Screening of functional single nucleotide polymorphisms in schizophrenia and its correlation with brain imaging
精神分裂症功能单核苷酸多态性位点筛选及其与脑影像学相关性研究

摘要

目的 通过生物信息学方法分析筛选与精神分裂症发病相关的功能性单核苷酸多态性，探讨功能相关易感位点多态性与精神分裂症发病及其脑影像学改变的关系。方法 从dbGaP数据库及精神病基因组学联盟下载精神分裂症数据集，采用富集分析方法分析不同数据集中重合的候选基因及基因通路。于2016年1月至2020年1月共纳入540名精神分裂症患者和540名对照组。收集所有受试者血液提取基因组DNA，并采集40例病例及40例对照静息态下脑部核磁共振影像资料，采用基于混合池的GWAS，选择4条重叠基因通路作为研究对象。用通过直接iPLEX质谱分析方法对包括4条通路在内的28个单核苷酸进行了基因分型，并以得到的阳性位点为分组标准，根据基因分型将有影像学资料的病例对照受试分为不同的亚组，在不同的亚组之间研究其脑影像学的差异，探索阳性易感基因与患者脑影像学改变的关系。结果 欧美精神分裂症数据集与本研究混合池GWAS分析共发现血管平滑肌收缩、钙信号通路、细胞粘附分子4条通路异常可能与精神分裂症的发病有关，rs12101060的等位基因（χ2=4.852，P=0.029）和基因型（χ2=4.796，P=0.029）分布具有统计学意义。等位基因A是风险变异（OR=7.317 95%CI:0.911-58.779）。rs12966547的等位基因（χ2=8.824，P=0.003）和基因型（χ2=11.484，P=0.003）分布也具有统计学意义。rs12966547的G突变变异是SCZ的危险因素（OR=1.537，95%CI:1.157-2.043）。所有具有统计学意义的SNP均定位在具有调节功能的基因中，其中rs12101060的等位基因，右眶额回存在疾病状态与rs12101060位点A+基因型的交互作用。结论 单核苷酸多态性引起的生物过程的异常调节可能是精神分裂症的原因，rs12101060与rs12966547位点多态性与我国精神分裂症的发病具有相关性，右眶额回可能是rs12101060位点 A+基因型特异改变的脑区。

Abstract

Objective: To analyze and screen functional single nucleotide polymorphisms related to the pathogenesis of schizophrenia by bioinformatics methods, and to explore the relationship between functional susceptibility site polymorphisms and the pathogenesis of schizophrenia and its brain imaging changes.
Methods: Schizophrenia data sets were downloaded from dbgap database and psychiatric genomics alliance. The candidate genes and gene pathways overlapped in different data sets were analyzed by enrichment analysis. A total of 540 schizophrenic patients and 540 controls were included from January 2016 to January 2020. Genomic DNA was extracted from the blood of all subjects, and the resting brain MRI data of 40 cases and 40 controls were collected. GWAS based on mixed pool was used to select 4 overlapping gene pathways as the research object. 28 single nucleotides including 4 pathways were genotyped by direct iplex mass spectrometry. Taking the obtained positive sites as the grouping standard, the case-control subjects with imaging data were divided into different subgroups according to genotyping, and the differences of brain imaging between different subgroups were studied, To explore the relationship between positive susceptibility genes and brain imaging changes.
Results: the European and American schizophrenia data set and the mixed pool GWAS analysis of this study found that the abnormalities of vascular smooth muscle contraction, calcium signaling pathway and cell adhesion molecule may be related to the pathogenesis of schizophrenia, and the allele of rs12101060( χ2 = 4.852, P = 0.029) and genotype (χ2 = 4.796, P = 0.029). Allele A was a risk variant (or = 7.317, 95% CI: 0.911-58.779). Allele of rs12966547 (χ2 = 8.824, P = 0.003) and genotype (χ2 = 11.484, P = 0.003). The G mutation of rs12966547 was a risk factor for SCZ (or = 1.537, 95% CI: 1.157-2.043). All SNPs with statistical significance were located in genes with regulatory function, including the allele of rs12101060, the interaction between disease status in the right orbital frontal gyrus and the a + genotype at rs12101060.
Conclusion  : the abnormal regulation of biological processes caused by single nucleotide polymorphisms may be the cause of schizophrenia. The polymorphisms of rs12101060 and rs12966547 are related to the pathogenesis of schizophrenia in China. The right orbital frontal gyrus may be the brain region with a + genotype specific changes at rs12101060.