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GWAS of Suicide Attempt in Psychiatric Disorders and Association With Major Depression Polygenic Risk Scores.

ABSTRACT: OBJECTIVE:More than 90% of people who attempt suicide have a psychiatric diagnosis; however, twin and family studies suggest that the genetic etiology of suicide attempt is partially distinct from that of the psychiatric disorders themselves. The authors present the largest genome-wide association study (GWAS) on suicide attempt, using cohorts of individuals with major depressive disorder, bipolar disorder, and schizophrenia from the Psychiatric Genomics Consortium. METHODS:The samples comprised 1,622 suicide attempters and 8,786 nonattempters with major depressive disorder; 3,264 attempters and 5,500 nonattempters with bipolar disorder; and 1,683 attempters and 2,946 nonattempters with schizophrenia. A GWAS on suicide attempt was performed by comparing attempters to nonattempters with each disorder, followed by a meta-analysis across disorders. Polygenic risk scoring was used to investigate the genetic relationship between suicide attempt and the psychiatric disorders. RESULTS:Three genome-wide significant loci for suicide attempt were found: one associated with suicide attempt in major depressive disorder, one associated with suicide attempt in bipolar disorder, and one in the meta-analysis of suicide attempt in mood disorders. These associations were not replicated in independent mood disorder cohorts from the UK Biobank and iPSYCH. No significant associations were found in the meta-analysis of all three disorders. Polygenic risk scores for major depression were significantly associated with suicide attempt in major depressive disorder (R2=0.25%), bipolar disorder (R2=0.24%), and schizophrenia (R2=0.40%). CONCLUSIONS:This study provides new information on genetic associations and demonstrates that genetic liability for major depression increases risk for suicide attempt across psychiatric disorders. Further collaborative efforts to increase sample size may help to robustly identify genetic associations and provide biological insights into the etiology of suicide attempt.

SUBMITTER: Mullins N

PROVIDER: S-EPMC6675659 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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GWAS of Suicide Attempt in Psychiatric Disorders and Association With Major Depression Polygenic Risk Scores.

Mullins Niamh N Bigdeli Tim B TB Børglum Anders D AD Coleman Jonathan R I JRI Demontis Ditte D Mehta Divya D Power Robert A RA Ripke Stephan S Stahl Eli A EA Starnawska Anna A Anjorin Adebayo A Corvin Aiden A Sanders Alan R AR Forstner Andreas J AJ Reif Andreas A Koller Anna C AC Świątkowska Beata B Baune Bernhard T BT Müller-Myhsok Bertram B Penninx Brenda W J H BWJH Pato Carlos C Zai Clement C Rujescu Dan D Hougaard David M DM Quested Digby D Levinson Douglas F DF Binder Elisabeth B EB Byrne Enda M EM Agerbo Esben E Streit Fabian F Mayoral Fermin F Bellivier Frank F Degenhardt Franziska F Breen Gerome G Morken Gunnar G Turecki Gustavo G Rouleau Guy A GA Grabe Hans J HJ Völzke Henry H Jones Ian I Giegling Ina I Agartz Ingrid I Melle Ingrid I Lawrence Jacob J Walters James T R JTR Strohmaier Jana J Shi Jianxin J Hauser Joanna J Biernacka Joanna M JM Vincent John B JB Kelsoe John J Strauss John S JS Lissowska Jolanta J Pimm Jonathan J Smoller Jordan W JW Guzman-Parra José J Berger Klaus K Scott Laura J LJ Jones Lisa A LA Azevedo M Helena MH Trzaskowski Maciej M Kogevinas Manolis M Rietschel Marcella M Boks Marco M Ising Marcus M Grigoroiu-Serbanescu Maria M Hamshere Marian L ML Leboyer Marion M Frye Mark M Nöthen Markus M MM Alda Martin M Preisig Martin M Nordentoft Merete M Boehnke Michael M O'Donovan Michael C MC Owen Michael J MJ Pato Michele T MT Renteria Miguel E ME Budde Monika M Weissman Myrna M MM Wray Naomi R NR Bass Nicholas N Craddock Nicholas N Smeland Olav B OB Andreassen Ole A OA Mors Ole O Gejman Pablo V PV Sklar Pamela P McGrath Patrick P Hoffmann Per P McGuffin Peter P Lee Phil H PH Mortensen Preben Bo PB Kahn René S RS Ophoff Roel A RA Adolfsson Rolf R Van der Auwera Sandra S Djurovic Srdjan S Kloiber Stefan S Heilmann-Heimbach Stefanie S Jamain Stéphane S Hamilton Steven P SP McElroy Susan L SL Lucae Susanne S Cichon Sven S Schulze Thomas G TG Hansen Thomas T Werge Thomas T Air Tracy M TM Nimgaonkar Vishwajit V Appadurai Vivek V Cahn Wiepke W Milaneschi Yuri Y Fanous Ayman H AH Kendler Kenneth S KS McQuillin Andrew A Lewis Cathryn M CM

The American journal of psychiatry 20190605 8

<h4>Objective</h4>More than 90% of people who attempt suicide have a psychiatric diagnosis; however, twin and family studies suggest that the genetic etiology of suicide attempt is partially distinct from that of the psychiatric disorders themselves. The authors present the largest genome-wide association study (GWAS) on suicide attempt, using cohorts of individuals with major depressive disorder, bipolar disorder, and schizophrenia from the Psychiatric Genomics Consortium.<h4>Methods</h4>The sa ...[more]

PMID: 31164008

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Project description:ImportanceInflammatory bowel disease (IBD) has been associated with psychiatric morbidity in adults, although previous studies have not accounted for familial confounding. In children, IBD has an even more severe course, but the association between childhood-onset IBD and psychiatric morbidity remains unclear.ObjectiveTo examine the risk of psychiatric morbidity in individuals with childhood-onset IBD, controlling for potential confounding shared between siblings.Design, setting, and participantsA population-based cohort study was conducted using data from the Swedish national health care and population registers of all children younger than 18 years born from 1973 to 2013. The study included 6464 individuals with a diagnosis of childhood-onset IBD (3228 with ulcerative colitis, 2536 with Crohn disease, and 700 with IBD unclassified) who were compared with 323 200 matched reference individuals from the general population and 6999 siblings of patients with IBD. Cox proportional hazards regression was used to estimate hazard ratios (HRs) with 95% CIs. Statistical analysis was performed from January 1, 1973, to December 1, 2013.Main outcomes and measuresThe primary outcome was any psychiatric disorder and suicide attempt. Secondary outcomes were the following specific psychiatric disorders: psychotic, mood, anxiety, eating, personality, and behavioral disorders; substance misuse; attention-deficit/hyperactivity disorder; autism spectrum disorders; and intellectual disability.ResultsThe study included 6464 individuals with a diagnosis of childhood-onset IBD (2831 girls and 3633 boys; mean [SD] age at diagnosis of IBD, 13 [4] years). During a median follow-up time of 9 years, 1117 individuals with IBD (17.3%) received a diagnosis of any psychiatric disorder (incidence rate, 17.1 per 1000 person-years), compared with 38 044 of 323 200 individuals (11.8%) in the general population (incidence rate, 11.2 per 1000 person-years), corresponding to an HR of 1.6 (95% CI, 1.5-1.7), equaling 1 extra case of any psychiatric disorder per 170 person-years. Inflammatory bowel disease was significantly associated with suicide attempt (HR, 1.4; 95% CI, 1.2-1.7) as well as mood disorders (HR, 1.6; 95% CI, 1.4-1.7), anxiety disorders (HR, 1.9; 95% CI, 1.7-2.0) eating disorders (HR, 1.6; 95% CI, 1.3-2.0), personality disorders (HR, 1.4; 95% CI, 1.1-1.8), attention-deficit/hyperactivity disorder (HR, 1.2; 95% CI, 1.1-1.4), and autism spectrum disorders (HR, 1.4; 95% CI, 1.1-1.7) Results were similar for boys and girls. Hazard ratios for any psychiatric disorder were highest in the first year of follow-up but remained statistically significant after more than 5 years. Psychiatric disorders were particularly common for patients with very early-onset IBD (<6 years) and for patients with a parental psychiatric history. Results were largely confirmed by sibling comparison, with similar estimates noted for any psychiatric disorder (HR, 1.6; 95% CI, 1.5-1.8) and suicide attempt (HR, 1.7; 95% CI, 1.2-2.3).Conclusions and relevanceOverall, childhood-onset IBD was associated with psychiatric morbidity, confirmed by between-sibling results. Particularly concerning is the increased risk of suicide attempt, suggesting that long-term psychological support be considered for patients with childhood-onset IBD.

Project description:A new era of human postmortem tissue research has emerged thanks to the development of 'omics technologies that measure genes, proteins, and spatial parameters in unprecedented detail. Also newly possible is the ability to construct polygenic scores, individual-level metrics of genetic risk (also known as polygenic risk scores/PRS), based on genome-wide association studies, GWAS. Here, we report on clinical, educational, and brain gene expression correlates of polygenic scores in ancestrally diverse samples from the Human Brain Collection Core (HBCC). Genotypes from 1418 donors were subjected to quality control filters, imputed, and used to construct polygenic scores. Polygenic scores for schizophrenia predicted schizophrenia status in donors of European ancestry (p = 4.7 × 10-8, 17.2%) and in donors with African ancestry (p = 1.6 × 10-5, 10.4% of phenotypic variance explained). This pattern of higher variance explained among European ancestry samples was also observed for other psychiatric disorders (depression, bipolar disorder, substance use disorders, anxiety disorders) and for height, body mass index, and years of education. For a subset of 223 samples, gene expression from dorsolateral prefrontal cortex (DLPFC) was available through the CommonMind Consortium. In this subgroup, schizophrenia polygenic scores also predicted an aggregate gene expression score for schizophrenia (European ancestry: p = 0.0032, African ancestry: p = 0.15). Overall, polygenic scores performed as expected in ancestrally diverse samples, given historical biases toward use of European ancestry samples and variable predictive power of polygenic scores across phenotypes. The transcriptomic results reported here suggest that inherited schizophrenia genetic risk influences gene expression, even in adulthood. For future research, these and additional polygenic scores are being made available for analyses, and for selecting samples, using postmortem tissue from the Human Brain Collection Core.

Dataset Information

GWAS of Suicide Attempt in Psychiatric Disorders and Association With Major Depression Polygenic Risk Scores.

Publications

GWAS of Suicide Attempt in Psychiatric Disorders and Association With Major Depression Polygenic Risk Scores.

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