GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors.
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Docherty Anna R, Mullins Niamh, Ashley-Koch Allison E, Qin Xuejun, Coleman Jonathan R I, Shabalin Andrey, Kang JooEun, Murnyak Balasz, Wendt Frank, Adams Mark, Campos Adrian I, DiBlasi Emily, Fullerton Janice M, Kranzler Henry R, Bakian Amanda V, Monson Eric T, Rentería Miguel E, Walss-Bass Consuelo, Andreassen Ole A, Behera Chittaranjan, Bulik Cynthia M, Edenberg Howard J, Kessler Ronald C, Mann J John, Nurnberger John I, Pistis Giorgio, Streit Fabian, Ursano Robert J, Polimanti Renato, Dennis Michelle, Garrett Melanie, Hair Lauren, Harvey Philip, Hauser Elizabeth R, Hauser Michael A, Huffman Jennifer, Jacobson Daniel, Madduri Ravi, McMahon Benjamin, Oslin David W, Trafton Jodie, Awasthi Swapnil, Berrettini Wade H, Bohus Martin, Chang Xiao, Chen Hsi-Chung, Chen Wei J, Christensen Erik D, Crow Scott, Duriez Philibert, Edwards Alexis C, Fernández-Aranda Fernando, Galfalvy Hanga, Gandal Michael, Gorwood Philip, Guo Yiran, Hafferty Jonathan D, Hakonarson Hakon, Halmi Katherine A, Hishimoto Akitoyo, Jain Sonia, Jamain Stéphane, Jiménez-Murcia Susana, Johnson Craig, Kaplan Allan S, Kaye Walter H, Keel Pamela K, Kennedy James L, Kim Minsoo, Klump Kelly L, Levey Daniel F, Li Dong, Liao Shih-Cheng, Lieb Klaus, Lilenfeld Lisa, Marshall Christian R, Mitchell James E, Okazaki Satoshi, Otsuka Ikuo, Pinto Dalila, Powers Abigail, Ramoz Nicolas, Ripke Stephan, Roepke Stefan, Rozanov Vsevolod, Scherer Stephen W, Schmahl Christian, Sokolowski Marcus, Starnawska Anna, Strober Michael, Su Mei-Hsin, Thornton Laura M, Treasure Janet, Ware Erin B, Watson Hunna J, Witt Stephanie H, Woodside D Blake, Yilmaz Zeynep, Zillich Lea, Adolfsson Rolf, Agartz Ingrid, Alda Martin, Alfredsson Lars, Appadurai Vivek, Artigas María Soler, Van der Auwera Sandra, Azevedo M Helena, Bass Nicholas, Bau Claiton H D, Baune Bernhard T, Bellivier Frank, Berger Klaus, Biernacka Joanna M, Bigdeli Tim B, Binder Elisabeth B, Boehnke Michael, Boks Marco P, Braff David L, Bryant Richard, Budde Monika, Byrne Enda M, Cahn Wiepke, Castelao Enrique, Cervilla Jorge A, Chaumette Boris, Corvin Aiden, Craddock Nicholas, Djurovic Srdjan, Foo Jerome C, Forstner Andreas J, Frye Mark, Gatt Justine M, Giegling Ina, Grabe Hans J, Green Melissa J, Grevet Eugenio H, Grigoroiu-Serbanescu Maria, Gutierrez Blanca, Guzman-Parra Jose, Hamshere Marian L, Hartmann Annette M, Hauser Joanna, Heilmann-Heimbach Stefanie, Hoffmann Per, Ising Marcus, Jones Ian, Jones Lisa A, Jonsson Lina, Kahn René S, Kelsoe John R, Kendler Kenneth S, Kloiber Stefan, Koenen Karestan C, Kogevinas Manolis, Krebs Marie-Odile, Landén Mikael, Leboyer Marion, Lee Phil H, Levinson Douglas F, Liao Calwing, Lissowska Jolanta, Mayoral Fermin, McElroy Susan L, McGrath Patrick, McGuffin Peter, McQuillin Andrew, Mehta Divya, Melle Ingrid, Mitchell Philip B, Molina Esther, Morken Gunnar, Nievergelt Caroline, Nöthen Markus M, O'Donovan Michael C, Ophoff Roel A, Owen Michael J, Pato Carlos, Pato Michele T, Penninx Brenda W J H, Potash James B, Power Robert A, Preisig Martin, Quested Digby, Ramos-Quiroga Josep Antoni, Reif Andreas, Ribasés Marta, Richarte Vanesa, Rietschel Marcella, Rivera Margarita, Roberts Andrea, Roberts Gloria, Rouleau Guy A, Rovaris Diego L, Sanders Alan R, Schofield Peter R, Schulze Thomas G, Scott Laura J, Serretti Alessandro, Shi Jianxin, Sirignano Lea, Sklar Pamela, Smeland Olav B, Smoller Jordan W, Sonuga-Barke Edmund J S, Trzaskowski Maciej, Tsuang Ming T, Turecki Gustavo, Vilar-Ribó Laura, Vincent John B, Völzke Henry, Walters James T R, Weickert Cynthia Shannon, Weickert Thomas W, Weissman Myrna M, Williams Leanne M, Wray Naomi R, Zai Clement C, Agerbo Esben, Børglum Anders D, Breen Gerome, Demontis Ditte, Erlangsen Annette, Gelernter Joel, Glatt Stephen J, Hougaard David M, Hwu Hai-Gwo, Kuo Po-Hsiu, Lewis Cathryn M, Li Qingqin S, Liu Chih-Min, Martin Nicholas G, McIntosh Andrew M, Medland Sarah E, Mors Ole, Nordentoft Merete, Olsen Catherine M, Porteous David, Smith Daniel J, Stahl Eli A, Stein Murray B, Wasserman Danuta, Werge Thomas, Whiteman David C, Willour Virginia, VA Million Veteran Program (MVP), MVP Suicide Exemplar Workgroup, Suicide Working Group of the Psychiatric Genomics Consortium, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Eating Disorder Working Group of the Psychiatric Genomics Consortium, German Borderline Genomics Consortium, Coon Hilary, Beckham Jean C, Kimbrel Nathan A, Ruderfer Douglas M
Аннотация
METHODS: This 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.
RESULTS: Multi-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.
CONCLUSIONS: This 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.