Publications by authors named "Chia-Yen Chen"

81 Publications

Enhancing Discovery of Genetic Variants for Posttraumatic Stress Disorder Through Integration of Quantitative Phenotypes and Trauma Exposure Information.

Biol Psychiatry 2021 Sep 28. Epub 2021 Sep 28.

Department of Psychiatry, Harvard Medical School, Boston, Massachusetts; McLean Hospital, Belmont, Massachusetts.

Background: Posttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype measurement and incorporation of lifetime trauma exposure (LTE) information could enhance the discovery power of PTSD genome-wide association studies (GWASs).

Methods: A GWAS on PTSD symptoms was performed in 51 cohorts followed by a fixed-effects meta-analysis (N = 182,199 European ancestry participants). A GWAS of LTE burden was performed in the UK Biobank cohort (N = 132,988). Genetic correlations were evaluated with linkage disequilibrium score regression. Multivariate analysis was performed using Multi-Trait Analysis of GWAS. Functional mapping and annotation of leading loci was performed with FUMA. Replication was evaluated using the Million Veteran Program GWAS of PTSD total symptoms.

Results: GWASs of PTSD symptoms and LTE burden identified 5 and 6 independent genome-wide significant loci, respectively. There was a 72% genetic correlation between PTSD and LTE. PTSD and LTE showed largely similar patterns of genetic correlation with other traits, albeit with some distinctions. Adjusting PTSD for LTE reduced PTSD heritability by 31%. Multivariate analysis of PTSD and LTE increased the effective sample size of the PTSD GWAS by 20% and identified 4 additional loci. Four of these 9 PTSD loci were independently replicated in the Million Veteran Program.

Conclusions: Through using a quantitative trait measure of PTSD, we identified novel risk loci not previously identified using prior case-control analyses. PTSD and LTE have a high genetic overlap that can be leveraged to increase discovery power through multivariate methods.
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http://dx.doi.org/10.1016/j.biopsych.2021.09.020DOI Listing
September 2021

Pairwise effects between lipid GWAS genes modulate lipid plasma levels and cellular uptake.

Nat Commun 2021 11 5;12(1):6411. Epub 2021 Nov 5.

Molecular Medicine Partnership Unit (MMPU), University of Heidelberg/EMBL, Heidelberg, Germany.

Complex traits are characterized by multiple genes and variants acting simultaneously on a phenotype. However, studying the contribution of individual pairs of genes to complex traits has been challenging since human genetics necessitates very large population sizes, while findings from model systems do not always translate to humans. Here, we combine genetics with combinatorial RNAi (coRNAi) to systematically test for pairwise additive effects (AEs) and genetic interactions (GIs) between 30 lipid genome-wide association studies (GWAS) genes. Gene-based burden tests from 240,970 exomes show that in carriers with truncating mutations in both, APOB and either PCSK9 or LPL ("human double knock-outs") plasma lipid levels change additively. Genetics and coRNAi identify overlapping AEs for 12 additional gene pairs. Overlapping GIs are observed for TOMM40/APOE with SORT1 and NCAN. Our study identifies distinct gene pairs that modulate plasma and cellular lipid levels primarily via AEs and nominates putative drug target pairs for improved lipid-lowering combination therapies.
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http://dx.doi.org/10.1038/s41467-021-26761-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8571362PMC
November 2021

Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders.

Biol Psychiatry 2022 01 23;91(1):102-117. Epub 2021 Mar 23.

Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, Illinois; Department of Psychiatry and Behavioral Sciences, North Shore University Health System, Evanston, Illinois.

Background: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk.

Methods: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH.

Results: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10; rs73033497, p = 8.8 × 10; rs7914279, p = 6.4 × 10), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05).

Conclusions: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.
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http://dx.doi.org/10.1016/j.biopsych.2021.02.972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8458480PMC
January 2022

Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics.

Neuropsychopharmacology 2021 09 25;46(10):1788-1801. Epub 2021 May 25.

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Broad-based cognitive deficits are an enduring and disabling symptom for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. While novel drug targets for schizophrenia and depression have emerged from recent large-scale genome-wide association studies (GWAS) of these psychiatric disorders, GWAS of general cognitive ability can suggest potential targets for nootropic drug repurposing. Here, we (1) meta-analyze results from two recent cognitive GWAS to further enhance power for locus discovery; (2) employ several complementary transcriptomic methods to identify genes in these loci that are credibly associated with cognition; and (3) further annotate the resulting genes using multiple chemoinformatic databases to identify "druggable" targets. Using our meta-analytic data set (N = 373,617), we identified 241 independent cognition-associated loci (29 novel), and 76 genes were identified by 2 or more methods of gene identification. Actin and chromatin binding gene sets were identified as novel pathways that could be targeted via drug repurposing. Leveraging our transcriptomic and chemoinformatic databases, we identified 16 putative genes targeted by existing drugs potentially available for cognitive repurposing.
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http://dx.doi.org/10.1038/s41386-021-01023-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357785PMC
September 2021

The causal role of circulating vitamin D concentrations in human complex traits and diseases: a large-scale Mendelian randomization study.

Sci Rep 2021 01 8;11(1):184. Epub 2021 Jan 8.

Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA.

Vitamin D has been associated with a variety of human complex traits and diseases in observational studies, but a causal relationship remains unclear. To examine a putative causal effect of vitamin D across phenotypic domains and disease categories, we conducted Mendelian randomization (MR) analyses using genetic instruments associated with circulating 25-hydroxyvitamin D [25(OH)D] concentrations. We leveraged genome-wide significant 25(OH)D-associated SNPs (N = 138) from a meta-analysis combining a vitamin D GWAS conducted in 401,460 white British UK Biobank (UKBB) participants and an independent vitamin D GWAS including 42,274 samples of European ancestry, and examined 190 large-scale health-related GWAS spanning a broad spectrum of complex traits, diseases and biomarkers. We applied multiple MR methods to estimate the causal effect of vitamin D while testing and controlling for potential biases from horizontal pleiotropy. Consistent with previous findings, genetically predicted increased 25(OH)D levels significantly decreased the risk of multiple sclerosis (OR = 0.824; 95% CI 0.689-0.986). The protective effect estimate was consistent across different MR methods and four different multiple sclerosis GWAS with varying sample sizes and genotyping platforms. On the contrary, we found limited evidence in support of a causal effect of 25(OH)D on anthropometric traits, obesity, cognitive function, sleep behavior, breast and prostate cancer, and autoimmune, cardiovascular, metabolic, neurological and psychiatric traits and diseases, and blood biomarkers. Our results may inform ongoing and future randomized clinical trials of vitamin D supplementation.
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http://dx.doi.org/10.1038/s41598-020-80655-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794542PMC
January 2021

Identifying drug targets for neurological and psychiatric disease via genetics and the brain transcriptome.

PLoS Genet 2021 01 8;17(1):e1009224. Epub 2021 Jan 8.

MRC Integrative Epidemiology Unit (IEU), Population Health Sciences, University of Bristol, Bristol, United Kingdom.

Discovering drugs that efficiently treat brain diseases has been challenging. Genetic variants that modulate the expression of potential drug targets can be utilized to assess the efficacy of therapeutic interventions. We therefore employed Mendelian Randomization (MR) on gene expression measured in brain tissue to identify drug targets involved in neurological and psychiatric diseases. We conducted a two-sample MR using cis-acting brain-derived expression quantitative trait loci (eQTLs) from the Accelerating Medicines Partnership for Alzheimer's Disease consortium (AMP-AD) and the CommonMind Consortium (CMC) meta-analysis study (n = 1,286) as genetic instruments to predict the effects of 7,137 genes on 12 neurological and psychiatric disorders. We conducted Bayesian colocalization analysis on the top MR findings (using P<6x10-7 as evidence threshold, Bonferroni-corrected for 80,557 MR tests) to confirm sharing of the same causal variants between gene expression and trait in each genomic region. We then intersected the colocalized genes with known monogenic disease genes recorded in Online Mendelian Inheritance in Man (OMIM) and with genes annotated as drug targets in the Open Targets platform to identify promising drug targets. 80 eQTLs showed MR evidence of a causal effect, from which we prioritised 47 genes based on colocalization with the trait. We causally linked the expression of 23 genes with schizophrenia and a single gene each with anorexia, bipolar disorder and major depressive disorder within the psychiatric diseases and 9 genes with Alzheimer's disease, 6 genes with Parkinson's disease, 4 genes with multiple sclerosis and two genes with amyotrophic lateral sclerosis within the neurological diseases we tested. From these we identified five genes (ACE, GPNMB, KCNQ5, RERE and SUOX) as attractive drug targets that may warrant follow-up in functional studies and clinical trials, demonstrating the value of this study design for discovering drug targets in neuropsychiatric diseases.
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http://dx.doi.org/10.1371/journal.pgen.1009224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819609PMC
January 2021

The genetic architecture of sporadic and multiple consecutive miscarriage.

Nat Commun 2020 11 25;11(1):5980. Epub 2020 Nov 25.

University of Queensland, St Lucia, QLD, Australia.

Miscarriage is a common, complex trait affecting ~15% of clinically confirmed pregnancies. Here we present the results of large-scale genetic association analyses with 69,054 cases from five different ancestries for sporadic miscarriage, 750 cases of European ancestry for multiple (≥3) consecutive miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association (rs146350366, minor allele frequency (MAF) 1.2%, P = 3.2 × 10, odds ratio (OR) = 1.4) for sporadic miscarriage in our European ancestry meta-analysis and three genome-wide significant associations for multiple consecutive miscarriage (rs7859844, MAF = 6.4%, P = 1.3 × 10, OR = 1.7; rs143445068, MAF = 0.8%, P = 5.2 × 10, OR = 3.4; rs183453668, MAF = 0.5%, P = 2.8 × 10, OR = 3.8). We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability, and genetic correlation analyses. Our results show that miscarriage etiopathogenesis is partly driven by genetic variation potentially related to placental biology, and illustrate the utility of large-scale biobank data for understanding this pregnancy complication.
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http://dx.doi.org/10.1038/s41467-020-19742-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689465PMC
November 2020

Genome-wide association analysis of opioid use disorder: A novel approach using clinical data.

Drug Alcohol Depend 2020 12 15;217:108276. Epub 2020 Sep 15.

Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, United States; Department of Biomedical Informatics, Harvard Medical School, United States; Department of Biomedical Informatics, Vanderbilt University Medical Center, United States; Partners eCare, Partners HealthCare, United States.

Background: Opioid use disorder (OUD) represents a large and pervasive global public health challenge. Previous genetic studies have demonstrated the significant heritability of OUD and identified several single-nucleotide polymorphisms (SNPs) associated with its prevalence.

Methods: In this paper, we conducted a genome-wide association analysis on opioid use disorder that leveraged genetic and clinical data contained in a biobank of 21,310 patients of European ancestry. We identified 1039 cases of opioid use disorder based on diagnostic codes from nearly 16 million encounters in electronic health records (EHRs).

Results: We discovered one novel OUD-associated locus on chromosome 4 that was significant at a genome-wide threshold (p = 2.40 × 10). Heritability analysis suggested that common SNPs explained 0.06 (se 0.02, p = 0.0065) of the phenotypic variation in OUD. When we restricted controls to those with previous opioid prescriptions, we were able to further strengthen the original signal and discovered another significant locus on chromosome 16. Pair-wise genetic correlation analysis yielded strong positive correlations between OUD and two other major substance use disorders, alcohol and nicotine, with the strongest correlation between nicotine and opioid use disorder (genetic correlation 0.65, se = 0.19, p = 0.00048), suggesting a significant shared genetic component across different substance disorders.

Conclusions: This pragmatic, clinically-focused approach may supplement more traditional methods to facilitate identification of new genetic underpinnings of OUD and related disorders.
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http://dx.doi.org/10.1016/j.drugalcdep.2020.108276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736461PMC
December 2020

An Exposure-Wide and Mendelian Randomization Approach to Identifying Modifiable Factors for the Prevention of Depression.

Am J Psychiatry 2020 10 14;177(10):944-954. Epub 2020 Aug 14.

Department of Psychiatry, Massachusetts General Hospital, Boston (Choi, Chen, Zheutlin, Dunn, Koenen, Smoller); Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston (Choi, Chen, Zheutlin, Dunn, Koenen, Smoller); Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston (Choi, Nishimi, Koenen, Smoller); Biogen, Cambridge, Mass. (Chen); Departments of Psychiatry and Family Medicine and Public Health, University of California, San Diego, La Jolla (Stein); Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Coleman, Breen); and Department of Epidemiology, Columbia University Mailman School of Public Health, New York (Ratanatharathorn).

Objective: Efforts to prevent depression, the leading cause of disability worldwide, have focused on a limited number of candidate factors. Using phenotypic and genomic data from over 100,000 UK Biobank participants, the authors sought to systematically screen and validate a wide range of potential modifiable factors for depression.

Methods: Baseline data were extracted for 106 modifiable factors, including lifestyle (e.g., exercise, sleep, media, diet), social (e.g., support, engagement), and environmental (e.g., green space, pollution) variables. Incident depression was defined as minimal depressive symptoms at baseline and clinically significant depression at follow-up. At-risk individuals for incident depression were identified by polygenic risk scores or by reported traumatic life events. An exposure-wide association scan was conducted to identify factors associated with incident depression in the full sample and among at-risk individuals. Two-sample Mendelian randomization was then used to validate potentially causal relationships between identified factors and depression.

Results: Numerous factors across social, sleep, media, dietary, and exercise-related domains were prospectively associated with depression, even among at-risk individuals. However, only a subset of factors was supported by Mendelian randomization evidence, including confiding in others (odds ratio=0.76, 95% CI=0.67, 0.86), television watching time (odds ratio=1.09, 95% CI=1.05, 1.13), and daytime napping (odds ratio=1.34, 95% CI=1.17, 1.53).

Conclusions: Using a two-stage approach, this study validates several actionable targets for preventing depression. It also demonstrates that not all factors associated with depression in observational research may translate into robust targets for prevention. A large-scale exposure-wide approach combined with genetically informed methods for causal inference may help prioritize strategies for multimodal prevention in psychiatry.
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http://dx.doi.org/10.1176/appi.ajp.2020.19111158DOI Listing
October 2020

The schizophrenia risk locus in SLC39A8 alters brain metal transport and plasma glycosylation.

Sci Rep 2020 08 4;10(1):13162. Epub 2020 Aug 4.

Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

A common missense variant in SLC39A8 is convincingly associated with schizophrenia and several additional phenotypes. Homozygous loss-of-function mutations in SLC39A8 result in undetectable serum manganese (Mn) and a Congenital Disorder of Glycosylation (CDG) due to the exquisite sensitivity of glycosyltransferases to Mn concentration. Here, we identified several Mn-related changes in human carriers of the common SLC39A8 missense allele. Analysis of structural brain MRI scans showed a dose-dependent change in the ratio of T2w to T1w signal in several regions. Comprehensive trace element analysis confirmed a specific reduction of only serum Mn, and plasma protein N-glycome profiling revealed reduced complexity and branching. N-glycome profiling from two individuals with SLC39A8-CDG showed similar but more severe alterations in branching that improved with Mn supplementation, suggesting that the common variant exists on a spectrum of hypofunction with potential for reversibility. Characterizing the functional impact of this variant will enhance our understanding of schizophrenia pathogenesis and identify novel therapeutic targets and biomarkers.
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http://dx.doi.org/10.1038/s41598-020-70108-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403432PMC
August 2020

Dietary Diversity Score: Implications for Obesity Prevention and Nutrient Adequacy in Renal Transplant Recipients.

Int J Environ Res Public Health 2020 07 14;17(14). Epub 2020 Jul 14.

Department of Nutrition and Health Sciences, Chinese Culture University, Taipei 11114, Taiwan.

Obesity affects both medical and surgical outcomes in renal transplant recipients (RTRs). Dietary diversity, an important component of a healthy diet, might be a useful nutritional strategy for monitoring patients with obesity. In this cross-sectional study, the data of 85 eligible RTRs were analyzed. Demographic data, routine laboratory data, and 3-day dietary data were collected. Participants were grouped into nonobesity and obesity groups based on body mass index (BMI) (for Asian adults, the cutoff point is 27 kg/m). Dietary diversity score (DDS) was computed by estimating scores for the six food groups emphasized in the Food Guide. The mean age and BMI of participants were 49.7 ± 12.6 years and 24.0 ± 3.8 kg/m, respectively. In the study population, 20.0% (n = 17) were obese. DDS was significantly lower in obese participants than in those who were not obese (1.53 ± 0.87 vs. 2.13 ± 0.98; = 0.029). In addition, DDS was correlated with nutrition adequacy of the diet. Multivariate analysis showed that the odds of obesity decreased with each unit increase in DDS (odds ratio, 0.278; 95% confidence interval, 0.101-0.766; = 0.013). We conclude that patients with higher dietary diversity have a lower prevalence of obesity.
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http://dx.doi.org/10.3390/ijerph17145083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399872PMC
July 2020

Evaluating the cardiovascular safety of sclerostin inhibition using evidence from meta-analysis of clinical trials and human genetics.

Sci Transl Med 2020 06;12(549)

Big Data Institute at the Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford OX3 7FZ, UK.

Inhibition of sclerostin is a therapeutic approach to lowering fracture risk in patients with osteoporosis. However, data from phase 3 randomized controlled trials (RCTs) of romosozumab, a first-in-class monoclonal antibody that inhibits sclerostin, suggest an imbalance of serious cardiovascular events, and regulatory agencies have issued marketing authorizations with warnings of cardiovascular disease. Here, we meta-analyze published and unpublished cardiovascular outcome trial data of romosozumab and investigate whether genetic variants that mimic therapeutic inhibition of sclerostin are associated with higher risk of cardiovascular disease. Meta-analysis of up to three RCTs indicated a probable higher risk of cardiovascular events with romosozumab. Scaled to the equivalent dose of romosozumab (210 milligrams per month; 0.09 grams per square centimeter of higher bone mineral density), the genetic variants were associated with lower risk of fracture and osteoporosis (commensurate with the therapeutic effect of romosozumab) and with a higher risk of myocardial infarction and/or coronary revascularization and major adverse cardiovascular events. The same variants were also associated with increased risk of type 2 diabetes mellitus and higher systolic blood pressure and central adiposity. Together, our findings indicate that inhibition of sclerostin may elevate cardiovascular risk, warranting a rigorous evaluation of the cardiovascular safety of romosozumab and other sclerostin inhibitors.
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http://dx.doi.org/10.1126/scitranslmed.aay6570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116615PMC
June 2020

Analysis of Genetically Regulated Gene Expression Identifies a Prefrontal PTSD Gene, SNRNP35, Specific to Military Cohorts.

Cell Rep 2020 06;31(9):107716

SAMRC Unit on Risk & Resilience in Mental Disorders, Department of Psychiatry, University of Cape Town, Cape Town 7700, South Africa.

To reveal post-traumatic stress disorder (PTSD) genetic risk influences on tissue-specific gene expression, we use brain and non-brain transcriptomic imputation. We impute genetically regulated gene expression (GReX) in 29,539 PTSD cases and 166,145 controls from 70 ancestry-specific cohorts and identify 18 significant GReX-PTSD associations corresponding to specific tissue-gene pairs. The results suggest substantial genetic heterogeneity based on ancestry, cohort type (military versus civilian), and sex. Two study-wide significant PTSD associations are identified in European and military European cohorts; ZNF140 is predicted to be upregulated in whole blood, and SNRNP35 is predicted to be downregulated in dorsolateral prefrontal cortex, respectively. In peripheral leukocytes from 175 marines, the observed PTSD differential gene expression correlates with the predicted differences for these individuals, and deployment stress produces glucocorticoid-regulated expression changes that include downregulation of both ZNF140 and SNRNP35. SNRNP35 knockdown in cells validates its functional role in U12-intron splicing. Finally, exogenous glucocorticoids in mice downregulate prefrontal Snrnp35 expression.
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http://dx.doi.org/10.1016/j.celrep.2020.107716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359754PMC
June 2020

Genome-wide association analysis of insomnia using data from Partners Biobank.

Sci Rep 2020 04 24;10(1):6928. Epub 2020 Apr 24.

Departmet of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, USA.

Insomnia is one of the most prevalent and burdensome mental disorders worldwide, affecting between 10-20% of adults and up to 48% of the geriatric population. It is further associated with substance usage and dependence, as well other psychiatric disorders. In this study, we combined electronic health record (EHR) derived phenotypes and genotype information to conduct a genome wide analysis of insomnia in a 18,055 patient cohort. Diagnostic codes were used to identify 3,135 patients with insomnia. Our genome-wide association study (GWAS) identified one novel genomic risk locus on chromosome 8 (lead SNP rs17052966, p = 4.53 × 10, odds ratio = 1.28, se = 0.04). The heritability analysis indicated that common SNPs accounts for 7% (se = 0.02, p = 0.015) of phenotypic variation. We further conducted a large-scale meta-analysis of our results and summary statistics of two recent insomnia GWAS and 13 significant loci were identified. The genetic correlation analysis yielded a strong positive genetic correlation between insomnia and alcohol use (rG = 0.56, se = 0.14, p < 0.001), nicotine use (rG = 0.50, se = 0.12, p < 0.001) and opioid use (rG = 0.43, se = 0.18, p = 0.02) disorders, suggesting a significant common genetic risk factors between insomnia and substance use.
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http://dx.doi.org/10.1038/s41598-020-63792-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181749PMC
April 2020

Association between GLP-1 receptor gene polymorphisms with reward learning, anhedonia and depression diagnosis.

Acta Neuropsychiatr 2020 Aug 26;32(4):218-225. Epub 2020 Mar 26.

Department of Psychiatry, Harvard Medical School, Boston, MA, USA.

Background: Glucagon-like peptide-1 receptors (GLP-1Rs) are widely expressed in the brain. Evidence suggests that they may play a role in reward responses and neuroprotection. However, the association of GLP-1R with anhedonia and depression diagnosis has not been studied. Here, we examined the association of GLP-1R polymorphisms with objective and subjective measures of anhedonia, as well as depression diagnosis.

Methods: Objective [response bias assessed by the probabilistic reward task (PRT)] and subjective [Snaith-Hamilton Pleasure Scale (SHAPS)] measures of anhedonia, clinical variables and DNA samples were collected from 100 controls and 164 patients at McLean Hospital. An independent sample genotyped as part of the Psychiatric Genomics Consortium (PGC) was used to study the effect of putative GLP-1R polymorphisms linked to response bias in PRT on depression diagnosis.

Results: The C allele in rs1042044 was significantly associated with increased PRT response bias, when controlling for age, sex, case-control status and PRT discriminability. AA genotype of rs1042044 showed higher anhedonia phenotype based on SHAPS scores. However, analysis of PGC major depressive disorder data showed no association between rs1042044 and depression diagnosis.

Conclusion: Findings suggest a possible association of rs1042044 with anhedonia but no association with depression diagnosis.
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http://dx.doi.org/10.1017/neu.2020.14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351594PMC
August 2020

Genomic influences on self-reported childhood maltreatment.

Transl Psychiatry 2020 01 27;10(1):38. Epub 2020 Jan 27.

US Army Medical Research and Materiel Command, Fort Detrick, MD, USA.

Childhood maltreatment is highly prevalent and serves as a risk factor for mental and physical disorders. Self-reported childhood maltreatment appears heritable, but the specific genetic influences on this phenotype are largely unknown. The aims of this study were to (1) identify genetic variation associated with self-reported childhood maltreatment, (2) estimate SNP-based heritability (h), (3) assess predictive value of polygenic risk scores (PRS) for childhood maltreatment, and (4) quantify genetic overlap of childhood maltreatment with mental and physical health-related phenotypes, and condition the top hits from our analyses when such overlap is present. Genome-wide association analysis for childhood maltreatment was undertaken, using a discovery sample from the UK Biobank (UKBB) (n = 124,000) and a replication sample from the Psychiatric Genomics Consortium-posttraumatic stress disorder group (PGC-PTSD) (n = 26,290). h for childhood maltreatment and genetic correlations with mental/physical health traits were calculated using linkage disequilibrium score regression. PRS was calculated using PRSice and mtCOJO was used to perform conditional analysis. Two genome-wide significant loci associated with childhood maltreatment (rs142346759, p = 4.35 × 10, FOXP1; rs10262462, p = 3.24 × 10, FOXP2) were identified in the discovery dataset but were not replicated in PGC-PTSD. h for childhood maltreatment was ~6% and the PRS derived from the UKBB was significantly predictive of childhood maltreatment in PGC-PTSD (r = 0.0025; p = 1.8 × 10). The most significant genetic correlation of childhood maltreatment was with depressive symptoms (r = 0.70, p = 4.65 × 10), although we show evidence that our top hits may be specific to childhood maltreatment. This is the first large-scale genetic study to identify specific variants associated with self-reported childhood maltreatment. Speculatively, FOXP genes might influence externalizing traits and so be relevant to childhood maltreatment. Alternatively, these variants may be associated with a greater likelihood of reporting maltreatment. A clearer understanding of the genetic relationships of childhood maltreatment, including particular abuse subtypes, with a range of phenotypes, may ultimately be useful in in developing targeted treatment and prevention strategies.
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http://dx.doi.org/10.1038/s41398-020-0706-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026037PMC
January 2020

Association between polygenic liability for schizophrenia and substance involvement: A nationwide population-based study in Taiwan.

Genes Brain Behav 2020 06 17;19(5):e12639. Epub 2020 Jan 17.

Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.

Schizophrenia and substance involvement frequently co-occur in individuals, and a bidirectional relationship between the two has been proposed; shared underlying genetic factors could be an alternative explanation. This study investigated the genetic overlap between schizophrenia and substance involvement, including tobacco, alcohol and betel nut use. The study subjects were recruited from the Taiwan Biobank, and genome-wide genotyping data was available for 18 327 participants without schizophrenia. We calculated the Psychiatric Genomics Consortium-derived polygenic risk score (PRS) for schizophrenia in each participant. The significance of the schizophrenia PRS associated with substance involvement was evaluated using a regression model with adjustments for gender, age and population stratification components. The modified effect of gender or birth decade was also explored. The schizophrenia PRS was positively associated with lifetime tobacco smoking in women (OR in per SD increase in PRS = 1.12 with 95% CI 1.04-1.20, P = .002), but not in men (OR = 0.99 with 95% CI 0.95-1.04, P = .74), and the gender-PRS interaction reached significance (P = .006). The OR between PRS and lifetime tobacco smoking increased with the birth decade (P of birth decade-PRS interaction = .0002). In women, OR increased from 0.97 (P = .85) for subjects with a birth decade before 1950 to 1.21 (P = .04) for subjects with a birth decade after 1980; in men, the corresponding OR increased from 0.88 (P = .04) to 1.13 (P = .11). There was no association between schizophrenia PRS and alcohol/betel nut use phenotypes. This study provides evidence for the genetic overlap between schizophrenia and tobacco use in women, and this overlap was stronger in the younger population.
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http://dx.doi.org/10.1111/gbb.12639DOI Listing
June 2020

Genome-wide association study of shared liability to anxiety disorders in Army STARRS.

Am J Med Genet B Neuropsychiatr Genet 2020 06 30;183(4):197-207. Epub 2019 Dec 30.

Department of Family Medicine & Public Health, University of California San Diego, La Jolla, California.

Anxiety disorders (ANX), namely generalized anxiety, panic disorder, and phobias, are common, etiologically complex syndromes that show increasing prevalence and comorbidity throughout adolescence and beyond. Few genome-wide association studies (GWAS) examining ANX risk have been published and almost exclusively in individuals of European ancestry. In this study, we phenotyped participants from the Army Study To Assess Risk and Resilience in Servicemembers (STARRS) to approximate DSM-based ANX diagnoses. We factor-analyzed those to create a single dimensional anxiety score for each subject. GWAS were conducted using that score within each of three ancestral groups (EUR, AFR, LAT) and then meta-analyzed across ancestries (N = 16,510). We sought to (a) replicate prior ANX GWAS findings in ANGST; (b) determine whether results extended to other ancestry groups; and (c) meta-analyze with ANGST for increased power to identify novel susceptibility loci. No reliable genome-wide significant SNP associations were detected in STARRS. However, SNPs within the CAMKMT gene located in region 2p21 associated with shared ANX risk in ANGST were replicated in EUR soldiers but not other ancestry groups. Combining EUR STARRS and ANGST (N = 28,950) yielded a more robust 2p21 association signal (p = 9.08x10 ). Gene-based analyses supported three genes within 2p21 and LBX1 on chromosome 10. More powerful ANX genetic studies will be required to identify further loci.
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http://dx.doi.org/10.1002/ajmg.b.32776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210051PMC
June 2020

Comparative genetic architectures of schizophrenia in East Asian and European populations.

Nat Genet 2019 12 18;51(12):1670-1678. Epub 2019 Nov 18.

Psychiatric Genetic Epidemiology and Neurobiology Laboratory (PsychGENe lab), Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, NY, USA.

Schizophrenia is a debilitating psychiatric disorder with approximately 1% lifetime risk globally. Large-scale schizophrenia genetic studies have reported primarily on European ancestry samples, potentially missing important biological insights. Here, we report the largest study to date of East Asian participants (22,778 schizophrenia cases and 35,362 controls), identifying 21 genome-wide-significant associations in 19 genetic loci. Common genetic variants that confer risk for schizophrenia have highly similar effects between East Asian and European ancestries (genetic correlation = 0.98 ± 0.03), indicating that the genetic basis of schizophrenia and its biology are broadly shared across populations. A fixed-effect meta-analysis including individuals from East Asian and European ancestries identified 208 significant associations in 176 genetic loci (53 novel). Trans-ancestry fine-mapping reduced the sets of candidate causal variants in 44 loci. Polygenic risk scores had reduced performance when transferred across ancestries, highlighting the importance of including sufficient samples of major ancestral groups to ensure their generalizability across populations.
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http://dx.doi.org/10.1038/s41588-019-0512-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885121PMC
December 2019

Genome-wide Association Studies in Ancestrally Diverse Populations: Opportunities, Methods, Pitfalls, and Recommendations.

Cell 2019 10 10;179(3):589-603. Epub 2019 Oct 10.

Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.

Genome-wide association studies (GWASs) have focused primarily on populations of European descent, but it is essential that diverse populations become better represented. Increasing diversity among study participants will advance our understanding of genetic architecture in all populations and ensure that genetic research is broadly applicable. To facilitate and promote research in multi-ancestry and admixed cohorts, we outline key methodological considerations and highlight opportunities, challenges, solutions, and areas in need of development. Despite the perception that analyzing genetic data from diverse populations is difficult, it is scientifically and ethically imperative, and there is an expanding analytical toolbox to do it well.
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http://dx.doi.org/10.1016/j.cell.2019.08.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939869PMC
October 2019

International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci.

Nat Commun 2019 10 8;10(1):4558. Epub 2019 Oct 8.

Durham VA Medical Center, Research, Durham, NC, USA.

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.
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http://dx.doi.org/10.1038/s41467-019-12576-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783435PMC
October 2019

Penetrance and Pleiotropy of Polygenic Risk Scores for Schizophrenia in 106,160 Patients Across Four Health Care Systems.

Am J Psychiatry 2019 10 16;176(10):846-855. Epub 2019 Aug 16.

Psychiatric and Neurodevelopmental Genetics Unit (Zheutlin, Chen, Ge, Smoller) and Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston (Chen); Stanley Center for Psychiatric Research, Broad Institute, Cambridge, Mass. (Zheutlin, Chen, Stahl, Smoller); Division of Genetic Medicine, Department of Medicine (Dennis, Straub, Ruderfer, Davis), Vanderbilt Genetics Institute (Dennis, Straub, Ruderfer, Davis), and Department of Biomedical Informatics (Ruderfer), Vanderbilt University Medical Center, Nashville; Department of Economics, School of Business and Economics, Vrije Universiteit Amsterdam, Amsterdam (Karlsson Linnér); Autism and Developmental Medicine Institute, Geisinger, Lewisburg, Pa. (Karlsson Linnér, Chabris); Charles Bronfman Institute for Personalized Medicine (Moscati), Pamela Sklar Division of Psychiatric Genomics (Huckins, Charney, Stahl), and Department of Genetics and Genomic Sciences (Huckins, Charney, Stahl, ), Icahn School of Medicine at Mount Sinai, New York; Department of Biomedical and Translational Informatics, Geisinger, Rockville, Md. (Restrepo, Kirchner); Research Information Science and Computing, Partners HealthCare, Somerville, Mass. (Castro).

Objective: Individuals at high risk for schizophrenia may benefit from early intervention, but few validated risk predictors are available. Genetic profiling is one approach to risk stratification that has been extensively validated in research cohorts. The authors sought to test the utility of this approach in clinical settings and to evaluate the broader health consequences of high genetic risk for schizophrenia.

Methods: The authors used electronic health records for 106,160 patients from four health care systems to evaluate the penetrance and pleiotropy of genetic risk for schizophrenia. Polygenic risk scores (PRSs) for schizophrenia were calculated from summary statistics and tested for association with 1,359 disease categories, including schizophrenia and psychosis, in phenome-wide association studies. Effects were combined through meta-analysis across sites.

Results: PRSs were robustly associated with schizophrenia (odds ratio per standard deviation increase in PRS, 1.55; 95% CI=1.4, 1.7), and patients in the highest risk decile of the PRS distribution had up to 4.6-fold higher odds of schizophrenia compared with those in the bottom decile (95% CI=2.9, 7.3). PRSs were also positively associated with other phenotypes, including anxiety, mood, substance use, neurological, and personality disorders, as well as suicidal behavior, memory loss, and urinary syndromes; they were inversely related to obesity.

Conclusions: The study demonstrates that an available measure of genetic risk for schizophrenia is robustly associated with schizophrenia in health care settings and has pleiotropic effects on related psychiatric disorders as well as other medical syndromes. The results provide an initial indication of the opportunities and limitations that may arise with the future application of PRS testing in health care systems.
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http://dx.doi.org/10.1176/appi.ajp.2019.18091085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6961974PMC
October 2019

Genome-wide analyses of psychological resilience in U.S. Army soldiers.

Am J Med Genet B Neuropsychiatr Genet 2019 07 13;180(5):310-319. Epub 2019 May 13.

Department of Psychiatry, Uniformed Services University of the Health Sciences, Bethesda, Maryland.

Though a growing body of preclinical and translational research is illuminating a biological basis for resilience to stress, little is known about the genetic basis of psychological resilience in humans. We conducted genome-wide association studies (GWASs) of self-assessed (by questionnaire) and outcome-based (incident mental disorders from predeployment to postdeployment) resilience among European (EUR) ancestry soldiers in the Army study to assess risk and resilience in servicemembers. Self-assessed resilience (N = 11,492) was found to have significant common-variant heritability (h = 0.162, se = 0.050, p = 5.37 × 10 ), and to be significantly negatively genetically correlated with neuroticism (r  = -0.388, p = .0092). GWAS results from the EUR soldiers revealed a genome-wide significant locus on an intergenic region on Chr 4 upstream from doublecortin-like kinase 2 (DCLK2) (four single nucleotide polymorphisms (SNPs) in LD; top SNP: rs4260523 [p = 5.65 × 10 ] is an eQTL in frontal cortex), a member of the doublecortin family of kinases that promote survival and regeneration of injured neurons. A second gene, kelch-like family member 36 (KLHL36) was detected at gene-wise genome-wide significance [p = 1.89 × 10 ]. A polygenic risk score derived from the self-assessed resilience GWAS was not significantly associated with outcome-based resilience. In very preliminary results, genome-wide significant association with outcome-based resilience was found for one locus (top SNP: rs12580015 [p = 2.37 × 10 ]) on Chr 12 downstream from solute carrier family 15 member 5 (SLC15A5) in subjects (N = 581) exposed to the highest level of deployment stress. The further study of genetic determinants of resilience has the potential to illuminate the molecular bases of stress-related psychopathology and point to new avenues for therapeutic intervention.
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http://dx.doi.org/10.1002/ajmg.b.32730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6551278PMC
July 2019

Polygenic prediction via Bayesian regression and continuous shrinkage priors.

Nat Commun 2019 04 16;10(1):1776. Epub 2019 Apr 16.

Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA.

Polygenic risk scores (PRS) have shown promise in predicting human complex traits and diseases. Here, we present PRS-CS, a polygenic prediction method that infers posterior effect sizes of single nucleotide polymorphisms (SNPs) using genome-wide association summary statistics and an external linkage disequilibrium (LD) reference panel. PRS-CS utilizes a high-dimensional Bayesian regression framework, and is distinct from previous work by placing a continuous shrinkage (CS) prior on SNP effect sizes, which is robust to varying genetic architectures, provides substantial computational advantages, and enables multivariate modeling of local LD patterns. Simulation studies using data from the UK Biobank show that PRS-CS outperforms existing methods across a wide range of genetic architectures, especially when the training sample size is large. We apply PRS-CS to predict six common complex diseases and six quantitative traits in the Partners HealthCare Biobank, and further demonstrate the improvement of PRS-CS in prediction accuracy over alternative methods.
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http://dx.doi.org/10.1038/s41467-019-09718-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467998PMC
April 2019

Prospective study of polygenic risk, protective factors, and incident depression following combat deployment in US Army soldiers.

Psychol Med 2020 04 15;50(5):737-745. Epub 2019 Apr 15.

Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.

Background: Whereas genetic susceptibility increases the risk for major depressive disorder (MDD), non-genetic protective factors may mitigate this risk. In a large-scale prospective study of US Army soldiers, we examined whether trait resilience and/or unit cohesion could protect against the onset of MDD following combat deployment, even in soldiers at high polygenic risk.

Methods: Data were analyzed from 3079 soldiers of European ancestry assessed before and after their deployment to Afghanistan. Incident MDD was defined as no MDD episode at pre-deployment, followed by a MDD episode following deployment. Polygenic risk scores were constructed from a large-scale genome-wide association study of major depression. We first examined the main effects of the MDD PRS and each protective factor on incident MDD. We then tested the effects of each protective factor on incident MDD across strata of polygenic risk.

Results: Polygenic risk showed a dose-response relationship to depression, such that soldiers at high polygenic risk had greatest odds for incident MDD. Both unit cohesion and trait resilience were prospectively associated with reduced risk for incident MDD. Notably, the protective effect of unit cohesion persisted even in soldiers at highest polygenic risk.

Conclusions: Polygenic risk was associated with new-onset MDD in deployed soldiers. However, unit cohesion - an index of perceived support and morale - was protective against incident MDD even among those at highest genetic risk, and may represent a potent target for promoting resilience in vulnerable soldiers. Findings illustrate the value of combining genomic and environmental data in a prospective design to identify robust protective factors for mental health.
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http://dx.doi.org/10.1017/S0033291719000527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8293300PMC
April 2020

Advanced Paternal Age and Early Onset of Schizophrenia in Sporadic Cases: Not Confounded by Parental Polygenic Risk for Schizophrenia.

Biol Psychiatry 2019 07 7;86(1):56-64. Epub 2019 Feb 7.

Institute of Epidemiology and Preventive Medicine, College of Public Health, Taipei, Taiwan; Department of Public Health, College of Public Health, Taipei, Taiwan; Centers of Genomic and Precision Medicine, National Taiwan University, Taipei, Taiwan. Electronic address:

Background: Whether paternal age effect on schizophrenia is a causation or just an association due to confounding by selection into late parenthood is still debated. We investigated the association between paternal age and early onset of schizophrenia in offspring, controlling for both paternal and maternal predisposition to schizophrenia as empirically estimated using polygenic risk score (PRS) derived from the Psychiatric Genomics Consortium.

Methods: Among 2923 sporadic schizophrenia cases selected from the Schizophrenia Trio Genomic Research in Taiwan project, 1649 had parents' genotyping data. The relationships of paternal schizophrenia PRS to paternal age at first birth (AFB) and of maternal schizophrenia PRS to maternal AFB were examined. A logistic regression model of patients' early onset of schizophrenia (≤18 years old) on paternal age was conducted.

Results: Advanced paternal age over 20 years exhibited a trend of an increasing proportion of early onset of schizophrenia (odds ratio per 10-year increase in paternal age = 1.28, p = .007) after adjusting for maternal age, sex, and age. Older paternal AFB also exhibited an increasing trend of paternal schizophrenia PRS. Additionally, a U-shaped relationship between maternal AFB and maternal schizophrenia PRS was observed. After adjusting for both paternal and maternal schizophrenia PRS, the association of paternal age with patients' early onset of schizophrenia remained (odds ratio = 1.29, p = .04).

Conclusions: The association between paternal age and early onset of schizophrenia was not confounded by parental PRS for schizophrenia, which partially captures parental genetic vulnerability to schizophrenia. Our findings support an independent role of paternal age per se in increased risk of early onset of schizophrenia in offspring.
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http://dx.doi.org/10.1016/j.biopsych.2019.01.023DOI Listing
July 2019

Contribution of Rare Copy Number Variants to Bipolar Disorder Risk Is Limited to Schizoaffective Cases.

Biol Psychiatry 2019 07 20;86(2):110-119. Epub 2018 Dec 20.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Background: Genetic risk for bipolar disorder (BD) is conferred through many common alleles, while a role for rare copy number variants (CNVs) is less clear. Subtypes of BD including schizoaffective disorder bipolar type (SAB), bipolar I disorder (BD I), and bipolar II disorder (BD II) differ according to the prominence and timing of psychosis, mania, and depression. The genetic factors contributing to the combination of symptoms among these subtypes are poorly understood.

Methods: Rare large CNVs were analyzed in 6353 BD cases (3833 BD I [2676 with psychosis, 850 without psychosis, and 307 with unknown psychosis history], 1436 BD II, 579 SAB, and 505 BD not otherwise specified) and 8656 controls. CNV burden and a polygenic risk score (PRS) for schizophrenia were used to evaluate the relative contributions of rare and common variants to risk of BD, BD subtypes, and psychosis.

Results: CNV burden did not differ between BD and controls when treated as a single diagnostic entity. However, burden in SAB was increased relative to controls (p = .001), BD I (p = .0003), and BD II (p = .0007). Burden and schizophrenia PRSs were increased in SAB compared with BD I with psychosis (CNV p = .0007, PRS p = .004), and BD I without psychosis (CNV p = .0004, PRS p = 3.9 × 10). Within BD I, psychosis was associated with increased schizophrenia PRSs (p = .005) but not CNV burden.

Conclusions: CNV burden in BD is limited to SAB. Rare and common genetic variants may contribute differently to risk for psychosis and perhaps other classes of psychiatric symptoms.
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http://dx.doi.org/10.1016/j.biopsych.2018.12.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586545PMC
July 2019

Assessment of Bidirectional Relationships Between Physical Activity and Depression Among Adults: A 2-Sample Mendelian Randomization Study.

JAMA Psychiatry 2019 04;76(4):399-408

Department of Psychiatry, Massachusetts General Hospital, Boston.

Importance: 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.

Objective: To examine bidirectional relationships between physical activity and depression using a genetically informed method for assessing potential causal inference.

Design, Setting, And Participants: This 2-sample 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 diverse 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.

Main Outcomes And Measures: MDD and physical activity.

Results: GWAS summary data were available for a combined sample 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).

Conclusions And Relevance: 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.
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http://dx.doi.org/10.1001/jamapsychiatry.2018.4175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450288PMC
April 2019

Genome-wide association analyses of risk tolerance and risky behaviors in over 1 million individuals identify hundreds of loci and shared genetic influences.

Nat Genet 2019 02 14;51(2):245-257. Epub 2019 Jan 14.

Team Loyalty BV, Hoofddorp, the Netherlands.

Humans vary substantially in their willingness to take risks. In a combined sample of over 1 million individuals, we conducted genome-wide association studies (GWAS) of general risk tolerance, adventurousness, and risky behaviors in the driving, drinking, smoking, and sexual domains. Across all GWAS, we identified hundreds of associated loci, including 99 loci associated with general risk tolerance. We report evidence of substantial shared genetic influences across risk tolerance and the risky behaviors: 46 of the 99 general risk tolerance loci contain a lead SNP for at least one of our other GWAS, and general risk tolerance is genetically correlated ([Formula: see text] ~ 0.25 to 0.50) with a range of risky behaviors. Bioinformatics analyses imply that genes near SNPs associated with general risk tolerance are highly expressed in brain tissues and point to a role for glutamatergic and GABAergic neurotransmission. We found no evidence of enrichment for genes previously hypothesized to relate to risk tolerance.
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http://dx.doi.org/10.1038/s41588-018-0309-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6713272PMC
February 2019
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