解析睡眠相关特征与常见脑部疾病之间的遗传和因果关系。

Dissecting the genetic and causal relationship between sleep-related traits and common brain disorders.

机构信息

The Affiliated Hospital of Qingdao University, The Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao University, Qingdao, 266003, China; School of Public Health, Qingdao University, Qingdao, China.

Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), the Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, 200030, China.

出版信息

Sleep Med. 2024 Jul;119:201-209. doi: 10.1016/j.sleep.2024.04.032. Epub 2024 Apr 27.

DOI:10.1016/j.sleep.2024.04.032

PMID:38703603

Abstract

BACKGROUND

There is a profound connection between abnormal sleep patterns and brain disorders, suggesting a shared influential association. However, the shared genetic basis and potential causal relationships between sleep-related traits and brain disorders are yet to be fully elucidated.

METHODS

Utilizing linkage disequilibrium score regression (LDSC) and bidirectional two-sample univariable Mendelian Randomization (UVMR) analyses with large-scale GWAS datasets, we investigated the genetic correlations and causal associations across six sleep traits and 24 prevalent brain disorders. Additionally, a multivariable Mendelian Randomization (MVMR) analysis evaluated the cumulative effects of various sleep traits on each brain disorder, complemented by genetic loci characterization to pinpoint pertinent genes and pathways.

RESULTS

LDSC analysis identified significant genetic correlations in 66 out of 144 (45.8 %) pairs between sleep-related traits and brain disorders, with the most pronounced correlations observed in psychiatric disorders (66 %, 48/72). UVMR analysis identified 29 causal relationships (FDR<0.05) between sleep traits and brain disorders, with 19 associations newly discovered according to our knowledge. Notably, major depression, attention-deficit/hyperactivity disorder, bipolar disorder, cannabis use disorder, and anorexia nervosa showed bidirectional causal relations with sleep traits, especially insomnia's marked influence on major depression (IVW beta 0.468, FDR = 5.24E-09). MVMR analysis revealed a nuanced interplay among various sleep traits and their impact on brain disorders. Genetic loci characterization underscored potential genes, such as HOXB2, while further enrichment analyses illuminated the importance of synaptic processes in these relationships.

CONCLUSIONS

This study provides compelling evidence for the causal relationships and shared genetic backgrounds between common sleep-related traits and brain disorders.

摘要

背景

异常的睡眠模式与大脑紊乱之间存在着深刻的联系，表明它们之间存在着共同的影响关联。然而，睡眠相关特征与大脑紊乱之间的共享遗传基础和潜在因果关系尚未得到充分阐明。

方法

我们利用连锁不平衡评分回归（LDSC）和双向两样本单变量孟德尔随机化（UVMR）分析，结合大规模 GWAS 数据集，研究了六种睡眠特征与 24 种常见大脑紊乱之间的遗传相关性和因果关系。此外，多变量孟德尔随机化（MVMR）分析评估了各种睡眠特征对每种大脑紊乱的累积影响，并通过遗传位点特征来确定相关基因和途径。

结果

LDSC 分析在 6 种睡眠相关特征和 24 种大脑紊乱之间的 144 对特征中，有 66 对（45.8%）存在显著的遗传相关性，其中精神障碍的相关性最为显著（66%，48/72）。UVMR 分析发现了 29 种睡眠特征与大脑紊乱之间的因果关系（FDR<0.05），其中有 19 种关联是根据我们的知识新发现的。值得注意的是，重度抑郁症、注意缺陷多动障碍、双相情感障碍、大麻使用障碍和神经性厌食症与睡眠特征之间存在双向因果关系，尤其是失眠对重度抑郁症的显著影响（IVW beta 0.468，FDR=5.24E-09）。MVMR 分析揭示了各种睡眠特征之间以及它们对大脑紊乱的影响之间的微妙相互作用。遗传位点特征强调了潜在的基因，如 HOXB2，而进一步的富集分析则说明了这些关系中突触过程的重要性。