Dataset Information

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

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.

SUBMITTER: Takata A

PROVIDER: S-EPMC4387883 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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

Takata Atsushi A Xu Bin B Ionita-Laza Iuliana I Roos J Louw JL Gogos Joseph A JA Karayiorgou Maria M

Neuron 20140501 4

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 ...[more]

PMID: 24853937

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Project description:This research aimed to investigate the role of glyoxalase 1 (Glo-1) polymorphisms in the susceptibility of schizophrenia. Using the real-time polymerase chain reaction (PCR) and spectrophotometric assays technology, significant differences in Glo-1 messenger ribonucleic acid (mRNA) expression (P = 3.98 × 10−5) and enzymatic activity (P = 1.40 × 10−6) were found in peripheral blood of first-onset antipsychotic-naïve patients with schizophrenia and controls. The following receiver operating characteristic (ROC) curves analysis showed that Glo-1 could predict the schizophrenia risk (P = 4.75 × 10−6 in mRNA, P = 1.43 × 10−7 in enzymatic activity, respectively). To identify the genetic source of Glo-1 risk in schizophrenia, Glo-1 polymorphisms (rs1781735, rs1130534, rs4746, and rs9470916) were genotyped with SNaPshot technology in 1,069 patients with schizophrenia and 1,023 healthy individuals. Then, the impact of risk polymorphism on the promoter activity, mRNA expression, and enzymatic activity was analyzed. The results revealed significant differences in the distributions of genotype (P = 0.020, false discovery rate (FDR) correction) and allele (P = 0.020, FDR correction) in rs1781735, in which G > T mutation significantly showed reduction in the promoter activity (P = 0.016), mRNA expression, and enzymatic activity (P = 0.001 and P = 0.015, respectively, GG vs. TT, in peripheral blood of patients with schizophrenia) of Glo-1. The expression quantitative trait locus (eQTL) findings were followed up with the resting-state functional magnetic resonance imaging (fMRI) analysis. The TT genotype of rs1781735, associated with lower RNA expression in the brain (P < 0.05), showed decreased neuronal activation in the left middle frontal gyrus in schizophrenia (P < 0.001). In aggregate, this study for the first time demonstrates how the genetic and biochemical basis of Glo-1 polymorphism culminates in the brain function changes associated with increased schizophrenia risk. Thus, establishing a combination of multiple levels of changes ranging from genetic variants, transcription, protein function, and brain function changes is a better predictor of schizophrenia risk.

Dataset Information

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

Publications

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

Similar Datasets

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