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

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

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1465-1478.e4
JournalNeuron
Volume109
Issue number9
DOIs
StatePublished - May 5 2021

Keywords

  • cadherins
  • exome
  • founder population
  • rare variants
  • schizophrenia

ASJC Scopus subject areas

  • Neuroscience(all)

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