Genetic Associations with Longevity Are Stronger in Females than in Males - A Bio-Demographic Analysis Contributing to a Research Basis for Precision Healthcare

Background: The "male-female health-survival paradox" that women live significantly longer, but have lower physical performance and more adverse health outcomes at older ages than men, is a phenomenon observed everywhere in the world. This study aims to provide an understanding of the "male-female health-survival paradox", through investigating whether genetic associations with longevity are stronger in males or females.   Methods: We conducted logistic regression and bio-demographic analyses, using the genome-wide association study (GWAS) datasets including 2,178 centenarians and 2,299 middle-aged controls of Chinese Longitudinal Healthy Longevity Study.   Findings: We found that averages of probabilities of longevity, associated with each of the six mutually exclusive groups of 11 male-specific and 11 female-specific top loci (P<10-5), 35 male-specific and 25 female-specific strong loci (10-5≤P<10-4), 191 male-specific and 311 female-specific moderate loci (10-4≤P<10-3), are all significantly higher in females than in males by margins of 13.8% to 25.8%. Our analyses demonstrate that the female vs. male ratios of relative benefit for longevity due to each of the six exclusive groups of sex-specific loci associated with longevity at tiered significance levels are all substantially in favor of females. These empirical findings and additional analyses of both sex-specific and not-sex-specific loci all indicate and reconfirm that genetic associations with longevity are substantially stronger in females than in males. Interpretation: The findings of this study may be interpreted in the context of human genetic evolution in which females may gain and accumulate advantages in genetic constitution to meet their reproductive and offspring-caring duties as mothers and grandmothers.    Funding Statement: The funding agencies provided financial support to the data and DNA samples collections and analyses, but they did not play any role in writing, interpreting the results and submission for consideration of publication of this manuscript. The authors were not paid by anyone to write this article. Declaration of Interests: The authors declare that they have no conflicts of interest. Ethics Approval Statement: The Research Ethics Committees of Peking University and Duke University granted approval for the Protection of Human Subjects for the Chinese Longitudinal Healthy Longevity Survey, including collection of the data and DNA samples used for present study. The survey respondents gave informed consent before participation.