Novel ultra-rare exonic variants identified in a founder population implicate cadherins in schizophrenia

The identification of rare variants associated with schizophrenia has proven challenging due to genetic heterogeneity, which is reduced in founder populations. In samples from the Ashkenazi Jewish population, we report that schizophrenia cases had a greater frequency of novel missense or loss of function (MisLoF) ultra-rare variants (URVs) compared to controls, and the MisLoF URV burden was inversely correlated with polygenic risk scores in cases. Characterizing 141 “case-only” genes (MisLoF URVs in ≥3 cases with none in controls), the cadherin gene set was associated with schizophrenia. We report a recurrent case mutation in PCDHA3 that results in the formation of cytoplasmic aggregates and failure to engage in homophilic interactions on the plasma membrane in cultured cells. Modeling purifying selection, we demonstrate that deleterious URVs are greatly overrepresented in the Ashkenazi population, yielding enhanced power for association studies. Identification of the cadherin/protocadherin family as risk genes helps specify the synaptic abnormalities central to schizophrenia. •Schizophrenia rare variant discovery is enhanced in the Ashkenazi founder population•Ultra-rare variant burden is inversely correlated with polygenic risk scores in cases•Ultra-rare exonic variants in schizophrenia cases are enriched in cadherin genes•A recurrent case mutation in PCDHA3 disrupts homophilic interactions in culture Lencz et al. demonstrate that the Ashkenazi Jewish population has an enhanced power for genetic discovery in schizophrenia. Cases had excess missense or loss-of-function ultra-rare variants, enriched in cadherins and neurodevelopmental genes. A recurrent case mutation in PCDHA3 results in the formation of cytoplasmic aggregates and failure to engage in membrane homophilic interactions.