Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways
Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways
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DOI：
10.1038/s41588-018-0151-7
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发表时间：
2018-07-01
期刊：
影响因子：
30.8
通讯作者：
Posthuma, Danielle
中科院分区：
文献类型：
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作者：
Nagel, Mats;Jansen, Philip R.;Posthuma, Danielle
神经质是精神病特征的重要危险因素，包括抑郁(1)、焦虑（2,3）和精神分裂症（4-6）。在分析时，先前的全基因组关联研究（GWAS）报道了16个与神经症相关的基因组位点。在这里，我们对神经症进行了一项大型GWAS荟萃分析（n = 449,484），并鉴定出136个独立的全基因组显著位点（分析时为124个新位点），涉及599个基因。功能随访分析显示在几个脑区富集，并涉及特定细胞类型，包括多巴胺能神经母细胞（P = 3.49 x 10(-8)），中棘神经元（P = 4.23 x 10(-8)）和血清素能神经元（P = 1.37 x 10(-7)）。基因集分析涉及三个特定途径：神经发生（P = 4.43 x 10(-9)），对可卡因过程的行为反应（P = 1.84 x 10(-7)）和轴突部分（P = 5.26 x 10(-8)）。我们发现，神经质的遗传信号部分源于两个基因上可区分的亚群（“抑郁影响”和“担忧”），这表明不同亚型个体之间存在不同的因果机制。孟德尔随机化分析显示，神经质与多种精神特征之间存在单向和双向效应。这些结果增强了神经生物学对神经质的理解，并为功能后续实验提供了具体的线索。
Neuroticism is an important risk factor for psychiatric traits, including depression(1), anxiety(2,3), and schizophrenia(4-6). At the time of analysis, previous genome-wide association studies(7-12) (GWAS) reported 16 genomic loci associated to neuroticism10-12. Here we conducted a large GWAS meta-analysis (n = 449,484) of neuroticism and identified 136 independent genome-wide significant loci (124 new at the time of analysis), which implicate 599 genes. Functional follow- up analyses showed enrichment in several brain regions and involvement of specific cell types, including dopaminergic neuroblasts (P = 3.49 x 10(-8)), medium spiny neurons (P = 4.23 x 10(-8)), and serotonergic neurons (P = 1.37 x 10(-7)). Gene set analyses implicated three specific pathways: neurogenesis (P = 4.43 x 10(-9)), behavioral response to cocaine processes (P = 1.84 x 10(-7)), and axon part (P = 5.26 x 10(-8)). We show that neuroticism's genetic signal partly originates in two genetically distinguishable subclusters(13) ('depressed affect' and 'worry'), suggesting distinct causal mechanisms for subtypes of individuals. Mendelian randomization analysis showed unidirectional and bidirectional effects between neuroticism and multiple psychiatric traits. These results enhance neurobiological understanding of neuroticism and provide specific leads for functional follow-up experiments.