@article{4facb8d623874454bbf7bac76923b260,
title = "Novel ultra-rare exonic variants identified in a founder population implicate cadherins in schizophrenia",
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.",
keywords = "cadherins, exome, founder population, rare variants, schizophrenia",
author = "Todd Lencz and Jin Yu and Khan, {Raiyan Rashid} and Erin Flaherty and Shai Carmi and Max Lam and Danny Ben-Avraham and Nir Barzilai and Susan Bressman and Ariel Darvasi and Cho, {Judy H.} and Clark, {Lorraine N.} and G{\"u}m{\"u}{\c s}, {Zeynep H.} and Joseph Vijai and Klein, {Robert J.} and Steven Lipkin and Kenneth Offit and Harry Ostrer and Ozelius, {Laurie J.} and Inga Peter and Malhotra, {Anil K.} and Tom Maniatis and Gil Atzmon and Itsik Pe'er",
note = "Funding Information: The authors are extremely grateful to Soren Germer, PhD and his team at the New York Genome Center for performing the Illumina sequencing. We acknowledge financial support from the Human Frontier Science Program (to S.C.); NIH research grants AG042188 (to G.A.), DK62429, DK062422, DK092235 (to J.H.C.), NS050487, NS060113 (to L.N.C.), AG021654, AG027734 (to N.B.), MH089964, MH095458, MH084098 (to T.L.), MH10857, MH114817 (to T.M.), and CA121852 (computational infrastructure, to I. Pe'er); NSF research grants 08929882 and 0845677 (to I. Pe'er); the Rachel and Lewis Rudin Foundation (to H.O.); the Northwell Health Foundation (to T.L.); the Brain & Behavior Foundation (to T.L.); the US-Israel Binational Science Foundation (to T.L. and A.D.); the LUNGevity Foundation (to Z.H.G.); the New York Crohn's Disease Foundation (to I. Peter); Edwin & Caroline Levy and Joseph & Carol Reich (to S.B.); the Parkinson's Disease Foundation (to L.N.C.); the Sharon Levine Corzine Cancer Research Fund (to K.O.); and the Andrew Sabin Family Research Fund (to K.O.). T.L. and I. Pe'er led the analysis, and T.L. and J.Y. led the writing of the manuscript. J.Y. and R.R.K. conducted the primary analyses of the exome data, with assistance from M.L. and S.C. E.F. and T.M. designed and E.F. conducted the in vitro analyses. T.L. led the funding of the study. T.L. A.D. G.A. D.B.-A. N.B. and L.N.C. provided the samples and conducted the lab work. T.L. I. Pe'er, N.B. S.B. A.D. J.H.C. L.N.C. Z.H.G. J.V. R.J.K. S.L. K.O. H.O. L.J.O. I. Peter, A.M.K. and G.A. initiated and designed the study and provided the funding. The authors declare no competing interests. Funding Information: The authors are extremely grateful to Soren Germer, PhD and his team at the New York Genome Center for performing the Illumina sequencing. We acknowledge financial support from the Human Frontier Science Program (to S.C.); NIH research grants AG042188 (to G.A.), DK62429 , DK062422 , DK092235 (to J.H.C.), NS050487 , NS060113 (to L.N.C.), AG021654 , AG027734 (to N.B.), MH089964 , MH095458 , MH084098 (to T.L.), MH10857 , MH114817 (to T.M.), and CA121852 (computational infrastructure, to I. Pe{\textquoteright}er); NSF research grants 08929882 and 0845677 (to I. Pe{\textquoteright}er); the Rachel and Lewis Rudin Foundation (to H.O.); the Northwell Health Foundation (to T.L.); the Brain & Behavior Foundation (to T.L.); the US-Israel Binational Science Foundation (to T.L. and A.D.); the LUNGevity Foundation (to Z.H.G.); the New York Crohn{\textquoteright}s Disease Foundation (to I. Peter); Edwin & Caroline Levy and Joseph & Carol Reich (to S.B.); the Parkinson{\textquoteright}s Disease Foundation (to L.N.C.); the Sharon Levine Corzine Cancer Research Fund (to K.O.); and the Andrew Sabin Family Research Fund (to K.O.). Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = may,
day = "5",
doi = "10.1016/j.neuron.2021.03.004",
language = "English (US)",
volume = "109",
pages = "1465--1478.e4",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "9",
}