A genome-wide association study of suicide attempts in the million veterans program identifies evidence of pan-ancestry and ancestry-specific risk loci

Abstract

To identify pan-ancestry and ancestry-specific loci associated with attempting suicide among veterans, we conducted a genome-wide association study (GWAS) of suicide attempts within a large, multi-ancestry cohort of U.S. veterans enrolled in the Million Veterans Program (MVP). Cases were defined as veterans with a documented history of suicide attempts in the electronic health record (EHR; N =14,089) and controls were defined as veterans with no documented history of suicidal thoughts or behaviors in the EHR ( N =395,064). GWAS was performed separately in each ancestry group, controlling for sex, age and genetic substructure. Pan-ancestry risk loci were identified through meta-analysis and included two genome-wide significant loci on chromosomes 20 ( p =3.64×10 −9 ) and 1 ( p =3.69×10 −8 ). A strong pan-ancestry signal at the Dopamine Receptor D2 locus ( p =1.77×10 −7 ) was also identified and subsequently replicated in a large, independent international civilian cohort ( p =7.97×10 −4 ). Additionally, ancestry-specific genome-wide significant loci were also detected in African-Americans, European-Americans, Asian-Americans, and Hispanic-Americans. Pathway analyses suggested overrepresentation of many biological pathways with high clinical significance, including oxytocin signaling, glutamatergic synapse, cortisol synthesis and secretion, dopaminergic synapse, and circadian rhythm. These findings confirm that the genetic architecture underlying suicide attempt risk is complex and includes both pan-ancestry and ancestry-specific risk loci. Moreover, pathway analyses suggested many commonly impacted biological pathways that could inform development of improved therapeutics for suicide prevention.

Digging deeper into GWAS signal using GRIN implicates additional genes contributing to suicidal behavior

“…While certain variants have been previously described ( e . g ., variants in DRD2, PDE4B , and SPATA17 8,9,11 ), the present study characterizes additional genes contributing to dendritic structure and multiple key neurotransmitter pathways associated with suicidality. Among these additional genes, missense variants in CDC42BPB 35 , DALRD3 26 , DHX30 25 , SMARCC1 22 , and ZNF589 36 are known to impair behavioral and neurodevelopmental processes.…”

“…After benchmarking GRIN on gold standard gene sets, we applied it to suicide attempt GWAS summary statistics from the Million Veteran Program (MVP 11 ) to understand which genes contribute to psychiatric pathophysiology in this military veteran population. We utilized both conventional MAGMA 4 and H-MAGMA 1 solely for gene assignment from SNPs at different genome-wide significance thresholds ( Fig.…”

“…Suicide attempts were identified from United States veterans as described previously 11 . Suicide attempts were characterized by using a combination of Veterans Healthcare Administration (VHA) databases from the VA: the Suicide Prevention Application Network (African, Asian, European, and Hispanic) were included for genome-wide association along with 14,535 cases of non-fatal suicide attempt and 294 fatal attempts.…”

“…We then applied GRIN to suicide attempt GWAS summary statistics, a complex psychiatric phenotype. Even though heritability estimates range from 17-55% 7,8 , this psychiatric disorder has elicited few genome-wide significant variants to date [8][9][10][11] . We analyzed independent suicide attempt GWAS results from the Million Veteran Program (MVP 11 ) and the International Suicide Genetics Consortium (ISGC 9 ).…”

“…Even though heritability estimates range from 17-55% 7,8 , this psychiatric disorder has elicited few genome-wide significant variants to date [8][9][10][11] . We analyzed independent suicide attempt GWAS results from the Million Veteran Program (MVP 11 ) and the International Suicide Genetics Consortium (ISGC 9 ). As few variants were significant at traditional genomewide significance, we explored SNPs at a less stringent threshold and used multiple SNP-to-gene assignment methods to elucidate the underlying mechanisms of the heritable components of suicidality.…”