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

By Todd Lencz, Jin Yu, Raiyan Rashid Kahn, Shai Carmi, Max Lam, Danny Ben-Avraham, Nir Barzilai, Susan Bressman, Ariel Darvasi, Judy Cho, Lorraine N. Clark, Zeynep H Gumus, Joseph Vijai, Robert J Klein, Steven Lipkin, Kenneth Offit, Harry Ostrer, Laurie J. Ozelius, Inga Peter, Anil K. Malhotra, Gil Atzmon, Itsik Pe'er

Posted 30 May 2020
medRxiv DOI: 10.1101/2020.05.29.20115352

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 or more 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.

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