精神分裂症遗传学研究方面取得新进展

　　

　　精神分裂症是一种严重影响患者思维、情感和行为的常见精神疾病。精神分裂症主要症状包括：阳性性状，阴性性状，认知症状和情绪紊乱。由于病因复杂，反复发作以及大多在青壮年发病，精神分裂症严重影响患者生活，同时也给患者家属和社会带来了沉重的负担。目前精神分裂症影响了全球大约1%的人口。精神分裂症的遗传力高达0.8左右，表明遗传因素在精神分裂症的发生中有重要作用。随着众多全基因组关联性分析（Genome-wide association study, GWAS）在不同人群中的开展，人们已经鉴别到许多与精神分裂症相关的易感基因。然而，精神分裂症的遗传机制到目前仍不清楚。

　　关于精神分裂症的遗传机制，目前有两个假说：Common Disease-Common Variants (CD-CV)和Common Disease-Rare Variants(CD-RV)。基于这两个假说，目前精神分裂症的遗传学研究大多集中在病例-对照研究和家系分析上。病例-对照遗传相关分析主要鉴别效应较小的常见遗传变体（Common Variants），而家系研究则主要侧重在效应较大的低频遗传变体（Rare Variants）。

　　中科院昆明动物研究所罗雄剑课题组通过与国际同行合作，对来自于病例-对照（N=32,143）和家系（N=6,289）的遗传数据进行了大规模的整合分析，发现MKL1基因内的遗传变异在病例-对照和家系精神分裂症样本中都与精神分裂症显著相关。表达分析表明，MKL1基因在小鼠和人类大脑中高度表达。进一步的蛋白相互作用分析揭示MKL1与另一个精神分裂症易感基因GSK3B有蛋白相互作用。

　　这些结果首次揭示MKL1基因可能是个真正的精神分裂症易感基因。基于MKL1基因内的遗传变异在病例-对照和家系样本中都与精神分裂症显著相关及MKL1基因在神经系统发育中的重要作用，这些结果支持精神分裂症的神经发育假说，同时也为进一步阐明精神分裂症的遗传机制和致病机理提供了重要的信息。 

　　相关研究论文Common Variants in the MKL1 Gene Confer Risk of Schizophrenia 发表在国际知名的精神病学研究期刊Schizophrenia Bulletin上。

　　该研究得到了昆明动物所****项目支持。

原文摘要：

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.