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Neuron. 2014 May 21;82(4):773-80. doi: 10.1016/j.neuron.2014.04.043.

Loss-of-function variants in schizophrenia risk and SETD1A as a candidate susceptibility gene.

Author information

1
Department of Psychiatry, Columbia University Medical Center, New York, NY 10032, USA.
2
Department of Biostatistics, Columbia University Medical Center, New York, NY 10032, USA.
3
Department of Psychiatry, Pretoria University, Weskoppies Hospital, Pretoria 0001, Republic of South Africa.
4
Department of Neuroscience, Columbia University Medical Center, New York, NY 10032, USA; Department of Physiology & Cellular Biophysics, Columbia University Medical Center, New York, NY 10032, USA. Electronic address: jag90@columbia.edu.
5
Department of Psychiatry, Columbia University Medical Center, New York, NY 10032, USA; New York State Psychiatric Institute, New York, NY 10032, USA. Electronic address: mk2758@columbia.edu.

Abstract

Loss-of-function (LOF) (i.e., nonsense, splice site, and frameshift) variants that lead to disruption of gene function are likely to contribute to the etiology of neuropsychiatric disorders. Here, we perform a systematic investigation of the role of both de novo and inherited LOF variants in schizophrenia using exome sequencing data from 231 case and 34 control trios. We identify two de novo LOF variants in the SETD1A gene, which encodes a subunit of histone methyltransferase, a finding unlikely to have occurred by chance, and provide evidence for a more general role of chromatin regulators in schizophrenia risk. Transmission pattern analyses reveal that LOF variants are more likely to be transmitted to affected individuals than controls. This is especially true for private LOF variants in genes intolerant to functional genetic variation. These findings highlight the contribution of LOF mutations to the genetic architecture of schizophrenia and provide important insights into disease pathogenesis.

PMID:
24853937
PMCID:
PMC4387883
DOI:
10.1016/j.neuron.2014.04.043
[Indexed for MEDLINE]
Free PMC Article

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