Sex Differences in Genetic Associations With Longevity

Yi Zeng, Chao Nie, Junxia Min, Huashuai Chen, Xiaomin Liu, Rui Ye, Zhihua Chen, Chen Bai, Enjun Xie, Zhaoxue Yin, Yuebin Lv, Jiehua Lu, Jianxin Li, Ting Ni, Lars Bolund, Kenneth C Land, Anatoli I Yashin, Angela M O'Rand, Liang Sun, Ze Yang & 22 others Wei Tao, Anastasia Gurinovich, Claudio Franceschi, Jichun Xie, Jun Gu, Yong Hou, Xiao Liu, Xun Xu, Jean-Marie Robine, Joris Deelen, Paola Sebastiani, Eline Slagboom, Thomas T Perls, Elizabeth R Hauser, William Gottschalk, Qihua Tan, Kaare Christensen, Xiaoming Shi, Mike Lutz, Xiao-Li Tian, Huanming Yang, James W. Vaupel

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Abstract

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.

Original languageEnglish
Article number1670
JournalJAMA Network Open
Volume1
Issue number4
Number of pages15
DOIs
Publication statusPublished - Aug 2018

Fingerprint

Sex Characteristics
Genome-Wide Association Study
Delivery of Health Care
Tryptophan
Case-Control Studies
China
Outcome Assessment (Health Care)

Keywords

  • Adult
  • Aged, 80 and over
  • Asian Continental Ancestry Group/genetics
  • Case-Control Studies
  • China/ethnology
  • Female
  • Genetic Loci
  • Genome-Wide Association Study
  • Humans
  • Longevity/genetics
  • Male
  • Middle Aged
  • Multifactorial Inheritance
  • Polymorphism, Single Nucleotide
  • Sex Characteristics
  • Sex Factors

Cite this

Zeng, Yi ; Nie, Chao ; Min, Junxia ; Chen, Huashuai ; Liu, Xiaomin ; Ye, Rui ; Chen, Zhihua ; Bai, Chen ; Xie, Enjun ; Yin, Zhaoxue ; Lv, Yuebin ; Lu, Jiehua ; Li, Jianxin ; Ni, Ting ; Bolund, Lars ; Land, Kenneth C ; Yashin, Anatoli I ; O'Rand, Angela M ; Sun, Liang ; Yang, Ze ; Tao, Wei ; Gurinovich, Anastasia ; Franceschi, Claudio ; Xie, Jichun ; Gu, Jun ; Hou, Yong ; Liu, Xiao ; Xu, Xun ; Robine, Jean-Marie ; Deelen, Joris ; Sebastiani, Paola ; Slagboom, Eline ; Perls, Thomas T ; Hauser, Elizabeth R ; Gottschalk, William ; Tan, Qihua ; Christensen, Kaare ; Shi, Xiaoming ; Lutz, Mike ; Tian, Xiao-Li ; Yang, Huanming ; Vaupel, James W. . / Sex Differences in Genetic Associations With Longevity. In: JAMA Network Open. 2018 ; Vol. 1, No. 4.
@article{575505c91d414c1fb1f183f064d45511,
title = "Sex Differences in Genetic Associations With Longevity",
abstract = "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.",
keywords = "Adult, Aged, 80 and over, Asian Continental Ancestry Group/genetics, Case-Control Studies, China/ethnology, Female, Genetic Loci, Genome-Wide Association Study, Humans, Longevity/genetics, Male, Middle Aged, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Sex Characteristics, Sex Factors",
author = "Yi Zeng and Chao Nie and Junxia Min and Huashuai Chen and Xiaomin Liu and Rui Ye and Zhihua Chen and Chen Bai and Enjun Xie and Zhaoxue Yin and Yuebin Lv and Jiehua Lu and Jianxin Li and Ting Ni and Lars Bolund and Land, {Kenneth C} and Yashin, {Anatoli I} and O'Rand, {Angela M} and Liang Sun and Ze Yang and Wei Tao and Anastasia Gurinovich and Claudio Franceschi and Jichun Xie and Jun Gu and Yong Hou and Xiao Liu and Xun Xu and Jean-Marie Robine and Joris Deelen and Paola Sebastiani and Eline Slagboom and Perls, {Thomas T} and Hauser, {Elizabeth R} and William Gottschalk and Qihua Tan and Kaare Christensen and Xiaoming Shi and Mike Lutz and Xiao-Li Tian and Huanming Yang and Vaupel, {James W.}",
year = "2018",
month = "8",
doi = "10.1001/jamanetworkopen.2018.1670",
language = "English",
volume = "1",
journal = "JAMA Network Open",
issn = "2574-3805",
publisher = "AMER MEDICAL ASSOC",
number = "4",

}

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, AI, O'Rand, AM, Sun, L, Yang, Z, Tao, W, Gurinovich, A, Franceschi, C, Xie, J, Gu, J, Hou, Y, Liu, X, Xu, X, Robine, J-M, Deelen, J, Sebastiani, P, Slagboom, E, Perls, TT, Hauser, ER, Gottschalk, W, Tan, Q, Christensen, K, Shi, X, Lutz, M, Tian, X-L, Yang, H & Vaupel, JW 2018, 'Sex Differences in Genetic Associations With Longevity', JAMA Network Open, vol. 1, no. 4, 1670. https://doi.org/10.1001/jamanetworkopen.2018.1670

Sex Differences in Genetic Associations With Longevity. / Zeng, Yi; Nie, Chao; Min, Junxia; Chen, Huashuai; Liu, Xiaomin; Ye, Rui; Chen, Zhihua; Bai, Chen; Xie, Enjun; Yin, Zhaoxue; Lv, Yuebin; Lu, Jiehua; Li, Jianxin; Ni, Ting; Bolund, Lars; Land, Kenneth C; Yashin, Anatoli I; O'Rand, Angela M; Sun, Liang; Yang, Ze; Tao, Wei; Gurinovich, Anastasia; Franceschi, Claudio; Xie, Jichun; Gu, Jun; Hou, Yong; Liu, Xiao; Xu, Xun; Robine, Jean-Marie; Deelen, Joris; Sebastiani, Paola; Slagboom, Eline; Perls, Thomas T; Hauser, Elizabeth R; Gottschalk, William; Tan, Qihua; Christensen, Kaare; Shi, Xiaoming; Lutz, Mike; Tian, Xiao-Li; Yang, Huanming; Vaupel, James W. .

In: JAMA Network Open, Vol. 1, No. 4, 1670, 08.2018.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Sex Differences in Genetic Associations With Longevity

AU - Zeng, Yi

AU - Nie, Chao

AU - Min, Junxia

AU - Chen, Huashuai

AU - Liu, Xiaomin

AU - Ye, Rui

AU - Chen, Zhihua

AU - Bai, Chen

AU - Xie, Enjun

AU - Yin, Zhaoxue

AU - Lv, Yuebin

AU - Lu, Jiehua

AU - Li, Jianxin

AU - Ni, Ting

AU - Bolund, Lars

AU - Land, Kenneth C

AU - Yashin, Anatoli I

AU - O'Rand, Angela M

AU - Sun, Liang

AU - Yang, Ze

AU - Tao, Wei

AU - Gurinovich, Anastasia

AU - Franceschi, Claudio

AU - Xie, Jichun

AU - Gu, Jun

AU - Hou, Yong

AU - Liu, Xiao

AU - Xu, Xun

AU - Robine, Jean-Marie

AU - Deelen, Joris

AU - Sebastiani, Paola

AU - Slagboom, Eline

AU - Perls, Thomas T

AU - Hauser, Elizabeth R

AU - Gottschalk, William

AU - Tan, Qihua

AU - Christensen, Kaare

AU - Shi, Xiaoming

AU - Lutz, Mike

AU - Tian, Xiao-Li

AU - Yang, Huanming

AU - Vaupel, James W.

PY - 2018/8

Y1 - 2018/8

N2 - 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.

AB - 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.

KW - Adult

KW - Aged, 80 and over

KW - Asian Continental Ancestry Group/genetics

KW - Case-Control Studies

KW - China/ethnology

KW - Female

KW - Genetic Loci

KW - Genome-Wide Association Study

KW - Humans

KW - Longevity/genetics

KW - Male

KW - Middle Aged

KW - Multifactorial Inheritance

KW - Polymorphism, Single Nucleotide

KW - Sex Characteristics

KW - Sex Factors

U2 - 10.1001/jamanetworkopen.2018.1670

DO - 10.1001/jamanetworkopen.2018.1670

M3 - Journal article

VL - 1

JO - JAMA Network Open

JF - JAMA Network Open

SN - 2574-3805

IS - 4

M1 - 1670

ER -