Sex Differences in Genetic Associations With Longevity.
Sex Differences in Genetic Associations With Longevity.
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DOI：
10.1001/jamanetworkopen.2018.1670
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发表时间：
2018-08
影响因子：
13.8
通讯作者：
Vaupel J
中科院分区：
文献类型：
--
作者：
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;Liu X;Xu X;Robine JM;Deelen J;Sebastiani P;Slagboom E;Perls T;Hauser E;Gottschalk W;Tan Q;Christensen K;Shi X;Lutz M;Tian XL;Yang H;Vaupel J
基因与长寿的关联是否存在性别差异？在这项2178例汉族病例和2299例汉族对照的病例对照研究中，性别特异性全基因组关联研究和性别特异性多基因风险评分分析显示，男性和女性在与寿命的遗传关联方面存在显著差异。研究结果表明，先前发表的长寿全基因组关联研究发现了一些性别无关的遗传变异，但遗漏了性别特异性的长寿位点和途径。这些新发现有助于填补研究文献的空白，进一步的调查可能会大大有助于个性化的医疗保健和更有效和有针对性的健康干预男性和女性老年人。本研究以人群为基础，对中国纵向健康长寿研究的参与者进行病例对照研究，采用性别特异性全基因组关联研究（GWAS）和多基因风险评分（PRS）分析，通过比较100岁以上的参与者和40至64岁的对照组参与者，研究遗传与长寿相关的性别差异。性别差异与人类寿命的基因关联在很大程度上仍然未知；对这一主题的调查对个性化医疗保健很重要。探索性别差异与长寿的基因关联。这项基于人群的病例对照研究使用性别特异性全基因组关联研究和多基因风险评分（PRS）分析来检查性别差异与寿命的遗传关联。564名年龄超过100岁的男性和1614名女性参与者与40至64岁的773名男性和1526名女性参与者进行了比较。所有受试者均为1998年和2008年至2014年招募的中国汉族纵向健康长寿研究参与者。性别特异性基因座和与寿命相关的途径，以及性别特异性基因座联合效应的测量。鉴定出11个雄性特异性长寿位点和11个雌性特异性长寿位点（P < 10−5），35个雄性特异性长寿位点和25个雌性特异性长寿位点（10−5≤P < 10−4）。这些基因座与长寿的关联在中国南北地区均有重复，但在其他性别中不显著（P = 0.13 ~ 0.97），位点-性别交互作用显著（P < 0.05）。LINC00871基因rs60210535位点与寿命的相关性在中国女性（P = 9.0 × 10−5）和美国女性（P = 4.6 × 10−5）中也存在，但在中国和美国男性中不显著。ABCG2基因rs2622624位点的关联在中国女性（P = 6.8 × 10−5）和欧洲女性（P = 0.003）中均存在，但在中国和欧洲男性中均不显著。11条男性特异性通路（炎症和免疫基因）和34条女性特异性通路（色氨酸代谢和PGC-1α诱导）与寿命显著相关（P < 0.005，错误发现率< 0.05）。PRS分析表明，在南北发现和目标样本中，4个排外群体（11个男性特异性位点和11个女性特异性位点）（P < 10−5）和35个男性特异性位点和25个女性特异性位点（10−5≤P < 10−4）与寿命的性别特异性关联被共同复制。利用南北组合数据集进行的分析表明，这4组性别特异性位点在一个性别中与寿命有显著的联合关系（P = 2.9 × 10−70 ~ 1.3 × 10−39），而在另一个性别中没有显著的联合关系（P = 1.3 × 10−39）。11 . to…70)，而PRS与性别之间的交互效应显著（P = 4.8 × 10−50 ~ 1.2 × 10−16）。基因与长寿相关的性别差异是显著的，但被先前发表的全基因组长寿相关研究所忽视。本研究填补了这一研究空白，为进一步研究性别特异性遗传变异及其与环境的相互作用对健康老龄化的影响提供了科学依据，为更有效、更有针对性地为男性和女性老年人提供个性化医疗服务提供了重要依据。
Are there sex differences in genetic associations with longevity? In this case-control study of 2178 cases and 2299 controls who were Chinese with Han ethnicity, sex-specific genome-wide association study and sex-specific polygenic risk score analyses on longevity showed substantial and significant differences in genetic associations with longevity between men and women. Findings indicated that previously published genome-wide association studies on longevity identified some sex-independent genetic variants but missed sex-specific longevity loci and pathways. These novel findings contribute to filling the gaps in the research literature, and further investigations may substantially contribute to individualized health care and more effective and targeted health interventions for male and female elderly individuals. This population-based case-control study of Chinese Longitudinal Healthy Longevity Study participants uses sex-specific genome-wide association study (GWAS) and polygenic risk score (PRS) analyses to examine sex differences in genetic associations with longevity by comparing participants older than 100 years with a control group of participants aged 40 to 64 years. Sex differences in genetic associations with human longevity remain largely unknown; investigations on this topic are important for individualized health care. To explore sex differences in genetic associations with longevity. 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. Sex-specific loci and pathways associated with longevity and PRS measures of joint effects of sex-specific loci. 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). 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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DOI：
10.1093/bioinformatics/btu848
发表时间：
2015-05-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Euesden J;Lewis CM;O'Reilly PF
通讯作者：
O'Reilly PF
DOI：
10.1016/s1473-3099(10)70049-9
发表时间：
2010-05
期刊：
The Lancet. Infectious diseases
影响因子：
--
作者：
Klein SL;Jedlicka A;Pekosz A
通讯作者：
Pekosz A
影响因子：
3.7
作者：
Marttila S;Jylhävä J;Nevalainen T;Nykter M;Jylhä M;Hervonen A;Tserel L;Peterson P;Hurme M
通讯作者：
Hurme M
DOI：
10.1093/gerona/glu166
发表时间：
2015-01-01
影响因子：
5.1
作者：
Broer, Linda;Buchman, Aron S.;Murabito, Joanne M.
通讯作者：
Murabito, Joanne M.
影响因子：
4.1
作者：
Melkamu, Tamene;Kita, Hirohito;O'Grady, Scott M.
通讯作者：
O'Grady, Scott M.