Sarah Colbert , The Suicide Working Group of the Psychiatric Genomics Consortium , Douglas Ruderfer , Anna Docherty , Niamh Mullins
{"title":"自杀想法和行为的全基因组关联研究:精神科基因组学联盟自杀问题工作组的最新报告","authors":"Sarah Colbert , The Suicide Working Group of the Psychiatric Genomics Consortium , Douglas Ruderfer , Anna Docherty , Niamh Mullins","doi":"10.1016/j.euroneuro.2024.08.049","DOIUrl":null,"url":null,"abstract":"<div><div>Suicidal thoughts and behaviors, specifically suicidal ideation (SI), suicide attempt (SA) and suicide death (SD), are substantially heritable, with twin and family studies estimating heritabilities in the range of 30-55%. Recently, genome-wide association studies (GWAS) have reached sufficient sample sizes to conduct well-powered analyses, leading to the identification of 4, 12 and 2 loci associated with SI, SA, and SD, respectively. Importantly, these phenotypes show strong, yet incomplete, genetic correlations with each other, motivating genetic studies of each phenotype separately to understand their underlying biology and the progression from one to the next. Here, we present an update on the progress of the latest and most extensive GWAS of SI, SA, and SD, conducted by the Psychiatric Genomics Consortium Suicide Working Group (PGC SUI).</div><div><strong>Methods:</strong> Data comprise 30 cohorts contributing to the SI GWAS (N cases=256,257, N controls=1,298,106), 42 cohorts contributing to the SA GWAS (N cases=73,087, N controls=1,327,350), and 6 cohorts contributing to the SD GWAS (N cases=6,775, N controls=841,216). Notably, these cohorts comprise individuals from four diverse genetic ancestry groups: admixed European ancestries (EUR), admixed African ancestries (AA), East Asian ancestries (EA) and admixed Latino ancestries (LAT). New phenotyping and analytic protocols have been developed by PGC SUI to ensure exceptional rigor and comparability across cohorts. GWAS meta-analyses will be conducted via inverse variance-weighted fixed effects models to identify novel genetic risk loci. Post-GWAS analyses include pathway, tissue and drug target enrichment, and examination of the SNP-heritabilities (h2SNP), and genetic relationships between SI, SA, and SD.</div><div>Preliminary analysis using the currently available SA data (SA cases = 47,174, controls = 941,010 from 26 cohorts) yielded a h2SNP of 5.6% (se = 0.003, p = 1.2e-68) and ten replicated and three novel genome-wide significant (GWS) loci, containing FYN, AIG1, and DCC. Eight GWS loci were identified in the EUR meta-analysis (h2SNP = 7%, se = 0.004) which replicated previous findings. No GWS loci were identified in the AA (h2SNP = 9.8%, se = 0.02), EA (h2SNP 5.1%, se = 0.04) or LAT (h2SNP = 10%, se =0.07) GWAS meta-analyses. We also identified significant enrichment in genes expressed in several brain tissues from GTEx and summary data-based Mendelian Randomization revealed two novel genes (GMPPB, FURIN) significantly associated with SA. This SA GWAS showed significant genetic correlations with published GWAS of SI (rg = 0.80, se = 0.04), SD (rg = 0.77, se = 0.05), and several psychiatric disorders (rgs = 0.26-0.70).</div><div>Additional data intake is almost complete within PGC SUI, and this presentation will share the final GWAS results and novel biological insights. Increased sample sizes in combination with streamlined protocols for phenotyping and analyzing suicidal thoughts and behaviors are yielding powerful genetic studies of SI, SA, and SD. Results from this study will characterize the genetic contributions to suicidal thoughts and behaviors and provide insights into their underlying biological mechanisms.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":null,"pages":null},"PeriodicalIF":6.1000,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"GENOME-WIDE ASSOCIATION STUDIES OF SUICIDAL THOUGHTS AND BEHAVIORS: AN UPDATE FROM THE PSYCHIATRIC GENOMICS CONSORTIUM SUICIDE WORKING GROUP\",\"authors\":\"Sarah Colbert , The Suicide Working Group of the Psychiatric Genomics Consortium , Douglas Ruderfer , Anna Docherty , Niamh Mullins\",\"doi\":\"10.1016/j.euroneuro.2024.08.049\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Suicidal thoughts and behaviors, specifically suicidal ideation (SI), suicide attempt (SA) and suicide death (SD), are substantially heritable, with twin and family studies estimating heritabilities in the range of 30-55%. Recently, genome-wide association studies (GWAS) have reached sufficient sample sizes to conduct well-powered analyses, leading to the identification of 4, 12 and 2 loci associated with SI, SA, and SD, respectively. Importantly, these phenotypes show strong, yet incomplete, genetic correlations with each other, motivating genetic studies of each phenotype separately to understand their underlying biology and the progression from one to the next. Here, we present an update on the progress of the latest and most extensive GWAS of SI, SA, and SD, conducted by the Psychiatric Genomics Consortium Suicide Working Group (PGC SUI).</div><div><strong>Methods:</strong> Data comprise 30 cohorts contributing to the SI GWAS (N cases=256,257, N controls=1,298,106), 42 cohorts contributing to the SA GWAS (N cases=73,087, N controls=1,327,350), and 6 cohorts contributing to the SD GWAS (N cases=6,775, N controls=841,216). Notably, these cohorts comprise individuals from four diverse genetic ancestry groups: admixed European ancestries (EUR), admixed African ancestries (AA), East Asian ancestries (EA) and admixed Latino ancestries (LAT). New phenotyping and analytic protocols have been developed by PGC SUI to ensure exceptional rigor and comparability across cohorts. GWAS meta-analyses will be conducted via inverse variance-weighted fixed effects models to identify novel genetic risk loci. Post-GWAS analyses include pathway, tissue and drug target enrichment, and examination of the SNP-heritabilities (h2SNP), and genetic relationships between SI, SA, and SD.</div><div>Preliminary analysis using the currently available SA data (SA cases = 47,174, controls = 941,010 from 26 cohorts) yielded a h2SNP of 5.6% (se = 0.003, p = 1.2e-68) and ten replicated and three novel genome-wide significant (GWS) loci, containing FYN, AIG1, and DCC. Eight GWS loci were identified in the EUR meta-analysis (h2SNP = 7%, se = 0.004) which replicated previous findings. No GWS loci were identified in the AA (h2SNP = 9.8%, se = 0.02), EA (h2SNP 5.1%, se = 0.04) or LAT (h2SNP = 10%, se =0.07) GWAS meta-analyses. We also identified significant enrichment in genes expressed in several brain tissues from GTEx and summary data-based Mendelian Randomization revealed two novel genes (GMPPB, FURIN) significantly associated with SA. This SA GWAS showed significant genetic correlations with published GWAS of SI (rg = 0.80, se = 0.04), SD (rg = 0.77, se = 0.05), and several psychiatric disorders (rgs = 0.26-0.70).</div><div>Additional data intake is almost complete within PGC SUI, and this presentation will share the final GWAS results and novel biological insights. Increased sample sizes in combination with streamlined protocols for phenotyping and analyzing suicidal thoughts and behaviors are yielding powerful genetic studies of SI, SA, and SD. Results from this study will characterize the genetic contributions to suicidal thoughts and behaviors and provide insights into their underlying biological mechanisms.</div></div>\",\"PeriodicalId\":12049,\"journal\":{\"name\":\"European Neuropsychopharmacology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":6.1000,\"publicationDate\":\"2024-10-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"European Neuropsychopharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0924977X24002487\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"European Neuropsychopharmacology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0924977X24002487","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
GENOME-WIDE ASSOCIATION STUDIES OF SUICIDAL THOUGHTS AND BEHAVIORS: AN UPDATE FROM THE PSYCHIATRIC GENOMICS CONSORTIUM SUICIDE WORKING GROUP
Suicidal thoughts and behaviors, specifically suicidal ideation (SI), suicide attempt (SA) and suicide death (SD), are substantially heritable, with twin and family studies estimating heritabilities in the range of 30-55%. Recently, genome-wide association studies (GWAS) have reached sufficient sample sizes to conduct well-powered analyses, leading to the identification of 4, 12 and 2 loci associated with SI, SA, and SD, respectively. Importantly, these phenotypes show strong, yet incomplete, genetic correlations with each other, motivating genetic studies of each phenotype separately to understand their underlying biology and the progression from one to the next. Here, we present an update on the progress of the latest and most extensive GWAS of SI, SA, and SD, conducted by the Psychiatric Genomics Consortium Suicide Working Group (PGC SUI).
Methods: Data comprise 30 cohorts contributing to the SI GWAS (N cases=256,257, N controls=1,298,106), 42 cohorts contributing to the SA GWAS (N cases=73,087, N controls=1,327,350), and 6 cohorts contributing to the SD GWAS (N cases=6,775, N controls=841,216). Notably, these cohorts comprise individuals from four diverse genetic ancestry groups: admixed European ancestries (EUR), admixed African ancestries (AA), East Asian ancestries (EA) and admixed Latino ancestries (LAT). New phenotyping and analytic protocols have been developed by PGC SUI to ensure exceptional rigor and comparability across cohorts. GWAS meta-analyses will be conducted via inverse variance-weighted fixed effects models to identify novel genetic risk loci. Post-GWAS analyses include pathway, tissue and drug target enrichment, and examination of the SNP-heritabilities (h2SNP), and genetic relationships between SI, SA, and SD.
Preliminary analysis using the currently available SA data (SA cases = 47,174, controls = 941,010 from 26 cohorts) yielded a h2SNP of 5.6% (se = 0.003, p = 1.2e-68) and ten replicated and three novel genome-wide significant (GWS) loci, containing FYN, AIG1, and DCC. Eight GWS loci were identified in the EUR meta-analysis (h2SNP = 7%, se = 0.004) which replicated previous findings. No GWS loci were identified in the AA (h2SNP = 9.8%, se = 0.02), EA (h2SNP 5.1%, se = 0.04) or LAT (h2SNP = 10%, se =0.07) GWAS meta-analyses. We also identified significant enrichment in genes expressed in several brain tissues from GTEx and summary data-based Mendelian Randomization revealed two novel genes (GMPPB, FURIN) significantly associated with SA. This SA GWAS showed significant genetic correlations with published GWAS of SI (rg = 0.80, se = 0.04), SD (rg = 0.77, se = 0.05), and several psychiatric disorders (rgs = 0.26-0.70).
Additional data intake is almost complete within PGC SUI, and this presentation will share the final GWAS results and novel biological insights. Increased sample sizes in combination with streamlined protocols for phenotyping and analyzing suicidal thoughts and behaviors are yielding powerful genetic studies of SI, SA, and SD. Results from this study will characterize the genetic contributions to suicidal thoughts and behaviors and provide insights into their underlying biological mechanisms.
期刊介绍:
European Neuropsychopharmacology is the official publication of the European College of Neuropsychopharmacology (ECNP). In accordance with the mission of the College, the journal focuses on clinical and basic science contributions that advance our understanding of brain function and human behaviour and enable translation into improved treatments and enhanced public health impact in psychiatry. Recent years have been characterized by exciting advances in basic knowledge and available experimental techniques in neuroscience and genomics. However, clinical translation of these findings has not been as rapid. The journal aims to narrow this gap by promoting findings that are expected to have a major impact on both our understanding of the biological bases of mental disorders and the development and improvement of treatments, ideally paving the way for prevention and recovery.