Novel Ultra-Rare Exonic Variants Identified in a Founder Population Implicate Cadherins in Schizophrenia

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Summary Identification of rare genetic variants associated with schizophrenia has proven challenging due to multiple sources of heterogeneity, which may be reduced in founder populations. We examined ultra-rare exonic variants in 786 patients with schizophrenia and 463 healthy comparison subjects, all drawn from the Ashkenazi Jewish population. Cases had a higher frequency of novel missense or loss of function (MisLoF) variants compared to controls. Characterizing 141 “case-only” genes (in which ≥ 3 cases in our dataset had MisLoF variants with none found in controls), we identified cadherins as a novel gene set associated with schizophrenia, including a recurrent mutation in PCDHA3 . Modeling the effects of purifying selection demonstrated that deleterious ultra-rare variants are greatly over-represented in the Ashkenazi population, resulting in enhanced power for rare variant association. Identification of cell adhesion genes in the cadherin/protocadherin family helps specify the synaptic abnormalities central to the disorder, and suggests novel potential treatment strategies.