Harnessing advances in the genetics of suicidality to identify and dissect psychosocial pathways to risk

Project Summary Suicidal thoughts and behaviors (STB) are substantially impacted by genetic factors. However, molecular genetic studies of suicidality, and their genetically informative epidemiologic counterparts, have historically been statistically underpowered, precluding substantive interpretation of the effects of genetic influences in a developmental or psychosocial context. Recent advances include well-powered genomewide association studies alongside twin/family modeling of Swedish national registry data on (non-fatal) suicide attempt and death. The clear signals observed in these studies provide initial insight to the genetic etiology of suicidality, including: (i) suicide attempt and death are substantially, but not entirely, genetically correlated, raising the possibility that genetic liability underlying these distinct outcomes may be differentially related to risk pathways; (ii) the qualitative and quantitative nature of genetic liability to suicidality shifts across the life course; and (iii) genetic influences underlying suicidality are likely related to multiple behavioral correlates of risk, notably behavioral disinhibition and depression. Additional gene identification studies are essential to further elucidate the molecular nature of suicidality. However, to fully characterize how genetic liability manifests into STB, gene-finding studies must be complemented by research efforts that address the relationship between aggregate genetic risk and distinct STB outcomes, STB occurring during different periods of development (e.g., adolescence versus adulthood), key behavioral mediators, and environmental precipitants. The current proposal will address this critical knowledge gap through the incorporation of aggregate genetic risk scores for suicide attempt or death into models of psychosocial risk for STB. We will implement our research aims in a range of target samples selected for the unique perspectives they enable: (i) They span the life course, from childhood to late adulthood (and through death in the case of national Swedish registries); (ii) several include longitudinal assessments; (iii) they are densely phenotypically characterized, with data available on multiple STB (e.g., ideation, plans, attempts), behavioral mediators, and environmental risk factors; and (iv) they include five population-based studies, enabling us to expand our understanding of STB etiology outside of highly selected samples, along with two samples ascertained for history of major depression, enabling us to assess whether pathways of risk to STB are consistent across groups, and whether genetic liability to suicidality is superseded by the powerful clinical context of depression. The assembled team’s complementary areas of expertise are ideally suited to successfully implement the research aims. The proposed analyses leverage the aforementioned recent advances in the genetics of suicidality while enabling unparalleled and critical context for understanding the complex and dynamic pathways to suicidal thoughts and behaviors.