MPIDR Working Paper

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

Zeng, Y., Chen, H., Liu, X., Ye, R., Xie, E., Chen, Z., Lu, J., Li, J., Tian, Y., Ni, T., Bolund, L., Land, K. C., Yashin, A., O'Rand, A. M., Sun, L., Yang, Z., Tao, W., Gurinovic, A., Franceschi, C., Xie, J., Gu, J., Hou, Y., Liu, X., Xu, X., Robine, J.-M., Deelen, J., Sebastiani, P., Slagboom, P. E., Perls, T. T., Hauser, E. R., Gottschalk, W., Tan, Q., Christensen, K., Lutz, M., Tian, X., Yang, H., Min, J., Nie, C., Vaupel, J. W.

MPIDR Working Paper WP-2017-004, 37 pages (February 2017).
Rostock, Max Planck Institute for Demographic Research


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<10-5), 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 (P<0.005, false discovery rate (FDR) <0.05). Male-specific pathways are enriched for inflammation and immunity genes, but female-specific pathways include tryptophan metabolic and PGC-1α pathways that converge to mitochondrial biogenesis. Polygenic risk score (PRS) analyses demonstrated that 11/12 male/female top loci (P<10-5 in one sex, P>0.05 in other sex), 44/58 male/female strong loci (10-5P<10-4 in one sex, P>0.4 or P>0.35 in other sex), and 191/311 male/female moderate loci (10-4P<10-3 in one sex, P>0.75 or P>0.7 in other sex) are jointly and highly associated with longevity exceeding a significance level P<10-8 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.