A founder population reveals genetic variation with major effect on serious mental illness.

Genetic studies of serious mental illness (SMI, including schizophrenia and bipolar disorder) have implicated two classes of risk variant: common variants 1-3 , each of small effect but collectively accounting for most population-level risk, and ultra-rare coding variants 4,5 which confer large risk in a small number of individuals. Most such studies cannot directly assess the impact of specific variants on SMI, transdiagnostically, as the phenotypic information that they collect is focused on a single diagnosis. Here we report results of association analysis of predicted deleterious variants from exome sequencing of 21,958 cases (SMI and severe major depressive disorder) and 19,826 controls from the Mision Origen biobank in the Paisa genetic isolate of Colombia. We identified transdiagnostic associations to seven genes, three at an exome-wide and four at a false discovery rate significance threshold. Five of these genes have not previously been implicated in SMI ( ADAP1 , WIPI1 , NFE2L1 , FBXO10 , and HLA - DPB1 ); for the first four of these the association is driven by variants enriched in the Paisa due to a founder effect, filling the gap between ultra-rare and common variants. The strongest association that we observe is to a frameshift variant (7:904169:T:TC) in ADAP1 that is genome-wide significant for SMI, schizophrenia, and bipolar disorder and increases risk for both diagnoses by more than threefold; it truncates ADAP1 , a brain-enriched Arf6 GTPase-activating/scaffolding protein that has been mechanistically linked to post-mitotic neuronal morphogenesis and regulation of dendritic differentiation 6 . Variant carriers differ significantly from other SMI cases in Mision Origen for psychotic, manic, and cognitive item-level phenotypes assessed through analyses of electronic health records 7-9 and displayed impaired executive function on neurocognitive testing. Variant carriers differ significantly from other SMI cases in Mision Origen for multiple item-level phenotypes (psychotic, manic, and cognitive) assigned through natural language processing of longitudinal electronic health records. Although the 7:904169:T:TC variant is not significantly associated with major depressive disorder, carriers compared to others with this diagnosis display a significant increase in symptoms typical of bipolar disorder. The variant's high allele frequency in Mision Origen (~0.4%) will enable population-level studies to stratify SMI based on causation and identify additional factors influencing risk and resilience.