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Sex Differences in Genetic Associations With Longevity
Yi Zeng1, Chao Nie1, Junxia Min1
1Center for the Study of Aging and Human Development, Medical School of Duke University, Durham, North Carolina (Zeng, H. Chen); Center for Healthy Aging and Development Studies, National School of Development, Raissun Institute for Advanced Studies, Peking University, Beijing, China (Zeng, Bai); BGI Education Center, University of Chinese Academy of Sciences, Shenzhen, China (Nie);BGI-Shenzhen, Shenzhen, China (Nie, Xiaomin Liu, Ye, Z. Chen, Bolund, Hou, Xiao Liu, Xu, H. Yang); The First Affiliated Hospital, Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou, China (Min, E. Xie); Business School of Xiangtan University, Xiangtan, China (H. Chen); Division of Non-Communicable Disease Control and Community Health, Chinese Center for Disease Control and Prevention, Beijing, China (Yin); National Institute of Environmental Health, Chinese Center for Disease Control and Prevention, Beijing, China (Lv, Shi); Department of Sociology, Peking University, Beijing, China (Lu, Li); School of Life Sciences, Fudan University, Shanghai, China (Ni); Department of Biomedicine, Aarhus University, Aarhus, Denmark (Bolund); Duke Population Research Institute, Duke University, Durham, North Carolina (Land, Yashin, O'Rand); The MOH Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Beijing, China (Sun, Z. Yang); School of Life Sciences, Peking University, Beijing, China (Tao, Gu); Boston University, Boston, Massachusetts (Gurinovich, Sebastiani, Perls); University of Bologna, Bologna, Italy (Franceschi); Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina (J. Xie); French National Institute on Health and Medical Research and Ecole Pratique des Hautes Etudes, University of Montpellier, Montpellier, France (Robine); Max Planck Institute for Biology of Ageing, Cologne, Germany (Deelen); Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, the Netherlands (Slagboom); Molecular Physiology Institute, Medical Center, Duke University, Durham, North Carolina (Hauser); Department of Neurology, Medical Center, Duke University, Durham, North Carolina (Gottschalk, Lutz); University of Southern Denmark, Odense, Denmark (Tan, Christensen); Human Aging Research Institute and School of Life Science, Nanchang University, Jiangxi, China (Tian); James D. Watson Institute of Genome Sciences, Hangzhou, China (H. Yang); Max Planck Institute for Demographic Research, Rostock, Germany (Vaupel).
Importance:
Sex differences in genetic associations with human longevity remain largely unknown; investigations on this topic are important for individualized health care.
Objective:
To explore sex differences in genetic associations with longevity.
Design Setting And Participants:
This population-based case-control study used sex-specific genome-wide association study and polygenic risk score (PRS) analyses to examine sex differences in genetic associations with longevity. Five hundred sixty-four male and 1614 female participants older than 100 years were compared with a control group of 773 male and 1526 female individuals aged 40 to 64 years. All were Chinese Longitudinal Healthy Longevity Study participants with Han ethnicity who were recruited in 1998 and 2008 to 2014.
Main Outcomes And Measures:
Sex-specific loci and pathways associated with longevity and PRS measures of joint effects of sex-specific loci.
Results:
Eleven male-specific and 11 female-specific longevity loci (P < 10-5) and 35 male-specific and 25 female-specific longevity loci (10-5 ≤ P < 10-4) were identified. Each of these loci's associations with longevity were replicated in north and south regions of China in one sex but were not significant in the other sex (P = .13-.97), and loci-sex interaction effects were significant (P < .05). The associations of loci rs60210535 of the LINC00871 gene with longevity were replicated in Chinese women (P = 9.0 × 10-5) and US women (P = 4.6 × 10-5) but not significant in Chinese and US men. The associations of the loci rs2622624 of the ABCG2 gene were replicated in Chinese women (P = 6.8 × 10-5) and European women (P = .003) but not significant in both Chinese and European men. Eleven male-specific pathways (inflammation and immunity genes) and 34 female-specific pathways (tryptophan metabolism and PGC-1α induced) were significantly associated with longevity (P < .005; false discovery rate < 0.05). The PRS analyses demonstrated that sex-specific associations with longevity of the 4 exclusive groups of 11 male-specific and 11 female-specific loci (P < 10-5) and 35 male-specific and 25 female-specific loci (10-5 ≤P < 10-4) were jointly replicated across north and south discovery and target samples. Analyses using the combined data set of north and south showed that these 4 groups of sex-specific loci were jointly and significantly associated with longevity in one sex (P = 2.9 × 10-70 to 1.3 × 10-39) but not jointly significant in the other sex (P = .11 to .70), while interaction effects between PRS and sex were significant (P = 4.8 × 10-50 to 1.2 × 10-16).
Conclusion And Relevance:
The sex differences in genetic associations with longevity are remarkable, but have been overlooked by previously published genome-wide association studies on longevity. This study contributes to filling this research gap and provides a scientific basis for further investigating effects of sex-specific genetic variants and their interactions with environment on healthy aging, which may substantially contribute to more effective and targeted individualized health care for male and female elderly individuals.
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