Intragenic deletions from whole genome sequencing of 1054 suicide deaths

Suicide is an urgent public health crisis that claimed over 48,000 lives in the US in 2022. The importance of genetics in suicide risk has been established by classical twin and family studies, and confirmed with recent large genome-wide association studies (GWAS). While the GWAS are beginning to reveal genetic risk due to common variants each with small effect on liability, these results explain only a fraction of the genetic risk. As with other complex health conditions, some of this unexplained risk is likely due to rarer variants with larger effect on liability. Using whole genome sequencing (WGS) data from 1,054 population-ascertained Utah suicide deaths, we investigated intragenic deletions as a class of genomic variation highly likely to disrupt gene function. To minimize the chance of false positive results, studied deletions were limited to those found in three large publicly-available control datasets (1000 Genomes, GnomAD, and Centers for Common Disease Genomics). Additional internal replication also required deletions to occur at least twice in WGS from an initial cohort of 670 suicide deaths then again in a second cohort of 384 suicide deaths. All results meeting these filters were manually validated. There were 11 validated deletions with at least 2-fold increase in frequency over occurrence in controls (range 2.28 to 4.46). These results implicated genes associated with risk of mental health conditions (MPST, IL4R, CDH13), epilepsy (CLCA4), intellectual disability (ZNF44), neuronal function (OSBPL2), metabolic function (FBOX36), lipid metabolism (TM9SF3), immune related functions (PIPOX, IL4R), and transcriptional repression (ZHX3). SNPs in genes implicated by the deletions have also been associated with mental health conditions, neuronal function, immune response, and other critical biological pathways including neuroinflammation and cellular response to stress. Demographic and clinical associations of suicide deaths with specific genetic deletions, highlight the prevalence of mood, anxiety and bipolar disorders and variations in age at suicide death among affected individuals. This work is the largest genome-wide analyses of WGS variation in suicide deaths to date. Pending replication, results will guide future functional studies with the eventual goals of increased understanding of mechanisms leading to risk.