Genetic risk discovery using WGS from a population-based resource of 10,000 suicide deaths with DNA

About This Grant

Although the rate of suicide death across the U.S. has risen dramatically over the past two decades, prevention of mortality remains challenging. This proposal will continue discovery efforts leveraging unique genetic data, comprehensive health records, and deep genealogical records. The variation in responses to environmental and social risks due to underlying genetic vulnerabilities creates an opportunity for discovery of subtypes of individuals at particularly high risk for mortality to lead to future clinical translation. Thus far, genetic discoveries associated with suicidality remain largely removed from translational utility, and are additionally primarily focused on the outcome of suicide attempt. Among individuals with evident suicidality, fewer than 10% go on to die by suicide, and roughly half of suicide deaths occur with no prior evidence of suicide attempts, suggesting that suicide attempt may be a poor proxy for determining risks leading to mortality. Data resources in the Utah Suicide Mortality Risk Study (USMRS) offer much needed opportunities to bridge this knowledge gap, including >12,000 suicide deaths linked to statewide electronic health records; ~9,000 with genotyping, and 1,053 selected for high extended familial risk with whole genome sequencing. All data linkage, subsequent de-identification, and analyses are possible via the Utah Population Database (UPDB); this comprehensive statewide resource also includes unique knowledge of familial risk through genealogical records that go back to the 1700s. In the previous award period, we used the WGS resource, prioritizing genomic regions using 43 very extended families at high risk of suicide death. We pursued non- synonymous variants in the NRXN1 gene which is important for synaptic function, demonstrating the utility of the familial approach. We more broadly characterized suicide deaths with significant extended familiality, finding significant reduction in age at death and significant increase in polygenic risk specific to suicide. We expanded our sequencing sample from N=281 to N=1,053, prioritizing suicide deaths in extended high-risk families. In addition to familial prioritization, we prioritized brain-related expression quantitative trait loci in the deaths with WGS, finding significance associated with RFPL3S (a gene important for arousal), in addition to implicating other gene pathways. We characterized non-transmitted genomic deletions using a conservative strategy of internal replication and rigorous bench validation. Our large sample of genotyped suicides provides information regarding background common genetic risks of hundreds of diagnoses and traits via polygenic scores. Additional ongoing work has also strongly implicated underlying transdiagnostic risks above and beyond psychiatric risks, driving new research directions. We propose to target discovery of mechanistic genomic change within homogeneous subtypes. Extended families provide one method of reducing heterogeneity. We also propose complementary strategies of risk discovery within extreme subtypes of physiological stress response and of brain-related function.