Characterization of the suicide attempt-associated chromosome 7 locus

Abstract

Suicide is one of the leading causes of death worldwide. Although suicidal behaviors demonstrate high heritability, identifying the underlying genetic factors has been challenging. Recent genome-wide association studies for suicidal behavior identified a SNP on chromosome 7, rs62474683, which was the most significantly associated SNP. As this SNP is intergenic, the mechanism by which it may be related to suicidal behaviors is unclear. In order to determine the potential functional effects of the rs62474683 genotype, and how it may be related to suicidal behavior, we ascertained expression of genes within a 1.8Mbp region surrounding this SNP in two brain regions in individuals who died by suicide, and investigated the relationship between genetic variation and gene expression. Additionally, we explored, at the single cell level, the effect of the variant on gene expression and chromatin accessibility. While we found several genes displaying differential expression, Forkhead box P2 (FOXP2) was the most consistently altered in brains of individuals who died by suicide. and its expression was related to rs62474683 genotype. Furthermore, the relationship between FOXP2 expression and suicide appeared to be both brain region- and cell type-specific. Finally, we found evidence for a direct relationship between the region containing rs62474683 and FOXP2, and identified Homeobox family transcription factors as potential mediators of the relationship between FOXP2 and the rs62474683 SNP. In conclusion, our study provides evidence for a functional relationship between the most significant suicide attempt-associated locus to date and genes displaying differential expression in individuals who died by suicide.