Loss-of-function variants in schizophrenia risk and SETD1A as a candidate susceptibility gene.
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.
Department of Psychiatry, Columbia University Medical Center, New York, NY 10032, USA.
Atsushi
A
Takata
Department of Psychiatry, Columbia University Medical Center, New York, NY 10032, USA.
Bin
B
Xu
Department of Biostatistics, Columbia University Medical Center, New York, NY 10032, USA.
Iuliana
I
Ionita-Laza
Department of Psychiatry, Pretoria University, Weskoppies Hospital, Pretoria 0001, Republic of South Africa.
J Louw
JL
Roos
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.
Joseph A
JA
Gogos
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.
Maria
M
Karayiorgou
D042002:Chromatin Assembly and Disassembly; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D015894:Genome, Human; D005838:Genotype; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006801:Humans; D016013:Likelihood Functions; D008297:Male; D012307:Risk Factors; D012559:Schizophrenia / Q000235:genetics*; D017422:Sequence Analysis, DNA
D011495:Histone-Lysine N-Methyltransferase; C526068:Setd1A protein, human