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

Baiqiang Xue; Xuemin Jian; Lixia Peng; Chuanhong Wu; Aamir Fahira; Ali Alamdar Shah Syed; Disong Xia; Baokun Wang; Mingming Niu; Yajie Jiang; Yonghe Ding; Chengwen Gao; Xiangzhong Zhao; Qian Zhang; Yongyong Shi; Zhiqiang Li

doi:10.1016/j.sleep.2024.04.032

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

Sleep Med. 2024 Apr 27:119:201-209. doi: 10.1016/j.sleep.2024.04.032. Online ahead of print.

Authors

Baiqiang Xue¹, Xuemin Jian², Lixia Peng³, Chuanhong Wu⁴, Aamir Fahira⁵, Ali Alamdar Shah Syed⁵, Disong Xia⁵, Baokun Wang³, Mingming Niu¹, Yajie Jiang¹, Yonghe Ding¹, Chengwen Gao⁶, Xiangzhong Zhao⁶, Qian Zhang⁶, Yongyong Shi⁷, Zhiqiang Li⁸

Affiliations

¹ 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.
² 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. Electronic address: jian13238440365@sjtu.edu.cn.
³ 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 Pharmacy, Qingdao University, Qingdao, 266003, China.
⁴ 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 Basic Medicine, Qingdao University, Qingdao, 266003, China.
⁵ 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.
⁶ 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.
⁷ 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; 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; School of Basic Medicine, Qingdao University, Qingdao, 266003, China; Shanghai Clinical Research Center for Mental Health, Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China; Shandong Provincial Key Laboratory of Metabolic Disease & the Metabolic Disease Institute of Qingdao University, Qingdao, 266003, China; Institute of Social Cognitive and Behavioral Sciences, Shanghai Jiao Tong University, Shanghai, 200030, China; Institute of Neuropsychiatric Science and Systems Biological Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China; Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai, 200030, China; Department of Psychiatry, the First Teaching Hospital of Xinjiang Medical University, Urumqi, 830054, China; Changning Mental Health Center, Shanghai, 200042, China. Electronic address: shiyongyong@gmail.com.
⁸ 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; School of Pharmacy, Qingdao University, Qingdao, 266003, China; School of Basic Medicine, Qingdao University, Qingdao, 266003, China; Shanghai Clinical Research Center for Mental Health, Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China; Shandong Provincial Key Laboratory of Metabolic Disease & the Metabolic Disease Institute of Qingdao University, Qingdao, 266003, China; Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai, 200030, China. Electronic address: lizqsjtu@163.com.

PMID: 38703603
DOI: 10.1016/j.sleep.2024.04.032

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.

Keywords: Brain disorders; Causal relationships; Genetic correlations; Mendelian randomization; Sleep-related traits.