GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors.
Docherty AR., Mullins N., Ashley-Koch AE., Qin X., Coleman JRI., Shabalin A., Kang J., Murnyak B., Wendt F., Adams M., Campos AI., DiBlasi E., Fullerton JM., Kranzler HR., Bakian AV., Monson ET., Rentería ME., Walss-Bass C., Andreassen OA., Behera C., Bulik CM., Edenberg HJ., Kessler RC., Mann JJ., Nurnberger JI., Pistis G., Streit F., Ursano RJ., Polimanti R., Dennis M., Garrett M., Hair L., Harvey P., Hauser ER., Hauser MA., Huffman J., Jacobson D., Madduri R., McMahon B., Oslin DW., Trafton J., Awasthi S., Berrettini WH., Bohus M., Chang X., Chen H-C., Chen WJ., Christensen ED., Crow S., Duriez P., Edwards AC., Fernández-Aranda F., Galfalvy H., Gandal M., Gorwood P., Guo Y., Hafferty JD., Hakonarson H., Halmi KA., Hishimoto A., Jain S., Jamain S., Jiménez-Murcia S., Johnson C., Kaplan AS., Kaye WH., Keel PK., Kennedy JL., Kim M., Klump KL., Levey DF., Li D., Liao S-C., Lieb K., Lilenfeld L., Marshall CR., Mitchell JE., Okazaki S., Otsuka I., Pinto D., Powers A., Ramoz N., Ripke S., Roepke S., Rozanov V., Scherer SW., Schmahl C., Sokolowski M., Starnawska A., Strober M., Su M-H., Thornton LM., Treasure J., Ware EB., Watson HJ., Witt SH., Woodside DB., Yilmaz Z., Zillich L., Adolfsson R., Agartz I., Alda M., Alfredsson L., Appadurai V., Artigas MS., Van der Auwera S., Azevedo MH., Bass N., Bau CHD., Baune BT., Bellivier F., Berger K., Biernacka JM., Bigdeli TB., Binder EB., Boehnke M., Boks MP., Braff DL., Bryant R., Budde M., Byrne EM., Cahn W., Castelao E., Cervilla JA., Chaumette B., Corvin A., Craddock N., Djurovic S., Foo JC., Forstner AJ., Frye M., Gatt JM., Giegling I., Grabe HJ., Green MJ., Grevet EH., Grigoroiu-Serbanescu M., Gutierrez B., Guzman-Parra J., Hamshere ML., Hartmann AM., Hauser J., Heilmann-Heimbach S., Hoffmann P., Ising M., Jones I., Jones LA., Jonsson L., Kahn RS., Kelsoe JR., Kendler KS., Kloiber S., Koenen KC., Kogevinas M., Krebs M-O., Landén M., Leboyer M., Lee PH., Levinson DF., Liao C., Lissowska J., Mayoral F., McElroy SL., McGrath P., McGuffin P., McQuillin A., Mehta D., Melle I., Mitchell PB., Molina E., Morken G., Nievergelt C., Nöthen MM., O'Donovan MC., Ophoff RA., Owen MJ., Pato C., Pato MT., Penninx BWJH., Potash JB., Power RA., Preisig M., Quested D., Ramos-Quiroga JA., Reif A., Ribasés M., Richarte V., Rietschel M., Rivera M., Roberts A., Roberts G., Rouleau GA., Rovaris DL., Sanders AR., Schofield PR., Schulze TG., Scott LJ., Serretti A., Shi J., Sirignano L., Sklar P., Smeland OB., Smoller JW., Sonuga-Barke EJS., Trzaskowski M., Tsuang MT., Turecki G., Vilar-Ribó L., Vincent JB., Völzke H., Walters JTR., Weickert CS., Weickert TW., Weissman MM., Williams LM., Wray NR., Zai CC., Agerbo E., Børglum AD., Breen G., Demontis D., Erlangsen A., Gelernter J., Glatt SJ., Hougaard DM., Hwu H-G., Kuo P-H., Lewis CM., Li QS., Liu C-M., Martin NG., McIntosh AM., Medland SE., Mors O., Nordentoft M., Olsen CM., Porteous D., Smith DJ., Stahl EA., Stein MB., Wasserman D., Werge T., Whiteman DC., Willour V., VA Million Veteran Program (MVP) None., MVP Suicide Exemplar Workgroup None., Suicide Working Group of the Psychiatric Genomics Consortium None., Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium None., Bipolar Disorder Working Group of the Psychiatric Genomics Consortium None., Schizophrenia Working Group of the Psychiatric Genomics Consortium None., Eating Disorder Working Group of the Psychiatric Genomics Consortium None., German Borderline Genomics Consortium None., Coon H., Beckham JC., Kimbrel NA., Ruderfer DM.
ObjectiveSuicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures.MethodsThis study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses.ResultsMulti-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10-8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10-80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors.ConclusionsThis multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death.