Common variants in the MKL1 gene confer risk of schizophrenia.
Genome-wide association studies (GWAS) of schizophrenia have identified multiple risk variants with robust association signals for schizophrenia. However, these variants could explain only a small proportion of schizophrenia heritability. Furthermore, the effect size of these risk variants is relatively small (eg, most of them had an OR less than 1.2), suggesting that additional risk variants may be detected when increasing sample size in analysis. Here, we report the identification of a genome-wide significant schizophrenia risk locus at 22q13.1 by combining 2 large-scale schizophrenia cohort studies. Our meta-analysis revealed that 7 single nucleotide polymorphism (SNPs) on chromosome 22q13.1 reached the genome-wide significance level (P < 5.0×10(-8)) in the combined samples (a total of 38441 individuals). Among them, SNP rs6001946 had the most significant association with schizophrenia (P = 2.04×10(-8)). Interestingly, all 7 SNPs are in high linkage disequilibrium and located in the MKL1 gene. Expression analysis showed that MKL1 is highly expressed in human and mouse brains. We further investigated functional links between MKL1 and proteins encoded by other schizophrenia susceptibility genes in the whole human protein interaction network. We found that MKL1 physically interacts with GSK3B, a protein encoded by a well-characterized schizophrenia susceptibility gene. Collectively, our results revealed that genetic variants in MKL1 might confer risk to schizophrenia. Further investigation of the roles of MKL1 in the pathogenesis of schizophrenia is warranted.
Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China; luoxiongjian@mail.kiz.ac.cn.
Xiong-Jian
XJ
Luo
First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi 341000, China;
Liang
L
Huang
Center for Biomarker Research and Personalized Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA;
Edwin J van den
EJ
Oord
Center for Biomarker Research and Personalized Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA;
Karolina A
KA
Aberg
Flaum Eye Institute and Department of Ophthalmology, University of Rochester, Rochester, NY 14642, USA;
Lin
L
Gan
Departments of Biomedical Informatics and Psychiatry, Vanderbilt University School of Medicine, Nashville, TN.
Zhongming
Z
Zhao
Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China;
Yong-Gang
YG
Yao
D015331:Cohort Studies; D055106:Genome-Wide Association Study; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D012559:Schizophrenia / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics*
C431575:MRTFA protein, human; D015534:Trans-Activators
GSK3B; MKL1; genetic association; protein-protein interaction; schizophrenia