Genome-wide association meta-analysis and Mendelian randomization analysis confirm the influence of ALDH2 on sleep durationin the Japanese population.

Takeshi Nishiyama, Masahiro Nakatochi, Atsushi Goto, Motoki Iwasaki, Tsuyoshi Hachiya, Yoichi Sutoh, Atsushi Shimizu, Chaochen Wang, Hideo Tanaka, Miki Watanabe, Akihiro Hosono, Yuya Tamai, Tamaki Yamada, Taiki Yamaji, Norie Sawada, Kentaro Fukumoto, Kotaro Otsuka, Kozo Tanno, Hiroaki Tomita, Kaname Kojima, Masao Nagasaki, Atsushi Hozawa, Asahi Hishida, Tae Sasakabe, Yuichiro Nishida, Megumi Hara, Hidemi Ito, Isao Oze, Yohko Nakamura, Haruo Mikami, Rie Ibusuki, Toshiro Takezaki, Teruhide Koyama, Nagato Kuriyama, Kaori Endoh, Kiyonori Kuriki, Tanvir C Turin, Takashima Naoyuki, Sakurako Katsuura-Kamano, Hirokazu Uemura, Rieko Okada, Sayo Kawai, Mariko Naito, Yukihide Momozawa, Michiaki Kubo, Makoto Sasaki, Masayuki Yamamoto, Shoichiro Tsugane, Kenji Wakai, Sadao Suzuki

Journal: Sleep 2020;42(6):zsz046

PMID: 30810208

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Abstract

Usual sleep duration has substantial heritability and is associated with various physical and psychiatric conditions as well as mortality. However, for its genetic locus, only PAX8 and VRK2 have been replicated in previous genome-wide association studies (GWAS). We conducted a GWAS meta-analysis of self-reported usual sleep duration using three population-based cohorts totaling 31 230 Japanese individuals. A genome-wide significant locus was identified at 12q24 (p-value < 5.0 × 10-8). Subsequently, a functional variant in the ALDH2 locus, rs671, was replicated in an independent sample of 5140 Japanese individuals (p-value = 0.004). The association signal, however, disappeared after adjusting for alcohol consumption, indicating the possibility that the rs671 genotype modifies sleep duration via alcohol consumption. This hypothesis explained a modest genetic correlation observed between sleep duration and alcohol consumption (rG = 0.23). A Mendelian randomization analysis using rs671 and other variants as instrumental variables confirmed this by showing a causal effect of alcohol consumption, but not of coffee consumption on sleep duration. Another genome-wide significant locus was identified at 5q33 after adjusting for drinking frequency. However, this locus was not replicated, nor was the PAX8 and VRK2. Our study has confirmed that a functional ALDH2 variant, rs671, most strongly influences on usual sleep duration possibly via alcohol consumption in the Japanese population, and presumably in East Asian populations. This highlights the importance of considering the involvement of alcohol consumption in future GWAS of usual sleep duration, even in non-East Asian populations, where rs671 is monomorphic.

Address: Department of Public Health, Nagoya City University Graduate School of Medicine, Nagoya, Japan.; Department of Public Health, Aichi Medical University School of Medicine, Nagakute, Japan.; Data Science Division, Data Coordinating Center, Department of Advanced Medicine, Nagoya University Hospital, Japan.; Division of Epidemiology, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan.; Division of Biomedical Information Analysis, Iwate Tohoku Medical Megabank Organization, Iwate Medical University, Iwate, Japan.; Osaka Prefectural Kishiwada Public Health Center, Osaka, Japan.; Department of Public Health, Nagoya City University Graduate School of Medicine, Nagoya, Japan.; Okazaki Public Health Center, Okazaki, Japan.; Department of Neuropsychiatry, School of Medicine, Iwate Medical University, Iwate, Japan.; Department of Neuropsychiatry, School of Medicine, Iwate Medical University, Iwate, Japan.; Division of Clinical Research and Epidemiology, Iwate Tohoku Medical Megabank Organization, Iwate Medical University, Iwate, Japan.; Division of Clinical Research and Epidemiology, Iwate Tohoku Medical Megabank Organization, Iwate Medical University, Iwate, Japan.; Department of Hygiene and Preventive Medicine, School of Medicine, Iwate Medical University, Iwate, Japan.; Department of Preventive Medicine and Epidemiology, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.; Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.; Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.; Department of Preventive Medicine, Faculty of Medicine, Saga University, Saga, Japan.; Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan.; Division of Molecular and Clinical Epidemiology, Aichi Cancer Center Research Institute, Nagoya, Japan.; Cancer Prevention Center, Chiba Cancer Center Research Institute, Chiba, Japan.; Department of International Islands and Community Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.; Department of Epidemiology for Community Health and Medicine, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan.; Laboratory of Public Health, Graduate School of Integrated Pharmaceutical and Nutritional Sciences, University of Shizuoka, Shizuoka, Japan.; Department of Health Science, Shiga University of Medical Science, Shiga, Japan.; Department of Preventive Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.; Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.; Department of Oral Epidemiology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.; Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.; Iwate Tohoku Medical Megabank Organization, Iwate Medical University, Iwate, Japan.; Division of Ultra-High Field MRI and Department of Radiology, Iwate Medical University, Iwate, Japan.; Center for Public Health Sciences, National Cancer Center, Tokyo, Japan.

DOI: 10.1093/sleep/zsz046

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MeSH Terms: Alcohol Drinking, Aldehyde Dehydrogenase, Mitochondrial, Asian People, Coffee, Female, Genome-Wide Association Study, Genotype, Humans, Japan, Male, Mendelian Randomization Analysis, Middle Aged, PAX8 Transcription Factor, Polymorphism, Single Nucleotide, Protein Serine-Threonine Kinases, Self Report, Sleep