Characterizing the Role of Copy Number Variants in Suicidality

It is firmly established that there is a genetic contribution to the biological basis of suicidality, which is partially distinct from the genetics of co-occurring psychiatric disorders. Recently, knowledge of the common genetic variation underlying suicidality has substantially advanced, through the efforts of international consortia to conduct large-scale analyses across studies. However, the role of rare genetic variation in suicidality remains poorly understood. Copy number variants (CNVs) are duplications or deletions of segments of DNA, and have been strongly implicated in psychiatric disorders. CNVs can disrupt multiple genes, and in contrast to common genetic variation, pathogenic CNVs are individually rare and confer large effects on risk. This project will conduct a comprehensive investigation of the role of CNVs in suicidality, leveraging the joint expertise and data resources of the Psychiatric Genomics Consortium Suicide and CNV Working Groups. We will use genetic data from at least 14 international studies comprising >97,000 suicidal ideation (SI) cases, >24,000 suicide attempt (SA) cases, and >500,000 controls. SI and SA will be robustly defined across studies according to the established phenotyping protocol of the Psychiatric Genomics Consortium Suicide Working Group.

We hypothesize that rare CNVs play a role in suicidality and that there are specific CNVs with larger effects on suicide phenotypes than on related psychiatric disorders. In Aim 1, we will analyze the association of CNVs across the entire genome with SI, SA and a combined suicidality phenotype (SI or SA), while controlling for the role of CNVs in co-occurring psychiatric disorders. We propose that characterizing the association of CNVs across the genome with suicidality will illuminate the biological pathways, brain regions and cell-types involved, providing novel insights into the underlying biology. In Aim 2, we will test for an increased aggregate burden of CNVs in sets of genes representing biological pathways, gene expression in different brain regions and brain cell-types. We posit that both rare CNVs and common genetic variation each increase risk for suicidality, and that individuals’ background of common genetic variation alters the impact of CNVs on suicidality risk. In Aim 3, we will calculate polygenic risk scores (PRS) which represent individuals’ burden of common genetic variation associated with SI and SA. We will examine the risk for suicide phenotypes conferred by PRS and CNVs separately, and subsequently test whether these effects sum together, or interact such that the effects of CNVs on risk are dependent on individuals’ PRS.Since suicide phenotypes lack pathological or biological defining features, understanding their genetic basis is a clear path to elucidate their biological etiologies, identify potential drug targets, modifiable risk factors, and high-risk groups that would benefit from intervention strategies. This study is expected to elucidate the role of rare CNVs in suicidality, uncover relevant genes and biological processes, and integrate common and rare genetic variation to inform risk prediction and stratification efforts. The genome-wide CNV association results will be widely available and the individual-level genetic and phenotypic data will be available with controlled access, enabling researchers to address additional future questions.