Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University Amsterdam, Amsterdam, the Netherlands.
Department of Child and Adolescent Psychiatry, Erasmus University Medical Center, Rotterdam, the Netherlands.
Nat Genet. 2019 Mar;51(3):394-403. doi: 10.1038/s41588-018-0333-3. Epub 2019 Feb 25.
Insomnia is the second most prevalent mental disorder, with no sufficient treatment available. Despite substantial heritability, insight into the associated genes and neurobiological pathways remains limited. Here, we use a large genetic association sample (n = 1,331,010) to detect novel loci and gain insight into the pathways, tissue and cell types involved in insomnia complaints. We identify 202 loci implicating 956 genes through positional, expression quantitative trait loci, and chromatin mapping. The meta-analysis explained 2.6% of the variance. We show gene set enrichments for the axonal part of neurons, cortical and subcortical tissues, and specific cell types, including striatal, hypothalamic, and claustrum neurons. We found considerable genetic correlations with psychiatric traits and sleep duration, and modest correlations with other sleep-related traits. Mendelian randomization identified the causal effects of insomnia on depression, diabetes, and cardiovascular disease, and the protective effects of educational attainment and intracranial volume. Our findings highlight key brain areas and cell types implicated in insomnia, and provide new treatment targets.
失眠是第二大常见精神障碍，但目前尚无充分的治疗方法。尽管遗传度很高，但对相关基因和神经生物学途径的了解仍然有限。在这里，我们使用一个大型的遗传关联样本（n=1,331,010）来检测新的基因座，并深入了解与失眠主诉相关的途径、组织和细胞类型。我们通过定位、表达数量性状基因座和染色质作图确定了 202 个基因座，涉及 956 个基因。荟萃分析解释了 2.6%的方差。我们展示了神经元轴突部分、皮质和皮质下组织以及特定细胞类型（包括纹状体、下丘脑和屏状核神经元）的基因集富集。我们发现与精神疾病特征和睡眠时间有相当大的遗传相关性，与其他与睡眠相关的特征有适度的相关性。孟德尔随机化确定了失眠对抑郁、糖尿病和心血管疾病的因果影响，以及教育程度和颅内体积的保护作用。我们的研究结果突出了与失眠相关的关键大脑区域和细胞类型，并提供了新的治疗靶点。
