest the existence of a shared genetic etiology between SA and known risk factors that is not mediated by psychiatric disorders.
Publisher: Elsevier BV
Date: 06-2021
Publisher: Springer Science and Business Media LLC
Date: 16-04-2018
DOI: 10.1038/S41467-018-03819-3
Abstract: Depression is a polygenic trait that causes extensive periods of disability. Previous genetic studies have identified common risk variants which have progressively increased in number with increasing s le sizes of the respective studies. Here, we conduct a genome-wide association study in 322,580 UK Biobank participants for three depression-related phenotypes: broad depression, probable major depressive disorder (MDD), and International Classification of Diseases (ICD, version 9 or 10)-coded MDD. We identify 17 independent loci that are significantly associated ( P 5 × 10 −8 ) across the three phenotypes. The direction of effect of these loci is consistently replicated in an independent s le, with 14 loci likely representing novel findings. Gene sets are enriched in excitatory neurotransmission, mechanosensory behaviour, post synapse, neuron spine and dendrite functions. Our findings suggest that broad depression is the most tractable UK Biobank phenotype for discovering genes and gene sets that further our understanding of the biological pathways underlying depression.
Publisher: Elsevier BV
Date: 11-2021
Publisher: Cold Spring Harbor Laboratory
Date: 14-09-2018
DOI: 10.1101/416008
Abstract: Over 90% of suicide attempters have a psychiatric diagnosis, however twin and family studies suggest that the genetic etiology of suicide attempt (SA) is partially distinct from that of the psychiatric disorders themselves. Here, we present the largest genome-wide association study (GWAS) on suicide attempt using major depressive disorder (MDD), bipolar disorder (BIP) and schizophrenia (SCZ) cohorts from the Psychiatric Genomics Consortium. S les comprise 1622 suicide attempters and 8786 non-attempters with MDD, 3264 attempters and 5500 non-attempters with BIP and 1683 attempters and 2946 non-attempters with SCZ. SA GWAS were performed comparing attempters to non-attempters in each disorder followed by meta-analysis across disorders. Polygenic risk scoring investigated the genetic relationship between SA and the psychiatric disorders. Three genome-wide significant loci for SA were found: one associated with SA in MDD, one in BIP, and one in the meta-analysis of SA in mood disorders. These associations were not replicated in independent mood disorder cohorts from the UK Biobank and i PSYCH. Polygenic risk scores for major depression were significantly associated with SA in MDD (P=0.0002), BIP (P=0.0006) and SCZ (P=0.0006). This study provides new information on genetic associations and the genetic etiology of SA across psychiatric disorders. The finding that polygenic risk scores for major depression predict suicide attempt across disorders provides a possible starting point for predictive modelling and preventative strategies. Further collaborative efforts to increase s le size hold potential to robustly identify genetic associations and gain biological insights into the etiology of suicide attempt.
Publisher: Wiley
Date: 12-12-2019
DOI: 10.1111/ADD.14845
Abstract: The use of cannabis has previously been linked to both depression and self-harm however, the role of genetics in this relationship is unclear. This study aimed to estimate the phenotypic and genetic associations between cannabis use and depression and self-harm. Cross-sectional data collected through UK Biobank were used to test the phenotypic association between cannabis use, depression and self-harm. UK Biobank genetic data were then combined with consortia genome-wide association study summary statistics to further test the genetic relationships between these traits using LD score regression, polygenic risk scoring and Mendelian randomization methods. United Kingdom, with additional international consortia data. A total of 126 291 British adults aged between 40 and 70 years, recruited into UK Biobank. Phenotypic outcomes were life-time history of cannabis use (including initial and continued cannabis use), depression (including single-episode and recurrent depression) and self-harm. Genome-wide genetic data were used and assessment centre, batch and the first six principal components were included as key covariates when handling genetic data. In UK Biobank, cannabis use is associated with an increased likelihood of depression [odds ratio (OR) = 1.64, 95% confidence interval (CI) = 1.59-1.70] and self-harm (OR = 2.85, 95% CI = 2.69-3.01). The strength of this phenotypic association is stronger when more severe trait definitions of cannabis use and depression are considered. Using consortia genome-wide summary statistics, significant genetic correlations are seen between cannabis use and depression [rg = 0.289, standard error (SE) = 0.036]. Polygenic risk scores for cannabis use and depression explain a small but significant proportion of variance in cannabis use, depression and self-harm within a UK Biobank target s le. However, two-s le Mendelian randomization analyses were not significant. Cannabis use appeared to be both phenotypically and genetically associated with depression and self-harm. Limitations in statistical power mean that conclusions could not be made on the direction of causality between these traits.
Publisher: Elsevier BV
Date: 10-2022
Publisher: Cold Spring Harbor Laboratory
Date: 11-09-2020
DOI: 10.1101/2020.09.10.20192310
Abstract: Polygenic scores (PGSs), which assess the genetic risk of in iduals for a disease, are calculated as a weighted count of risk alleles identified in genome-wide association studies (GWASs). PGS methods differ in which DNA variants are included and the weights assigned to them some require an independent tuning s le to help inform these choices. PGSs are evaluated in independent target cohorts with known disease status. Variability between target cohorts is observed in applications to real data sets, which could reflect a number of factors, e.g., phenotype definition or technical factors. The Psychiatric Genomics Consortium working groups for schizophrenia (SCZ) and major depressive disorder (MDD) bring together many independently collected case- control cohorts. We used these resources (31K SCZ cases, 41K controls 248K MDD cases, 563K controls) in repeated application of leave-one-cohort-out meta-analyses, each used to calculate and evaluate PGS in the left-out (target) cohort. Ten PGS methods (the baseline PC+T method and nine methods that model genetic architecture more formally: SBLUP, LDpred2-Inf, LDpred-funct, LDpred2, Lassosum, PRS-CS, PRS-CS-auto, SBayesR, MegaPRS) are compared. Compared to PC+T, the other nine methods give higher prediction statistics, MegaPRS, LDPred2 and SBayesR significantly so, up to 9.2% variance in liability for SCZ across 30 target cohorts, an increase of 44%. For MDD across 26 target cohorts these statistics were 3.5% and 59%, respectively. Although the methods that more formally model genetic architecture have similar performance, MegaPRS, LDpred2, and SBayesR rank highest in most comparison and are recommended in applications to psychiatric disorders.
Publisher: American Medical Association (AMA)
Date: 11-2021
Publisher: Royal College of Psychiatrists
Date: 02-2016
DOI: 10.1192/BJP.BP.114.154997
Abstract: We previously reported an association between 5HTTLPR genotype and outcome following cognitive–behavioural therapy (CBT) in child anxiety (Cohort 1). Children homozygous for the low-expression short-allele showed more positive outcomes. Other similar studies have produced mixed results, with most reporting no association between genotype and CBT outcome. To replicate the association between 5HTTLPR and CBT outcome in child anxiety from the Genes for Treatment study (GxT Cohort 2, n = 829). Logistic and linear mixed effects models were used to examine the relationship between 5HTTLPR and CBT outcomes. Mega-analyses using both cohorts were performed. There was no significant effect of 5HTTLPR on CBT outcomes in Cohort 2. Mega-analyses identified a significant association between 5HTTLPR and remission from all anxiety disorders at follow-up (odds ratio 0.45, P = 0.014), but not primary anxiety disorder outcomes. The association between 5HTTLPR genotype and CBT outcome did not replicate. Short-allele homozygotes showed more positive treatment outcomes, but with small, non-significant effects. Future studies would benefit from utilising whole genome approaches and large, homogenous s les.
Publisher: Elsevier BV
Date: 07-2023
Publisher: Royal College of Psychiatrists
Date: 15-08-2018
DOI: 10.1192/BJO.2018.47
Publisher: Cold Spring Harbor Laboratory
Date: 03-08-2018
DOI: 10.1101/383331
Abstract: Mood disorders (including major depressive disorder and bipolar disorder) affect 10-20% of the population. They range from brief, mild episodes to severe, incapacitating conditions that markedly impact lives. Despite their diagnostic distinction, multiple approaches have shown considerable sharing of risk factors across the mood disorders. To clarify their shared molecular genetic basis, and to highlight disorder-specific associations, we meta-analysed data from the latest Psychiatric Genomics Consortium (PGC) genome-wide association studies of major depression (including data from 23andMe) and bipolar disorder, and an additional major depressive disorder cohort from UK Biobank (total: 185,285 cases, 439,741 controls non-overlapping N = 609,424). Seventy-three loci reached genome-wide significance in the meta-analysis, including 15 that are novel for mood disorders. More genome-wide significant loci from the PGC analysis of major depression than bipolar disorder reached genome-wide significance. Genetic correlations revealed that type 2 bipolar disorder correlates strongly with recurrent and single episode major depressive disorder. Systems biology analyses highlight both similarities and differences between the mood disorders, particularly in the mouse brain cell types implicated by the expression patterns of associated genes. The mood disorders also differ in their genetic correlation with educational attainment – positive in bipolar disorder but negative in major depressive disorder. The mood disorders share several genetic associations, and can be combined effectively to increase variant discovery. However, we demonstrate several differences between these disorders. Analysing subtypes of major depressive disorder and bipolar disorder provides evidence for a genetic mood disorders spectrum.
Publisher: Springer Science and Business Media LLC
Date: 16-09-2014
DOI: 10.1038/TP.2014.83
Abstract: Anxiety disorders that are the most commonly occurring psychiatric disorders in childhood, are associated with a range of social and educational impairments and often continue into adulthood. Cognitive behaviour therapy (CBT) is an effective treatment option for the majority of cases, although up to 35–45% of children do not achieve remission. Recent research suggests that some genetic variants may be associated with a more beneficial response to psychological therapy. Epigenetic mechanisms such as DNA methylation work at the interface between genetic and environmental influences. Furthermore, epigenetic alterations at the serotonin transporter ( SERT ) promoter region have been associated with environmental influences such as stressful life experiences. In this study, we measured DNA methylation upstream of SERT in 116 children with an anxiety disorder, before and after receiving CBT. Change during treatment in percentage DNA methylation was significantly different in treatment responders vs nonresponders. This effect was driven by one CpG site in particular, at which responders increased in methylation, whereas nonresponders showed a decrease in DNA methylation. This is the first study to demonstrate differences in SERT methylation change in association with response to a purely psychological therapy. These findings confirm that biological changes occur alongside changes in symptomatology following a psychological therapy such as CBT.
Publisher: IEEE
Date: 24-09-2021
Publisher: American Society of Hematology
Date: 28-04-2022
Abstract: The process of proplatelet formation (PPF) requires coordinated interaction between megakaryocytes (MKs) and the extracellular matrix (ECM), followed by a dynamic reorganization of the actin and microtubule cytoskeleton. Localized fluxes of intracellular calcium ions (Ca2+) facilitate MK-ECM interaction and PPF. Glutamate-gated N-methyl-D-aspartate receptor (NMDAR) is highly permeable to Ca2+. NMDAR antagonists inhibit MK maturation ex vivo however, there are no in vivo data. Using the Cre-loxP system, we generated a platelet lineage–specific knockout mouse model of reduced NMDAR function in MKs and platelets (Pf4-Grin1−/− mice). Effects of NMDAR deletion were examined using well-established assays of platelet function and production in vivo and ex vivo. We found that Pf4-Grin1−/− mice had defects in megakaryopoiesis, thrombopoiesis, and platelet function, which manifested as reduced platelet counts, lower rates of platelet production in the immune model of thrombocytopenia, and prolonged tail bleeding time. Platelet activation was impaired to a range of agonists associated with reduced Ca2+ responses, including metabotropic like, and defective platelet spreading. MKs showed reduced colony and proplatelet formation. Impaired reorganization of intracellular F-actin and α-tubulin was identified as the main cause of reduced platelet function and production. Pf4-Grin1−/− MKs also had lower levels of transcripts encoding crucial ECM elements and enzymes, suggesting NMDAR signaling is involved in ECM remodeling. In summary, we provide the first genetic evidence that NMDAR plays an active role in platelet function and production. NMDAR regulates PPF through a mechanism that involves MK-ECM interaction and cytoskeletal reorganization. Our results suggest that NMDAR helps guide PPF in vivo.
Publisher: Wiley
Date: 19-04-2022
DOI: 10.1002/GEPI.22449
Abstract: Substantial advances have been made in identifying genetic contributions to depression, but little is known about how the effect of genes can be modulated by the environment, creating a gene-environment interaction. Using multivariate reaction norm models (MRNMs) within the UK Biobank (N = 61294-91644), we investigate whether the polygenic and residual variance components of depressive symptoms are modulated by 17 a priori selected covariate traits-12 environmental variables and 5 biomarkers. MRNMs, a mixed-effects modelling approach, provide unbiased polygenic-covariate interaction estimates for a quantitative trait by controlling for outcome-covariate correlations and residual-covariate interactions. A continuous depressive symptom variable was the outcome in 17 MRNMs-one for each covariate trait. Each MRNM had a fixed-effects model (fixed effects included the covariate trait, demographic variables, and principal components) and a random effects model (where polygenic-covariate and residual-covariate interactions are modelled). Of the 17 selected covariates, 11 significantly modulate deviations in depressive symptoms through the modelled interactions, but no single interaction explains a large proportion of phenotypic variation. Results are dominated by residual-covariate interactions, suggesting that covariate traits (including neuroticism, childhood trauma, and BMI) typically interact with unmodelled variables, rather than a genome-wide polygenic component, to influence depressive symptoms. Only average sleep duration has a polygenic-covariate interaction explaining a demonstrably nonzero proportion of the variability in depressive symptoms. This effect is small, accounting for only 1.22% (95% confidence interval: [0.54, 1.89]) of variation. The presence of an interaction highlights a specific focus for intervention, but the negative results here indicate a limited contribution from polygenic-environment interactions.
Publisher: Wiley
Date: 09-03-2018
DOI: 10.1111/JCPP.12872
Publisher: Springer Science and Business Media LLC
Date: 09-04-2018
DOI: 10.1038/S41562-018-0332-5
Abstract: The etiology of in idual differences in educational attainment and occupational status includes genetic as well as environmental factors1-5 and can change as societies change3,6,7. The extent of genetic influence on these social outcomes can be viewed as an index of success in achieving meritocratic values of equality of opportunity by rewarding talent and hard work, which are to a large extent influenced by genetic factors, rather than rewarding environmentally driven privilege. To the extent that the end of the Soviet Union and the independence of Estonia led to an increase in meritocratic selection of in iduals in education and occupation, genetic influence should be higher in the post-Soviet era than in the Soviet era. Here we confirmed this hypothesis: DNA differences (single-nucleotide polymorphisms, SNPs) explained twice as much variance in educational attainment and occupational status in the post-Soviet era compared to the Soviet era in both polygenic score analyses and SNP heritability analyses of 12 500 Estonians. This is the first demonstration of a change in the extent of genetic influence in the same population following a massive and abrupt social change - in this case, the shift from a communist to a capitalist society.
Publisher: American Psychological Association (APA)
Date: 08-2019
DOI: 10.1037/PAS0000700
Publisher: Springer Science and Business Media LLC
Date: 05-2019
Publisher: Wiley
Date: 18-07-2020
DOI: 10.1002/AJMG.B.32807
Publisher: Cold Spring Harbor Laboratory
Date: 04-08-2021
DOI: 10.1101/2021.08.02.21261499
Abstract: Substantial advances have been made in identifying genetic contributions to depression, but little is known about how the effect of genes can be modulated by the environment, creating a gene-environment interaction. Using multivariate reaction norm models (MRNMs) within the UK Biobank (N=61294-91644), we investigate whether the polygenic and residual variation of depressive symptoms are modulated by 25 a-priori selected covariate traits: 12 environmental variables, 5 biomarkers and polygenic risk scores for 8 mental health disorders. MRNMs provide unbiased polygenic-covariate interaction estimates for a quantitative trait by controlling for outcome-covariate correlations and residual-covariate interactions. Of the 25 selected covariates, 11 significantly modulate depressive symptoms, but no single interaction explains a large proportion of phenotypic variation. Results are dominated by residual-covariate interactions, suggesting that covariate traits (including neuroticism, childhood trauma and BMI) typically interact with unmodelled variables, rather than a genome-wide polygenic score, to influence depressive symptoms. Only average sleep duration has a polygenic-covariate interaction explaining a demonstrably non-zero proportion of the variability in depressive symptoms. This effect is small, accounting for only 1.22% (95% CI [0.54,1.89]) of variation. The presence of an interaction highlights a specific focus for intervention, but the negative results here indicate a limited contribution from polygenic-environment interactions.
Publisher: Hindawi Limited
Date: 07-10-2015
DOI: 10.1002/DA.22430
Publisher: Springer Science and Business Media LLC
Date: 18-05-2020
Publisher: Elsevier BV
Date: 06-2018
Publisher: Springer Science and Business Media LLC
Date: 08-10-2019
DOI: 10.1038/S41467-019-12576-W
Abstract: The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5–20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson’s disease gene involved in dopamine regulation, PARK2 , is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations.
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: Elsevier BV
Date: 10-2020
Publisher: Cold Spring Harbor Laboratory
Date: 11-2018
DOI: 10.1101/458562
Abstract: Post-traumatic stress disorder (PTSD) is a common and debilitating disorder. The risk of PTSD following trauma is heritable, but robust common variants have yet to be identified by genome-wide association studies (GWAS). We have collected a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls. We first demonstrate significant genetic correlations across 60 PTSD cohorts to evaluate the comparability of these phenotypically heterogeneous studies. In this largest GWAS meta-analysis of PTSD to date we identify a total of 6 genome-wide significant loci, 4 in European and 2 in African-ancestry analyses. Follow-up analyses incorporated local ancestry and sex-specific effects, and functional studies. Along with other novel genes, a non-coding RNA (ncRNA) and a Parkinson’s Disease gene, PARK2 , were associated with PTSD. Consistent with previous reports, SNP-based heritability estimates for PTSD range between 10-20%. Despite a significant shared liability between PTSD and major depressive disorder, we show evidence that some of our loci may be specific to PTSD. These results demonstrate the role of genetic variation contributing to the biology of differential risk for PTSD and the necessity of expanding GWAS beyond European ancestry.
Publisher: Springer Science and Business Media LLC
Date: 25-06-2018
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: Cambridge University Press (CUP)
Date: 04-06-2021
DOI: 10.1017/S0033291721000830
Abstract: Posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) are commonly reported co-occurring mental health consequences of psychological trauma exposure. The disorders have high genetic overlap. Trauma is a complex phenotype but research suggests that trauma sensitivity has a heritable basis. We investigated whether sensitivity to trauma in those with MDD reflects a similar genetic component in those with PTSD. Genetic correlations between PTSD and MDD in in iduals reporting trauma and MDD in in iduals not reporting trauma were estimated, as well as with recurrent MDD and single-episode MDD, using genome-wide association study (GWAS) summary statistics. Genetic correlations were replicated using PTSD data from the Psychiatric Genomics Consortium and the Million Veteran Program. Polygenic risk scores were generated in UK Biobank participants who met the criteria for lifetime MDD ( N = 29 471). We investigated whether genetic loading for PTSD was associated with reporting trauma in these in iduals. Genetic loading for PTSD was significantly associated with reporting trauma in in iduals with MDD [OR 1.04 (95% CI 1.01–1.07), Empirical- p = 0.02]. PTSD was significantly more genetically correlated with recurrent MDD than with MDD in in iduals not reporting trauma ( r g differences = ~0.2, p 0.008). Participants who had experienced recurrent MDD reported significantly higher rates of trauma than participants who had experienced single-episode MDD (χ 2 166, p 0.001) Our findings point towards the existence of genetic variants associated with trauma sensitivity that might be shared between PTSD and MDD, although replication with better powered GWAS is needed. Our findings corroborate previous research highlighting trauma exposure as a key risk factor for recurrent MDD.
Publisher: Springer Science and Business Media LLC
Date: 25-02-2019
Publisher: Elsevier BV
Date: 11-2018
DOI: 10.1016/J.JOCA.2018.06.015
Abstract: The chondrocyte circadian clock is altered in osteoarthritis. This change is implicated in the disease-associated changes in chondrocyte phenotype and cartilage loss. Why the clock is changed is unknown. N-methyl-D-aspartate receptors (NMDAR) are critical for regulating the hypothalamic clock. Chondrocytes also express NMDAR and the type of NMDAR subunits expressed changes in osteoarthritis. To determine if NMDAR regulate the chondrocyte clock and phenotype. Chondrocytes isolated from macroscopically-normal (MN) and osteoarthritic human cartilage were treated with NMDAR antagonists or transfected with GRIN2A or GRIN2B-targetting siRNA. H5 chondrocytes were transfected with GluN2B-expression plasmids. Clock genes and chondrocyte phenotypic markers were measured by RT-qPCR. PER2 litude was higher and BMAL1 litude lower in osteoarthritic compared to MN chondrocytes. In osteoarthritic chondrocytes, NMDAR inhibition restored PER2 and BMAL1 expression to levels similar to MN chondrocytes, and resulted in reduced MMP13 and COL10A1. Paradoxically, NMDAR inhibition in MN chondrocytes resulted in increased PER2, decreased BMAL1 and increased MMP13 and COL10A1. Osteoarthritic, but not MN chondrocytes expressed GluN2B NMDAR subunits. GluN2B knockdown in osteoarthritic chondrocytes restored expression of circadian clock components and phenotypic markers to levels similar to MN chondrocytes. Ectopic expression of GluN2B resulted in reduced BMAL1, increased PER2 and altered SOX9, RUNX2 and MMP13 expression. Knockdown of PER2 mitigated the effects of GluN2B on SOX9 and MMP13. NMDAR regulate the chondrocyte clock and phenotype suggesting NMDAR may also regulate clocks in other peripheral tissues. GluN2B expression in osteoarthritis may contribute to pathology by altering the chondrocyte clock.
Publisher: Springer Science and Business Media LLC
Date: 07-03-2018
DOI: 10.1038/S41467-017-02769-6
Abstract: Genomic prediction has the potential to contribute to precision medicine. However, to date, the utility of such predictors is limited due to low accuracy for most traits. Here theory and simulation study are used to demonstrate that widespread pleiotropy among phenotypes can be utilised to improve genomic risk prediction. We show how a genetic predictor can be created as a weighted index that combines published genome-wide association study (GWAS) summary statistics across many different traits. We apply this framework to predict risk of schizophrenia and bipolar disorder in the Psychiatric Genomics consortium data, finding substantial heterogeneity in prediction accuracy increases across cohorts. For six additional phenotypes in the UK Biobank data, we find increases in prediction accuracy ranging from 0.7% for height to 47% for type 2 diabetes, when using a multi-trait predictor that combines published summary statistics from multiple traits, as compared to a predictor based only on one trait.
Publisher: Elsevier BV
Date: 2018
DOI: 10.1002/RTH2.12068
Publisher: Georg Thieme Verlag KG
Date: 04-2020
Abstract: The release of calcium ions (Ca2+) from the endoplasmic reticulum (ER) and related store-operated calcium entry (SOCE) regulate maturation of normal megakaryocytes. The N-methyl-D-aspartate (NMDA) receptor (NMDAR) provides an additional mechanism for Ca2+ influx in megakaryocytic cells, but its role remains unclear. We created a model of NMDAR hypofunction in Meg-01 cells using CRISPR-Cas9 mediated knockout of the GRIN1 gene, which encodes an obligate, GluN1 subunit of the NMDAR. We found that compared with unmodified Meg-01 cells, Meg-01-GRIN1 −/− cells underwent atypical differentiation biased toward erythropoiesis, associated with increased basal ER stress and cell death. Resting cytoplasmic Ca2+ levels were higher in Meg-01-GRIN1 −/− cells, but ER Ca2+ release and SOCE were lower after activation. Lysosome-related organelles accumulated including immature dense granules that may have contributed an alternative source of intracellular Ca2+. Microarray analysis revealed that Meg-01-GRIN1 −/− cells had deregulated expression of transcripts involved in Ca2+ metabolism, together with a shift in the pattern of hematopoietic transcription factors toward erythropoiesis. In keeping with the observed pro-cell death phenotype induced by GRIN1 deletion, memantine (NMDAR inhibitor) increased cytotoxic effects of cytarabine in unmodified Meg-01 cells. In conclusion, NMDARs comprise an integral component of the Ca2+ regulatory network in Meg-01 cells that help balance ER stress and megakaryocytic-erythroid differentiation. We also provide the first evidence that megakaryocytic NMDARs regulate biogenesis of lysosome-related organelles, including dense granules. Our results argue that intracellular Ca2+ homeostasis may be more important for normal megakaryocytic and erythroid differentiation than currently recognized thus, modulation may offer therapeutic opportunities.
Publisher: Royal College of Psychiatrists
Date: 19-04-2018
DOI: 10.1192/BJO.2018.19
Publisher: Springer Science and Business Media LLC
Date: 27-04-2020
Publisher: Springer Science and Business Media LLC
Date: 25-07-2017
DOI: 10.1038/MP.2017.88
Abstract: Anorexia nervosa (AN) is a complex neuropsychiatric disorder presenting with dangerously low body weight, and a deep and persistent fear of gaining weight. To date, only one genome-wide significant locus associated with AN has been identified. We performed an exome-chip based genome-wide association studies (GWAS) in 2158 cases from nine populations of European origin and 15 485 ancestrally matched controls. Unlike previous studies, this GWAS also probed association in low-frequency and rare variants. Sixteen independent variants were taken forward for in silico and de novo replication (11 common and 5 rare). No findings reached genome-wide significance. Two notable common variants were identified: rs10791286, an intronic variant in OPCML ( P =9.89 × 10 −6 ), and rs7700147, an intergenic variant ( P =2.93 × 10 −5 ). No low-frequency variant associations were identified at genome-wide significance, although the study was well-powered to detect low-frequency variants with large effect sizes, suggesting that there may be no AN loci in this genomic search space with large effect sizes.
Publisher: S. Karger AG
Date: 2016
DOI: 10.1159/000444023
Abstract: b i Background: /i /b The differential susceptibly hypothesis suggests that certain genetic variants moderate the effects of both negative and positive environments on mental health and may therefore be important predictors of response to psychological treatments. Nevertheless, the identification of such variants has so far been limited to preselected candidate genes. In this study we extended the differential susceptibility hypothesis from a candidate gene to a genome-wide approach to test whether a polygenic score of environmental sensitivity predicted response to cognitive behavioural therapy (CBT) in children with anxiety disorders. b i Methods: /i /b We identified variants associated with environmental sensitivity using a novel method in which within-pair variability in emotional problems in 1,026 monozygotic twin pairs was examined as a function of the pairs' genotype. We created a polygenic score of environmental sensitivity based on the whole-genome findings and tested the score as a moderator of parenting on emotional problems in 1,406 children and response to in idual, group and brief parent-led CBT in 973 children with anxiety disorders. b i Results: /i /b The polygenic score significantly moderated the effects of parenting on emotional problems and the effects of treatment. In iduals with a high score responded significantly better to in idual CBT than group CBT or brief parent-led CBT (remission rates: 70.9, 55.5 and 41.6%, respectively). b i Conclusions: /i /b Pending successful replication, our results should be considered exploratory. Nevertheless, if replicated, they suggest that in iduals with the greatest environmental sensitivity may be more likely to develop emotional problems in adverse environments but also benefit more from the most intensive types of treatment.
Publisher: Elsevier BV
Date: 2022
Publisher: Wiley
Date: 02-12-2019
DOI: 10.1002/AJMG.B.32700
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: Oxford University Press (OUP)
Date: 2008
DOI: 10.1093/RHEUMATOLOGY/KEM287
Abstract: Anatomical MRI brain scans may not reflect neurological dysfunction in patients with NPSLE. We used blood-oxygen-level-dependent functional MRI (BOLD-fMRI) to investigate working memory function in NPSLE patients. Twenty-seven females took part: nine NPSLE patients (mean age 40 yrs SLEDAI 10.9) nine RA patients and nine healthy controls. Subjects were tested using the n-back paradigm for working memory, where patients indicate when a stimulus matches one presented n trials previously. Functional scans used 3 mm slices x 30, repetition time 2570 ms, echo time 50 ms. Echo planar images were superimposed onto T1w anatomical images (Siemens 1.5 T). Data analysis used Brain Voyager QX Version 1.7. During the memory task, there was activation in areas serving working memory, executive function and attention in all groups. Nine regions of interest were selected for activation during working memory (N-back task vs fixation, P < or = 0.005). In six out of nine regions, there was greater activation in the NPSLE group. This reached significance in three regions: the posterior inferior parietal lobules of both hemispheres [Brodmann area (BA) 7] separately and combined (P = 0.014, 0.016 and 0.004, respectively), and the supplementary motor area (mid-line frontal lobe) (BA32/6 P = 0.032). NPSLE patients showed greater frontoparietal activation than the other groups during the memory task, suggesting a greater need to recruit extra cortical pathways, possibly to supplement impaired function of standard pathways.
Publisher: Wiley
Date: 28-12-2018
DOI: 10.1002/AJMG.B.32709
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: Frontiers Media SA
Date: 13-03-2019
Publisher: Elsevier BV
Date: 02-2022
Publisher: Informa UK Limited
Date: 07-12-2020
DOI: 10.1080/09537104.2020.1852542
Abstract: Ionotropic glutamate receptors include
Publisher: Informa UK Limited
Date: 15-05-2023
Publisher: American Psychiatric Association Publishing
Date: 08-2019
Publisher: Springer Science and Business Media LLC
Date: 23-05-2019
DOI: 10.1038/S41398-019-0481-Y
Abstract: Major depressive disorder and the anxiety disorders are highly prevalent, disabling and moderately heritable. Depression and anxiety are also highly comorbid and have a strong genetic correlation ( r g ≈ 1). Cognitive behavioural therapy is a leading evidence-based treatment but has variable outcomes. Currently, there are no strong predictors of outcome. Therapygenetics research aims to identify genetic predictors of prognosis following therapy. We performed genome-wide association meta-analyses of symptoms following cognitive behavioural therapy in adults with anxiety disorders ( n = 972), adults with major depressive disorder ( n = 832) and children with anxiety disorders ( n = 920 meta-analysis n = 2724). We estimated the variance in therapy outcomes that could be explained by common genetic variants ( h 2 SNP ) and polygenic scoring was used to examine genetic associations between therapy outcomes and psychopathology, personality and learning. No single nucleotide polymorphisms were strongly associated with treatment outcomes. No significant estimate of h 2 SNP could be obtained, suggesting the heritability of therapy outcome is smaller than our analysis was powered to detect. Polygenic scoring failed to detect genetic overlap between therapy outcome and psychopathology, personality or learning. This study is the largest therapygenetics study to date. Results are consistent with previous, similarly powered genome-wide association studies of complex traits.
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: 23-10-2021
DOI: 10.1101/2021.10.13.21261078
Abstract: Obsessive-compulsive disorder (OCD) is a heritable disorder, but no definitive, replicated OCD susceptibility loci have yet been identified by any genome-wide association study (GWAS). Here, we report results from a GWAS in the largest OCD case-control s le (N = 14,140 OCD cases and N = 562,117 controls) to date. We explored the genetic architecture of OCD, including its genetic relationships to other psychiatric and non-psychiatric phenotypes. In the GWAS analysis, we identified one SNP associated with OCD at a genome-wide significant level. Subsequent gene-based analyses identified additional two genes as potentially implicated in OCD pathogenesis. All SNPs combined explained 16% of the heritability of OCD. We show sub-stantial positive genetic correlations between OCD and a range of psychiatric disorders, including anxiety disorders, anorexia nervosa, and major depression. We thus for the first time provide evidence of a genome-wide locus implicated in OCD and strengthen previous literature suggesting a polygenic nature of this disorder.
Publisher: Springer Science and Business Media LLC
Date: 04-02-2019
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: 22-12-2020
Publisher: Springer Science and Business Media LLC
Date: 26-04-2018
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: Cold Spring Harbor Laboratory
Date: 19-11-2018
DOI: 10.1101/469023
Abstract: The prevalence of depression is higher in in iduals suffering from autoimmune diseases, but the mechanisms underlying the observed comorbidities are unknown. Epidemiological findings point to a bi-directional relationship - that depression increases the risk of developing an autoimmune disease, and vice-versa. Shared genetic etiology is a plausible explanation for the overlap between depression and autoimmune diseases. In this study we tested whether genetic variation in the Major Histocompatibility Complex (MHC), which is associated with risk for autoimmune diseases, is also associated with risk for depression. We fine-mapped the classical MHC (chr6: 29.6-33.1 Mb), imputing 216 Human Leukocyte Antigen (HLA) alleles and four Complement Component 4 (C4) haplotypes in studies from the Psychiatric Genomics Consortium (PGC) Major Depressive Disorder (MDD) working group and the UK Biobank (UKB). In the 26 PGC-MDD studies, cases met a lifetime diagnosis of MDD, determined by a structured diagnostic interview. In the UKB, cases and controls were identified from an online mental health questionnaire. The total s le size was 45,149 depression cases and 86,698 controls. We tested for association between depression status and imputed MHC variants in each study and performed an inverse-variance weighted meta-analysis across the PGC-MDD and UKB s les, applying both a conservative region-wide significance threshold (3.9-e6) and a candidate threshold (1.6e-4). No HLA alleles or C4 haplotypes were associated with depression at the conservative threshold in the PGC, UKB or meta-analysis. HLA-B*08:01 was associated with modest protection for depression at the candidate threshold in the meta-analysis. Under the conservative threshold, 70 SNPs were detected in the UKB and 143 SNPs were detected in the meta-analysis, mirroring previous findings from highly powered GWAS of depression. We found no evidence that HLA alleles, which play a major role in the genetic susceptibility to autoimmune diseases, or C4 haplotypes, which are strongly associated with schizophrenia, confer risk for depression. These results indicate that autoimmune diseases and depression do not share common risk loci of moderate or large effect in the MHC.
Publisher: Springer Science and Business Media LLC
Date: 16-12-2021
DOI: 10.1038/S41398-021-01707-X
Abstract: The volume of subcortical structures represents a reliable, quantitative, and objective phenotype that captures genetic effects, environmental effects such as trauma, and disease effects such as posttraumatic stress disorder (PTSD). Trauma and PTSD represent potent exposures that may interact with genetic markers to influence brain structure and function. Genetic variants, associated with subcortical volumes in two large normative discovery s les, were used to compute polygenic scores (PGS) for the volume of seven subcortical structures. These were applied to a target s le enriched for childhood trauma and PTSD. Subcortical volume PGS from the discovery s le were strongly associated in our trauma/PTSD enriched s le ( n = 7580) with respective subcortical volumes of the hippoc us ( p = 1.10 × 10 −20 ), thalamus ( p = 7.46 × 10 −10 ), caudate ( p = 1.97 × 10 −18 ), putamen ( p = 1.7 × 10 −12 ), and nucleus accumbens ( p = 1.99 × 10 −7 ). We found a significant association between the hippoc al volume PGS and hippoc al volume in control subjects from our s le, but was absent in in iduals with PTSD (GxE (beta = −0.10, p = 0.027)). This significant GxE (PGS × PTSD) relationship persisted ( p 1 × 10 −19 ) in four out of five threshold peaks (0.024, 0.133, 0.487, 0.730, and 0.889) used to calculate hippoc al volume PGSs. We detected similar GxE (G × ChildTrauma) relationships in the amygdala for exposure to childhood trauma (rs4702973 p = 2.16 × 10 −7 ) or PTSD (rs10861272 p = 1.78 × 10 −6 ) in the CHST11 gene. The hippoc us and amygdala are pivotal brain structures in mediating PTSD symptomatology. Trauma exposure and PTSD modulate the effect of polygenic markers on hippoc al volume (GxE) and the amygdala volume PGS is associated with PTSD risk, which supports the role of amygdala volume as a risk factor for PTSD.
Publisher: American Psychiatric Association Publishing
Date: 09-2017
Publisher: American Psychiatric Association Publishing
Date: 10-2023
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: 08-08-2017
DOI: 10.1101/173435
Abstract: Schizophrenia (SCZ) and bipolar disorder (BD) are highly heritable disorders that share a significant proportion of common risk variation. Understanding the genetic factors underlying the specific symptoms of these disorders will be crucial for improving diagnosis, intervention and treatment. In case-control data consisting of 53,555 cases (20,129 BD, 33,426 SCZ) and 54,065 controls, we identified 114 genome-wide significant loci (GWS) when comparing all cases to controls, of which 41 represented novel findings. Two genome-wide significant loci were identified when comparing SCZ to BD and a third was found when directly incorporating functional information. Regional joint association identified a genomic region of overlapping association in BD and SCZ with disease-independent causal variants indicating a fourth region contributing to differences between these disorders. Regional SNP-heritability analyses demonstrated that the estimated heritability of BD based on the SCZ GWS regions was significantly higher than that based on the average genomic region (91 regions, p = 1.2×10 −6 ) while the inverse was not significant (19 regions, p=0.89). Using our BD and SCZ GWAS we calculated polygenic risk scores and identified several significant correlations with: 1) SCZ subphenotypes: negative symptoms (SCZ, p=3.6×10 −6 ) and manic symptoms (BD, p=2×10 −5 ), 2) BD subphenotypes: psychotic features (SCZ p=1.2×10 −10 , BD p=5.3×10 −5 ) and age of onset (SCZ p=7.9×10 −4 ). Finally, we show that psychotic features in BD has significant SNP-heritability (h 2 snp =0.15, SE=0.06), and a significant genetic correlation with SCZ (r g =0.34) in addition there is a significant sign test result between SCZ GWAS and a GWAS of BD cases contrasting those with and without psychotic features (p=0.0038, one-side binomial test). For the first time, we have identified specific loci pointing to a potential role of 4 genes ( DARS2 , ARFGEF2 , DCAKD and GATAD2A ) that distinguish between BD and SCZ, providing an opportunity to understand the biology contributing to clinical differences of these disorders. Our results provide the best evidence so far of genomic components distinguishing between BD and SCZ that contribute directly to specific symptom dimensions.
Publisher: Springer Science and Business Media LLC
Date: 27-01-2020
Publisher: Cold Spring Harbor Laboratory
Date: 23-08-2019
DOI: 10.1101/741512
Abstract: Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa (BN) and problem alcohol use (genetic correlation [ r g ], twin-based=0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge-eating, AN without binge-eating, and a BN factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder (MDD). Total s le sizes per phenotype ranged from ~2,400 to ~537,000 in iduals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN ( r g =0.18 false discovery rate q =0.0006), cannabis initiation and AN ( r g =0.23 q .0001), and cannabis initiation and AN with binge-eating ( r g =0.27 q =0.0016). Conversely, significant negative genetic correlations were observed between three non-diagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge-eating ( r gs =-0.19 to −0.23 qs .04). The genetic correlation between AUD and AN was no longer significant after co-varying for MDD loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships between these behaviors.
Publisher: Springer Science and Business Media LLC
Date: 30-08-2018
Publisher: Cold Spring Harbor Laboratory
Date: 24-05-2019
DOI: 10.1101/645077
Abstract: It’s imperative to understand the specific and shared aetiologies of major depression and cardio-metabolic disease, as both traits are frequently comorbid and each represents a major burden to society. This study examined whether there is a genetic association between major depression and cardio-metabolic traits and if this association is stratified by age at onset for major depression. Polygenic risk scores analysis and linkage disequilibrium score regression was performed to examine whether differences in shared genetic aetiology exist between depression case control status (N cases = 40,940, N controls = 67,532), earlier (N = 15,844), and later onset depression (N = 15,800) with body mass index, coronary artery disease, stroke, and type 2 diabetes in eleven data sets from the Psychiatric Genomics Consortium, Generation Scotland, and UK Biobank. All cardio-metabolic polygenic risk scores were associated with depression status. Significant genetic correlations were found between depression and body mass index, coronary artery disease, and type 2 diabetes. Higher polygenic risk for body mass index, coronary artery disease and type 2 diabetes was associated with both early and later onset depression, while higher polygenic risk for stroke was associated with later onset depression only. Significant genetic correlations were found between body mass index and later onset depression, and between coronary artery disease and both early and late onset depression. The phenotypic associations between major depression and cardio-metabolic traits may partly reflect their overlapping genetic aetiology irrespective of the age depression first presents.
Publisher: Royal College of Psychiatrists
Date: 17-06-2019
DOI: 10.1192/BJO.2019.46
Publisher: Cold Spring Harbor Laboratory
Date: 21-07-2022
DOI: 10.1101/2022.07.20.500802
Abstract: Most genome-wide association studies (GWAS) of major depression (MD) have been conducted in s les of European ancestry. Here we report a multi-ancestry GWAS of MD, adding data from 21 studies with 88,316 MD cases and 902,757 controls to previously reported data from in iduals of European ancestry. This includes s les of African (36% of effective s le size), East Asian (26%) and South Asian (6%) ancestry and Hispanic/Latinx participants (32%). The multi-ancestry GWAS identified 190 significantly associated loci, 53 of them novel. For previously reported loci from GWAS in European ancestry the power-adjusted transferability ratio was 0.6 in the Hispanic/Latinx group and 0.3 in each of the other groups. Fine-mapping benefited from additional s le ersity: the number of credible sets with ≤5 variants increased from 3 to 12. A transcriptome-wide association study identified 354 significantly associated genes, 205 of them novel. Mendelian Randomisation showed a bidirectional relationship with BMI exclusively in s les of European ancestry. This first multi-ancestry GWAS of MD demonstrates the importance of large erse s les for the identification of target genes and putative mechanisms.
Publisher: Elsevier BV
Date: 07-2020
Publisher: Elsevier BV
Date: 03-2020
Publisher: American Psychiatric Association Publishing
Date: 10-2020
Publisher: Elsevier BV
Date: 02-2023
DOI: 10.1016/J.BIOPSYCH.2022.08.012
Abstract: Attention-deficit/hyperactivity disorder (ADHD) and posttraumatic stress disorder (PTSD) are associated, but it is unclear if this is a causal relationship or confounding. We used genetic analyses and sibling comparisons to clarify the direction of this relationship. Linkage disequilibrium score regression and 2-s le Mendelian randomization were used to test for genetic correlation (r ADHD and PTSD had consistent r Our findings add novel evidence supporting the need for early and effective treatment of ADHD, as patients with this diagnosis are at significantly higher risk to develop PTSD later in life.
Publisher: Cold Spring Harbor Laboratory
Date: 05-05-2020
DOI: 10.1101/2020.05.04.076042
Abstract: The origin of sex differences in prevalence and presentation of neuropsychiatric and behavioral traits is largely unknown. Given established genetic contributions and correlations across these traits, we tested for a sex-differentiated genetic architecture within and between traits. Using genome-wide association study (GWAS) summary statistics for 20 neuropsychiatric and behavioral traits, we tested for differences in SNP-based heritability (h 2 ) and genetic correlation (r g ) between sexes. For each trait, we computed z-scores from sex-stratified GWAS regression coefficients and identified genes with sex-differentiated effects. We calculated Pearson correlation coefficients between z-scores for each trait pair, to assess whether specific pairs share variants with sex-differentiated effects. Finally, we tested for sex differences in between-trait genetic correlations. With current s le sizes (and power), we found no significant, consistent sex differences in SNP-based h 2 . Between-sex, within-trait genetic correlations were consistently high, although significantly less than 1 for educational attainment and risk-taking behavior. We identified genome-wide significant genes with sex-differentiated effects for eight traits. Several trait pairs shared sex-differentiated effects. The top 0.1% of genes with sex-differentiated effects across traits overlapped with neuron- and synapse-related gene sets. Most between-trait genetic correlation estimates were similar across sex, with several exceptions (e.g. educational attainment & risk-taking behavior). Sex differences in the common autosomal genetic architecture of neuropsychiatric and behavioral phenotypes are small and polygenic, requiring large s le sizes. Genes with sex-differentiated effects are enriched for neuron-related gene sets. This work motivates further investigation of genetic, as well as environmental, influences on sex differences.
Publisher: Elsevier BV
Date: 10-2019
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: 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: Public Library of Science (PLoS)
Date: 20-12-2018
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: Cold Spring Harbor Laboratory
Date: 18-09-2020
DOI: 10.1101/2020.09.17.20187054
Abstract: Bipolar disorder (BD) is a heritable mental illness with complex etiology. We performed a genome-wide association study (GWAS) of 41,917 BD cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. BD risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippoc us. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating eQTL data implicated 15 genes robustly linked to BD via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of BD subtypes indicated high but imperfect genetic correlation between BD type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of BD, identify novel therapeutic leads and prioritize genes for functional follow-up studies.
Publisher: Cold Spring Harbor Laboratory
Date: 24-07-2017
DOI: 10.1101/167577
Abstract: Major depressive disorder (MDD) is a notably complex illness with a lifetime prevalence of 14%. 1 It is often chronic or recurrent and is thus accompanied by considerable morbidity, excess mortality, substantial costs, and heightened risk of suicide. 2-7 MDD is a major cause of disability worldwide. 8 We conducted a genome-wide association (GWA) meta-analysis in 130,664 MDD cases and 330,470 controls, and identified 44 independent loci that met criteria for statistical significance. We present extensive analyses of these results which provide new insights into the nature of MDD. The genetic findings were associated with clinical features of MDD, and implicated prefrontal and anterior cingulate cortex in the pathophysiology of MDD (regions exhibiting anatomical differences between MDD cases and controls). Genes that are targets of antidepressant medications were strongly enriched for MDD association signals (P=8.5×10 −10 ), suggesting the relevance of these findings for improved pharmacotherapy of MDD. Sets of genes involved in gene splicing and in creating isoforms were also enriched for smaller MDD GWA P-values, and these gene sets have also been implicated in schizophrenia and autism. Genetic risk for MDD was correlated with that for many adult and childhood onset psychiatric disorders. Our analyses suggested important relations of genetic risk for MDD with educational attainment, body mass, and schizophrenia: the genetic basis of lower educational attainment and higher body mass were putatively causal for MDD whereas MDD and schizophrenia reflected a partly shared biological etiology. All humans carry lesser or greater numbers of genetic risk factors for MDD, and a continuous measure of risk underlies the observed clinical phenotype. MDD is not a distinct entity that neatly demarcates normalcy from pathology but rather a useful clinical construct associated with a range of adverse outcomes and the end result of a complex process of intertwined genetic and environmental effects. These findings help refine and define the fundamental basis of MDD.
Publisher: Cold Spring Harbor Laboratory
Date: 07-08-2017
DOI: 10.1101/173062
Abstract: Bipolar disorder is a highly heritable psychiatric disorder that features episodes of mania and depression. We performed the largest genome-wide association study to date, including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 sentinel variants at loci with P ×10 -4 in an independent s le of 9,412 cases and 137,760 controls. In the combined analysis, 30 loci reached genome-wide significant evidence for association, of which 20 were novel. These significant loci contain genes encoding ion channels and neurotransmitter transporters ( CACNA1C , GRIN2A , SCN2A , SLC4A1 ), synaptic components ( RIMS1 , ANK3 ), immune and energy metabolism components. Bipolar disorder type I (depressive and manic episodes ~ 73% of our cases) is strongly genetically correlated with schizophrenia whereas bipolar disorder type II (depressive and hypomanic episodes ~ 17% of our cases) is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential new biological mechanisms for bipolar disorder.
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: 16-11-2020
Publisher: American Medical Association (AMA)
Date: 05-2019
Publisher: Cold Spring Harbor Laboratory
Date: 05-07-2022
Publisher: Royal College of Psychiatrists
Date: 09-2016
DOI: 10.1192/BJP.BP.115.168229
Abstract: Anxiety disorders are common, and cognitive–behavioural therapy (CBT) is a first-line treatment. Candidate gene studies have suggested a genetic basis to treatment response, but findings have been inconsistent. To perform the first genome-wide association study (GWAS) of psychological treatment response in children with anxiety disorders ( n = 980). Presence and severity of anxiety was assessed using semi-structured interview at baseline, on completion of treatment (post-treatment), and 3 to 12 months after treatment completion (follow-up). DNA was genotyped using the Illumina Human Core Exome-12v1.0 array. Linear mixed models were used to test associations between genetic variants and response (change in symptom severity) immediately post-treatment and at 6-month follow-up. No variants passed a genome-wide significance threshold ( P =5×10 –8 ) in either analysis. Four variants met criteria for suggestive significance ( P ×10 –6 ) in association with response post-treatment, and three variants in the 6-month follow-up analysis. This is the first genome-wide therapygenetic study. It suggests no common variants of very high effect underlie response to CBT. Future investigations should maximise power to detect single-variant and polygenic effects by using larger, more homogeneous cohorts.
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: Wiley
Date: 27-06-2016
DOI: 10.1002/AJMG.B.32467
Publisher: Elsevier BV
Date: 04-2022
Publisher: Elsevier BV
Date: 06-2015
Publisher: Frontiers Media SA
Date: 17-06-2020
Location: United Kingdom of Great Britain and Northern Ireland
Location: Poland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Jonathan Coleman.