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Sex Differences in Genetic Associations With Longevity.

Publication ,  Journal Article
Zeng, Y; Nie, C; Min, J; Chen, H; Liu, X; Ye, R; Chen, Z; Bai, C; Xie, E; Yin, Z; Lv, Y; Lu, J; Li, J; Ni, T; Bolund, L; Land, KC; Sun, L ...
Published in: JAMA Netw Open
August 2018

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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Published In

JAMA Netw Open

DOI

EISSN

2574-3805

Publication Date

August 2018

Volume

1

Issue

4

Start / End Page

e181670

Location

United States

Related Subject Headings

  • Sex Factors
  • Sex Characteristics
  • Polymorphism, Single Nucleotide
  • Multifactorial Inheritance
  • Middle Aged
  • Male
  • Longevity
  • Humans
  • Genome-Wide Association Study
  • Genetic Loci
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Zeng, Y., Nie, C., Min, J., Chen, H., Liu, X., Ye, R., … Vaupel, J. (2018). Sex Differences in Genetic Associations With Longevity. JAMA Netw Open, 1(4), e181670. https://doi.org/10.1001/jamanetworkopen.2018.1670
Zeng, Yi, Chao Nie, Junxia Min, Huashuai Chen, Xiaomin Liu, Rui Ye, Zhihua Chen, et al. “Sex Differences in Genetic Associations With Longevity.JAMA Netw Open 1, no. 4 (August 2018): e181670. https://doi.org/10.1001/jamanetworkopen.2018.1670.
Zeng Y, Nie C, Min J, Chen H, Liu X, Ye R, et al. Sex Differences in Genetic Associations With Longevity. JAMA Netw Open. 2018 Aug;1(4):e181670.
Zeng, Yi, et al. “Sex Differences in Genetic Associations With Longevity.JAMA Netw Open, vol. 1, no. 4, Aug. 2018, p. e181670. Pubmed, doi:10.1001/jamanetworkopen.2018.1670.
Zeng Y, Nie C, Min J, Chen H, Liu X, Ye R, Chen Z, Bai C, Xie E, Yin Z, Lv Y, Lu J, Li J, Ni T, Bolund L, Land KC, Yashin A, O’Rand AM, Sun L, Yang Z, Tao W, Gurinovich A, Franceschi C, Xie J, Gu J, Hou Y, Xu X, Robine J-M, Deelen J, Sebastiani P, Slagboom E, Perls T, Hauser E, Gottschalk W, Tan Q, Christensen K, Shi X, Lutz M, Tian X-L, Yang H, Vaupel J. Sex Differences in Genetic Associations With Longevity. JAMA Netw Open. 2018 Aug;1(4):e181670.

Published In

JAMA Netw Open

DOI

EISSN

2574-3805

Publication Date

August 2018

Volume

1

Issue

4

Start / End Page

e181670

Location

United States

Related Subject Headings

  • Sex Factors
  • Sex Characteristics
  • Polymorphism, Single Nucleotide
  • Multifactorial Inheritance
  • Middle Aged
  • Male
  • Longevity
  • Humans
  • Genome-Wide Association Study
  • Genetic Loci