Integrative analyses of major histocompatibility complex loci in the genome-wide association studies of major depressive disorder.
Integrative analyses of major histocompatibility complex loci in the genome-wide association studies of major depressive disorder.
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重度抑郁症全基因组关联研究中主要组织相容性复杂位点的综合分析
DOI：
10.1038/s41386-019-0346-3
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发表时间：
2019
影响因子：
7.6
通讯作者：
Li Ming
中科院分区：
文献类型：
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作者：
Li Huijuan;Chang Hong;Song Xueqin;Liu Weipeng;Li Lingyi;Wang Lu;Yang Yongfeng;Zhang Luwen;Li Wenqiang;Zhang Yan;Zhou Dong-Sheng;Li Xingxing;Zhang Chen;Fang Yiru;Sun Yan;Dai Jia-Pei;Luo Xiong-Jian;Yao Yong-Gang;Xiao Xiao;Lv Luxian;Li Ming
最近的欧洲全基因组关联研究（GWAS）揭示了MDD与包含主要组织相容性复合体（MHC）基因（MHC区域）的基因组区域中许多零至高连锁变异之间的强统计相关性，但其潜在的生物学机制仍不清楚。为了更好地了解该基因组区域在MDD神经生物学中的作用，我们采用融合功能基因组学方法整合了MDD相关生物学表型的GWAS数据、脑样本的基因表达分析结果以及中国独立MDD样本的遗传分析。我们观察到MHC区域的独立MDD风险变异在预测方向上也与相关的生物学表型显著相关，包括情绪和认知相关表型。基因表达分析进一步揭示了人脑中几个MHC区域基因的mRNA表达水平与MDD风险snp和诊断状态相关。例如，大脑富集基因znf603p在携带重度抑郁症风险等位基因的个体和重度抑郁症患者中始终显示出较低的mRNA水平。值得注意的是，我们进一步发现MHC区域独立的MDD风险snp可能会聚合影响同一基因的mRNA水平，欧洲人和汉族人群在MHC区域的MDD风险关联中具有大量共享的遗传和分子基础。这些结果突出了MDD发病机制中MHC区域的几个潜在关键基因。它们对多种精神相关表型的共同影响也涉及不同心理过程（如情绪和/或认知）共享的神经过程，从而揭示了它们潜在的生物学机制。
Recent European genome-wide association studies (GWAS) have revealed strong statistical correlations between MDD and numerous zero-to-high linked variants in the genomic region containing major histocompatibility complex (MHC) genes (MHC region), but the underlying biological mechanisms are still unclear. To better understand the roles of this genomic region in the neurobiology of MDD, we applied a convergent functional genomics approach to integrate GWAS data of MDD relevant biological phenotypes, gene-expression analyses results obtained from brain samples, and genetic analyses of independent Chinese MDD samples. We observed that independent MDD risk variants in the MHC region were also significantly associated with the relevant biological phenotypes in the predicted directions, including the emotional and cognitive-related phenotypes. Gene-expression analyses further revealed that mRNA expression levels of several MHC region genes in the human brain were associated with MDD risk SNPs and diagnostic status. For instance, a brain-enriched geneZNF603Pconsistently showed lower mRNA levels in the individuals carrying MDD risk alleles and in MDD patients. Remarkably, we further found that independent MDD risk SNPs in the MHC region likely converged to affect the mRNA level(s) of the same gene(s), and Europeans and Han Chinese populations have a substantial shared genetic and molecular basis underlying MDD risk associations in the MHC region. These results highlighted several potential pivotal genes at the MHC region in the pathogenesis of MDD. Their common impacts on multiple psychiatric relevant phenotypes also implicated the neurological processes shared by different psychological processes, such as mood and/or cognition, shedding lights on their potential biological mechanisms.