title: Novel loci and pathways significantly associated with longevity.
abstract: Only two genome-wide significant loci associated with longevity have been identified so far, probably because of insufficient sample sizes of centenarians, whose genomes may harbor genetic variants associated with health and longevity. Here we report a genome-wide association study (GWAS) of Han Chinese with a sample size 2.7 times the largest previously published GWAS on centenarians. We identified 11 independent loci associated with longevity replicated in Southern-Northern regions of China, including two novel loci (rs2069837-IL6; rs2440012-ANKRD20A9P) with genome-wide significance and the rest with suggestive significance (P < 3.65 × 10(-5)). Eight independent SNPs overlapped across Han Chinese, European and U.S. populations, and APOE and 5q33.3 were replicated as longevity loci. Integrated analysis indicates four pathways (starch, sucrose and xenobiotic metabolism; immune response and inflammation; MAPK; calcium signaling) highly associated with longevity (P ≤ 0.006) in Han Chinese. The association with longevity of three of these four pathways (MAPK; immunity; calcium signaling) is supported by findings in other human cohorts. Our novel finding on the association of starch, sucrose and xenobiotic metabolism pathway with longevity is consistent with the previous results from Drosophilia. This study suggests protective mechanisms including immunity and nutrient metabolism and their interactions with environmental stress play key roles in human longevity.
authors.affiliation: Center for the Study of Aging and Human Development and Geriatrics Division, Medical School of Duke University, Durham, North Carolina, USA.|Center for Healthy Aging and Development Studies, National School of Development, Peking University, Beijing, China.
authors.forename: Yi
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authors.lastname: Zeng
authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Chao
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authors.affiliation: The First Affiliated Hospital, Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Junxia
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authors.lastname: Min
authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Xiaomin
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authors.lastname: Liu
authors.affiliation: Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, The Second Military Medical University, Shanghai, China.
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Li
authors.affiliation: Center for the Study of Aging and Human Development and Geriatrics Division, Medical School of Duke University, Durham, North Carolina, USA.|Business School of Xiangtan University, Xiangtan, China.
authors.forename: Huashuai
authors.initials: H
authors.lastname: Chen
authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Hanshi
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authors.lastname: Xu
authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Mingbang
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authors.affiliation: State Key Laboratory of Genetics Engineering &MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Ting
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authors.lastname: Ni
authors.affiliation: Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing, China.
authors.forename: Yang
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authors.lastname: Li
authors.affiliation: Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing, China.
authors.forename: Han
authors.initials: H
authors.lastname: Yan
authors.affiliation: Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing, China.
authors.forename: Jin-Pei
authors.initials: JP
authors.lastname: Zhang
authors.affiliation: Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing, China.
authors.forename: Chun
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authors.affiliation: Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing, China.
authors.forename: Li-Qing
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authors.affiliation: Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing, China.
authors.forename: Han-Ming
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authors.lastname: Wang
authors.affiliation: Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing, China.
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authors.affiliation: Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing, China.
authors.forename: Gu-Yan
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authors.affiliation: Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, The Second Military Medical University, Shanghai, China.
authors.forename: Li
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authors.affiliation: Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, The Second Military Medical University, Shanghai, China.
authors.forename: Feng
authors.initials: F
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authors.affiliation: BGI-Shenzhen, Shenzhen, China.|Department of Bio-Medical Engineering, School of Life Sciences, Anhui Medical University, Hefei, China.
authors.forename: Yanwei
authors.initials: Y
authors.lastname: Qi
authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Xiao
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authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Hongzhi
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authors.affiliation: BGI-Shenzhen, Shenzhen, China.
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authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Lijuan
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authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Zhaochun
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authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Yufeng
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authors.lastname: Zhou
authors.affiliation: BGI-Shenzhen, Shenzhen, China.
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authors.affiliation: Department of Sociology, Peking University, Beijing, China.
authors.forename: Jiehua
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authors.affiliation: Department of Sociology, Peking University, Beijing, China.
authors.forename: Jianxin
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authors.affiliation: The First Affiliated Hospital, Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou, China.
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authors.affiliation: BGI-Shenzhen, Shenzhen, China.|Department of Biomedicine, Aarhus University, Aarhus, Denmark.
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authors.lastname: Bolund
authors.affiliation: Population Research Institute, Duke University, Durham, North Carolina, USA.
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authors.affiliation: Population Research Institute, Duke University, Durham, North Carolina, USA.
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authors.affiliation: Duke Molecular Physiology Institute, Medical Center, Duke University, Durham, North Carolina, USA.
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authors.affiliation: National Institutes of Geriatrics, Beijing Hospital, Ministry of Health, Beijing, China.
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authors.affiliation: Department of Neurology, Medical Center, Duke University, Durham, North Carolina, USA.
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authors.affiliation: School of Life Sciences, Peking University, Beijing, China.
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authors.affiliation: BGI-Shenzhen, Shenzhen, China.|James D. Watson Institute of Genome Sciences, Hangzhou, China.
authors.forename: Jian
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authors.affiliation: BGI-Shenzhen, Shenzhen, China.|Department of Biology, University of Copenhagen, Copenhagen, Denmark.
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authors.affiliation: BGI-Shenzhen, Shenzhen, China.
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authors.affiliation: College of Public Health and Human Sciences, Oregon State University, USA.
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authors.affiliation: The Danish Aging Research Centre, Unit of Epidemiology, Biostatistics and Biodemography, Institute of Public Health, University of Southern Denmark, Odense, Denmark.
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authors.lastname: Nygaard
authors.affiliation: The Danish Aging Research Centre, Unit of Epidemiology, Biostatistics and Biodemography, Institute of Public Health, University of Southern Denmark, Odense, Denmark.
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authors.affiliation: The Danish Aging Research Centre, Unit of Epidemiology, Biostatistics and Biodemography, Institute of Public Health, University of Southern Denmark, Odense, Denmark.
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authors.affiliation: Department of Neurology, Medical Center, Duke University, Durham, North Carolina, USA.
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authors.affiliation: School of Life Sciences, Peking University, Beijing, China.
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authors.affiliation: The Danish Aging Research Centre, Unit of Epidemiology, Biostatistics and Biodemography, Institute of Public Health, University of Southern Denmark, Odense, Denmark.
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authors.affiliation: Geriatrics Section, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
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authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
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authors.affiliation: Department of Molecular Epidemiology and Netherlands Consortium for Healthy Ageing, Leiden University Medical Center, Leiden, The Netherlands.
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authors.affiliation: Department of Molecular Epidemiology and Netherlands Consortium for Healthy Ageing, Leiden University Medical Center, Leiden, The Netherlands.
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authors.affiliation: Duke Molecular Physiology Institute, Medical Center, Duke University, Durham, North Carolina, USA.
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authors.affiliation: Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, The Second Military Medical University, Shanghai, China.
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authors.affiliation: Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing, China.
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authors.affiliation: BGI-Shenzhen, Shenzhen, China.|James D. Watson Institute of Genome Sciences, Hangzhou, China.
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mesh_terms: D001057:Apolipoproteins E / Q000235:genetics; D044466:Asian People / Q000235:genetics; D002681:China; D053263:Gene Regulatory Networks; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006801:Humans; D008136:Longevity / Q000235:genetics*; D026901:Membrane Transport Proteins / Q000235:genetics; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D020641:Polymorphism, Single Nucleotide; D025341:Principal Component Analysis
chemical_list: D001057:Apolipoproteins E; D026901:Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; C400783:TOMM40 protein, human