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Based on sex-stratified genome-wide association study (GWAS) of Han Chinese, 2,178 centenarians and 2,299 middle-aged controls, we identified 11 male- and 12 female-specific independent loci that are significantly associated with longevity (P-5), replicated in independent North and South regions in one sex, but are not significant (P>0.05) in the other sex. We found that the association of rs60210535 at LINC00871 with longevity replicated well between Chinese females (P=4.6x10-5) and U.S. females (P=9.0x10-5), but was not significant in both Chinese and U.S. males (P>0.05). We discovered that 11 male-specific and 34 female-specific pathways are significantly associated with longevity (PFDR) P-5 in one sex, P>0.05 in other sex), 44/58 male/female strong loci (10-5≤P-4 in one sex, P>0.4 or P>0.35 in other sex), and 191/311 male/female moderate loci (10-4≤P-3 in one sex, P>0.75 or P>0.7 in other sex) are jointly and highly associated with longevity exceeding a significance level P10-8 in one sex, but not jointly associated with longevity in the other sex (P>0.05). Our integrated PRS and novel sex-specific genetic relative benefit/loss ratio analyses indicate that females’ genetic constitution favors longevity more than males’. Further interdisciplinary collaborative efforts are warranted, such as replications from other populations, international meta-analyses with much larger sample size, lab tests, and in silico functional validations. Significance Statement: On average, women live significantly longer lives than men but they have lower physical performance and more adverse health outcomes at older ages compared to men: patterns that signify the male-female health-survival paradox (1). Research on sex differences in health and mortality has proliferated, but has yet to achieve a good understanding of the effects of genetic variants on the sex gap in longevity and health. Based on sex-stratified genome-wide association analysis (GWAS) of Han Chinese including centenarians with a sample size 2.7 times as large as other published largest single GWAS on longevity involving centenarians (2), the present study aims to contribute a better understanding of sex differences in genetic associations with longevity.

Sex differences in genetic associations with longevity in Han Chinese: sex-stratified genome-wide association study and polygenic risk score analysis