Genome-wide association studies identify 77 loci for suicidality and provide novel biological insights.
| Title: | Genome-wide association studies identify 77 loci for suicidality and provide novel biological insights. |
|---|---|
| Authors: | Colbert SMC; Department of Psychiatry, Icahn School of Medicine at Mount Sinai.; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai.; Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai.; Department of Artificial Intelligence and Human Health, Icahn School of Medicine at Mount Sinai.; Ruderfer D; Department of Biomedical Informatics, Vanderbilt University Medical Center.; Vanderbilt Genetics Institute, Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center.; Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center.; Docherty AR; Department of Psychiatry, University of Utah Spencer Fox Eccles School of Medicine.; Huntsman Mental Health Institute.; Clinical and Translational Science Institute & the Center for Genomic Medicine, University of Utah.; Mullins N; Department of Psychiatry, Icahn School of Medicine at Mount Sinai.; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai.; Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai.; Department of Artificial Intelligence and Human Health, Icahn School of Medicine at Mount Sinai. |
| Corporate Authors: | Psychiatric Genomics Consortium Suicide Working Group |
| Source: | MedRxiv : the preprint server for health sciences [medRxiv] 2025 Oct 23. Date of Electronic Publication: 2025 Oct 23. |
| Publication Type: | Journal Article; Preprint |
| Language: | English |
| Journal Info: | Country of Publication: United States NLM ID: 101767986 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: medRxiv Subsets: PubMed not MEDLINE |
| Abstract: | Suicidality is heritable and a leading cause of global morbidity and mortality, yet its biological etiology remains largely elusive. We conducted multi-ancestry genome-wide association study meta-analyses of suicidal ideation (259,747 cases), suicide attempt (64,993 cases), suicide death (9,197 cases), and suicidal behavior (suicide attempt/ death, 75,300 cases), across 54 cohorts (e.g., the Psychiatric Genomics Consortium, Million Veteran Program, UK Biobank). We identified 77 significant loci across meta-analyses, including 59 previously unreported for suicidality. SNP-based heritability ranged from 2.0-6.7% and there were strong, yet incomplete, genetic correlations between suicidality phenotypes (0.70-0.88). Fine-mapping prioritized 27 putative causal SNPs and 20 credible genes. Enrichment analyses implicated synaptic pathways and neuronal populations predominantly in subcortical brain regions (e.g., amygdala excitatory, medium spiny, hippocampal CA1-3). Together, these findings establish suicidality as a polygenic set of traits with both shared and distinct genetic influences, providing a foundation for future studies of suicide biology and etiology. |
| References: | Nat Genet. 2016 Oct;48(10):1279-83. (PMID: 27548312); Nat Genet. 2020 Dec;52(12):1355-1363. (PMID: 33199916); Suicide Life Threat Behav. 2000 Spring;30(1):18-33. (PMID: 10782716); Nat Genet. 2016 May;48(5):481-7. (PMID: 27019110); Nat Genet. 2022 May;54(5):573-580. (PMID: 35513724); Science. 2023 Oct 13;382(6667):eadd7046. (PMID: 37824663); Psychol Rev. 2010 Apr;117(2):575-600. (PMID: 20438238); N Engl J Med. 2020 Jan 16;382(3):266-274. (PMID: 31940700); Br J Psychiatry. 2008 Feb;192(2):98-105. (PMID: 18245022); PLoS Comput Biol. 2015 Apr 17;11(4):e1004219. (PMID: 25885710); Transl Psychiatry. 2025 Feb 20;15(1):63. (PMID: 39979244); Transl Psychiatry. 2023 May 12;13(1):167. (PMID: 37173343); World J Biol Psychiatry. 2015;16(8):544-66. (PMID: 25112792); Mol Psychiatry. 2022 Apr;27(4):2264-2272. (PMID: 35347246); Nature. 2010 Oct 28;467(7319):1061-73. (PMID: 20981092); Am J Hum Genet. 2023 Feb 2;110(2):179-194. (PMID: 36634672); Glob Public Health. 2020 Dec;15(12):1894-1901. (PMID: 32744898); Nucleic Acids Res. 2021 Jan 8;49(D1):D1144-D1151. (PMID: 33237278); Nat Genet. 2024 Jun;56(6):1310-1318. (PMID: 38831010); Nat Genet. 2018 Nov;50(11):1600-1607. (PMID: 30297966); Am J Psychiatry. 2023 Oct 1;180(10):723-738. (PMID: 37777856); Am J Psychiatry. 2019 Aug 1;176(8):651-660. (PMID: 31164008); Drug Discov Today. 2012 Dec;17(23-24):1289-98. (PMID: 22889966); Nat Genet. 2016 Oct;48(10):1284-1287. (PMID: 27571263); Psychol Med. 2003 Apr;33(3):395-405. (PMID: 12701661); Nat Genet. 2015 Mar;47(3):291-5. (PMID: 25642630); Nat Genet. 2015 Nov;47(11):1236-41. (PMID: 26414676); Gigascience. 2015 Feb 25;4:7. (PMID: 25722852); Bioinformatics. 2020 Feb 1;36(3):930-933. (PMID: 31393554); Neuron. 2019 Jul 17;103(2):217-234.e4. (PMID: 31171447); Biol Psychiatry. 2022 Feb 1;91(3):313-327. (PMID: 34861974); Curr Behav Neurosci Rep. 2019;6:141-150. (PMID: 33224711); Trends Neurosci. 2007 May;30(5):228-35. (PMID: 17408758); Am J Med Genet B Neuropsychiatr Genet. 2014 Jul;165B(5):428-37. (PMID: 24964207); PLoS Med. 2009 Aug;6(8):e1000123. (PMID: 19668361); Cell. 2025 Feb 06;188(3):640-652.e9. (PMID: 39814019); Nat Genet. 2000 May;25(1):25-9. (PMID: 10802651); Complex Psychiatry. 2023 Jan 18;9(1-4):11-23. (PMID: 38058956); Science. 2020 Sep 11;369(6509):1318-1330. (PMID: 32913098); Complex Psychiatry. 2021 Aug;7(1-2):34-44. (PMID: 35592092); Nat Genet. 2022 Sep;54(9):1355-1363. (PMID: 35982161); Psychol Bull. 2017 Feb;143(2):187-232. (PMID: 27841450); Psychol Med. 2002 Jan;32(1):11-24. (PMID: 11883722); Lancet Psychiatry. 2014 Jun;1(1):63-72. (PMID: 26360403); PLoS Genet. 2023 Mar 20;19(3):e1010623. (PMID: 36940203); Am J Psychiatry. 2013 May;170(5):511-20. (PMID: 23511308); Nat Genet. 2024 Sep;56(9):1841-1850. (PMID: 39187616); Nat Commun. 2017 Nov 28;8(1):1826. (PMID: 29184056); BMC Bioinformatics. 2011 Mar 17;12:77. (PMID: 21414208); Am J Psychiatry. 1999 Feb;156(2):181-9. (PMID: 9989552); Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50. (PMID: 16199517); Nat Genet. 2015 Nov;47(11):1228-35. (PMID: 26414678); Genetics. 1992 Oct;132(2):583-9. (PMID: 1427045); Bioinformatics. 2010 Sep 1;26(17):2190-1. (PMID: 20616382); Psychol Med. 2001 Jul;31(5):837-45. (PMID: 11459381); Behav Genet. 2023 Nov;53(5-6):404-415. (PMID: 37713023); Am J Med Genet B Neuropsychiatr Genet. 2021 Dec;186(8):485-507. (PMID: 34726322); Am J Psychiatry. 2020 Oct 1;177(10):917-927. (PMID: 32998551); Nat Commun. 2018 Jun 11;9(1):2282. (PMID: 29891976); Nature. 2022 Oct;610(7933):704-712. (PMID: 36224396); Prev Med. 2021 Nov;152(Pt 1):106604. (PMID: 34538375); Mol Psychiatry. 2020 Oct;25(10):2410-2421. (PMID: 30116032); Am J Psychiatry. 2021 Nov;178(11):1060-1069. (PMID: 34256608); Psychiatry Res. 2025 May;347:116391. (PMID: 40020535); Wien Klin Wochenschr. 2007;119(15-16):463-75. (PMID: 17721766); Compr Psychiatry. 2019 Dec 26;98:152158. (PMID: 32004858); Nature. 2025 Mar;639(8056):968-975. (PMID: 39843750); J R Stat Soc Series B Stat Methodol. 2020 Dec;82(5):1273-1300. (PMID: 37220626); Ann Eugen. 1951 Mar;15(4):323-54. (PMID: 24540312); Nat Genet. 2016 Nov;48(11):1443-1448. (PMID: 27694958); Nat Commun. 2025 Jan 4;16(1):395. (PMID: 39755698); Nat Commun. 2021 Dec 8;12(1):7117. (PMID: 34880243); Pharmacol Biochem Behav. 2012 Feb;100(4):656-64. (PMID: 21889952); Nat Med. 2023 Sep;29(9):2224-2232. (PMID: 37653343); Depress Anxiety. 2010 Sep;27(9):791-8. (PMID: 20217852); Genet Epidemiol. 2012 Apr;36(3):214-24. (PMID: 22714935); Nat Neurosci. 2021 Oct;24(10):1367-1376. (PMID: 34446935); Psychiatr Clin North Am. 2000 Mar;23(1):11-25. (PMID: 10729928); Am J Med Genet B Neuropsychiatr Genet. 2021 Dec;186(8):445-455. (PMID: 34821019); Commun Med (Lond). 2025 May 16;5(1):176. (PMID: 40379965); Bioinformatics. 2010 Mar 15;26(6):841-2. (PMID: 20110278); JAMA Psychiatry. 2023 Feb 1;80(2):135-145. (PMID: 36515925); Am J Med Genet B Neuropsychiatr Genet. 2024 Oct;195(7):e32982. (PMID: 38551161); Nat Neurosci. 2025 Jul;28(7):1393-1403. (PMID: 40562893); Nat Hum Behav. 2019 May;3(5):513-525. (PMID: 30962613); Biol Psychiatry. 2020 Jul 15;88(2):169-184. (PMID: 31926635); Science. 2019 Nov 29;366(6469):1134-1139. (PMID: 31727856) |
| Grant Information: | R01 MH124851 United States MH NIMH NIH HHS; P30 ES005605 United States ES NIEHS NIH HHS; R01 MH132733 United States MH NIMH NIH HHS; R01 DA054869 United States DA NIDA NIH HHS; R01 MH124873 United States MH NIMH NIH HHS; R01 MH124875 United States MH NIMH NIH HHS; R01 MH123619 United States MH NIMH NIH HHS; S10 OD018522 United States OD NIH HHS; S10 OD026880 United States OD NIH HHS; R01 MH124847 United States MH NIMH NIH HHS; R01 MH124871 United States MH NIMH NIH HHS; R01 MH124839 United States MH NIMH NIH HHS |
| Entry Date(s): | Date Created: 20251124 Date Completed: 20251202 Latest Revision: 20260306 |
| Update Code: | 20260306 |
| PubMed Central ID: | PMC12633560 |
| DOI: | 10.1101/2025.10.22.25338076 |
| PMID: | 41282879 |
| Database: | MEDLINE |
Journal Article; Preprint