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

Author

Listed:
  • Yi Zeng

    (Max Planck Institute for Demographic Research, Rostock, Germany)

  • Huashuai Chen
  • Xiaomin Liu
  • Rui Ye
  • Enjun Xie
  • Zhihua Chen
  • Jiehua Lu
  • Jianxin Li
  • Yaohua Tian
  • Ting Ni
  • Lars Bolund
  • Kenneth C. Land
  • Anatoliy Yashin
  • Angela M. O'Rand
  • Liang Sun
  • Ze Yang
  • Wei Tao
  • Anastasia Gurinovic
  • Claudio Franceschi
  • Jichun Xie
  • Jun Gu
  • Yong Hou
  • Xiao Liu
  • Xun Xu
  • Jean-Marie Robine
  • Joris Deelen
  • Paola Sebastiani
  • P. Eline Slagboom
  • Thomas T. Perls
  • Elizabeth R. Hauser
  • William Gottschalk
  • Qihua Tan

    (Max Planck Institute for Demographic Research, Rostock, Germany)

  • Kaare Christensen
  • Mike Lutz
  • Xiao-Li Tian
  • Huanming Yang
  • Junxia Min
  • Chao Nie
  • James W. Vaupel

    (Max Planck Institute for Demographic Research, Rostock, Germany)

Abstract

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 -5 ≤ P <10 -4 in one sex, P >0.4 or P >0.35 in other sex), and 191/311 male/female moderate loci (10 -4 ≤ P <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.

Suggested Citation

  • Yi Zeng & Huashuai Chen & Xiaomin Liu & Rui Ye & Enjun Xie & Zhihua Chen & Jiehua Lu & Jianxin Li & Yaohua Tian & Ting Ni & Lars Bolund & Kenneth C. Land & Anatoliy Yashin & Angela M. O'Rand & Liang S, 2017. "Sex differences in genetic associations with longevity in Han Chinese: sex-stratified genome-wide association study and polygenic risk score analysis," MPIDR Working Papers WP-2017-004, Max Planck Institute for Demographic Research, Rostock, Germany.
  • Handle: RePEc:dem:wpaper:wp-2017-004
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    References listed on IDEAS

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    1. repec:aph:ajpbhl:10.2105/ajph.2012.301181_7 is not listed on IDEAS
    2. Herman Oyen & Wilma Nusselder & Carol Jagger & Petra Kolip & Emmanuelle Cambois & Jean-Marie Robine, 2013. "Gender differences in healthy life years within the EU: an exploration of the “health–survival” paradox," International Journal of Public Health, Springer;Swiss School of Public Health (SSPH+), vol. 58(1), pages 143-155, February.
    3. Hastie, Nicholas D. & van der Loos, Matthijs J. H. M. & Vitart, Veronique & Völzke, Henry & Wellmann, Jürgen & Yu, Lei & Zhao, Wei & Allik, Jüri & Attia, John R. & Bandinelli, Stefania & Bastardot,, 2013. "GWAS of 126,559 Individuals Identifies Genetic Variants Associated with Educational Attainment," Scholarly Articles 13383543, Harvard University Department of Economics.
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    More about this item

    JEL classification:

    • J1 - Labor and Demographic Economics - - Demographic Economics
    • Z0 - Other Special Topics - - General

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