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Nat Commun. 2019 Aug 14;10(1):3669. doi: 10.1038/s41467-019-11558-2.

A meta-analysis of genome-wide association studies identifies multiple longevity genes.

Author information

1
Max Planck Institute for Biology of Ageing, 50866, Cologne, Germany. Joris.Deelen@age.mpg.de.
2
Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands. Joris.Deelen@age.mpg.de.
3
California Pacific Medical Center Research Institute, San Francisco, CA, 94158, USA. DEvans@sfcc-cpmc.net.
4
McKusick-Nathans Institute of Genetic Medicine, Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
5
Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, 1007 MB, Amsterdam, The Netherlands.
6
Department of Clinical Genetics, Amsterdam UMC, 1007 MB, Amsterdam, The Netherlands.
7
Delft Bioinformatics Lab, Delft University of Technology, 2600 GA, Delft, The Netherlands.
8
The Danish Aging Research Center, Department of Public Health, University of Southern Denmark, 5000, Odense C, Denmark.
9
BGI-Shenzhen, Shenzhen, 518083, China.
10
China National Genebank, BGI-Shenzhen, Shenzhen, 518120, China.
11
Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, Saint Louis, MO, 63110, USA.
12
Department of Biostatistics, University of Washington, Seattle, WA, 98115, USA.
13
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, 98101, USA.
14
Department of Epidemiology, Erasmus MC, 3000 CA, Rotterdam, The Netherlands.
15
Department of Biology, Faculty of Natural Science, University of Haifa, Haifa, 3498838, Israel.
16
Departments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
17
Institute for Social Research, Survey Research Center, University of Michigan, Ann Arbor, MI, 48104, USA.
18
Department of Biostatistics, Boston University School of Public Health, Boston, MA, 02118, USA.
19
School of Public Health, Department of Biostatistics, University of Michigan, Ann Arbor, MI, 48109, USA.
20
Icelandic Heart Association, 201, Kópavogur, Iceland.
21
Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Health Technology, Tampere University, 33520, Tampere, Finland.
22
Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK.
23
Institute of Clinical Molecular Biology, Kiel University, 24105, Kiel, Germany.
24
Sema4, a Mount Sinai venture, Stamford, CT, 06902, USA.
25
Bioinformatics Program, Boston University, Boston, MA, 02118, USA.
26
Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands.
27
Fondation Jean Dausset-CEPH, 75010, Paris, France.
28
Clinical Biochemistry and Pharmacology, Odense University Hospital, 5000, Odense C, Denmark.
29
Department of Clinical Genetics, Odense University Hospital, 5000, Odense C, Denmark.
30
Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, 2100, Copenhagen, Denmark.
31
Institute of Health & Society, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK.
32
MMDN, Univ. Montpellier, EPHE, Unité Inserm 1198, PSL Research University, 34095, Montpellier, France.
33
California Pacific Medical Center Research Institute, San Francisco, CA, 94158, USA.
34
Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK.
35
Department of Public Health, University of Southern Denmark, 5000, Odense C, Denmark.
36
Centre National de Recherche en Génomique Humaine, CEA-Institut de Biologie François Jacob, 91000, Evry, France.
37
Newcastle University Institute for Ageing, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK.
38
Department of Applied Mathematics and Centre of Bioinformatics, Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod, 603022, Russia.
39
IRCCS Institute of Neurological Sciences of Bologna (ISNB), 40124, Bologna, Italy.
40
EREN, UMR U1153 Inserm/U1125 Inra/Cnam/Paris 13, Université Paris 13, CRESS, 93017, Bobigny, France.
41
Faculty of Medicine, University of Iceland, 101, Reykjavik, Iceland.
42
Laboratory of Epidemiology and Population Sciences, National Institute on Aging, NIH, Bethesda, MD, 20892, USA.
43
Department of Epidemiology and Biostatistics, Vrije Universiteit Amsterdam, Amsterdam UMC, 1007 MB, Amsterdam, The Netherlands.
44
Amsterdam Public Health Research Institute, 1007 MB, Amsterdam, The Netherlands.
45
Department of Microbiology and Immunology, Faculty of Medicine and Health Technology, Tampere University, 33014, Tampere, Finland.
46
Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, 1081 HV, Amsterdam, The Netherlands.
47
Faculty of Social Sciences (Health Sciences) and Gerontology Research Center (GEREC), Tampere University, 33104, Tampere, Finland.
48
Department of Clinical Physiology, Tampere University Hospital and Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Health Technology, Tampere University, 33521, Tampere, Finland.
49
Azrieli Faculty of Medicine, Bar Ilan University, Safed, 13010, Israel.
50
Hinda and Arthur Marcus Institute for Aging Research, Hebrew SeniorLife, Boston, MA, 02131, USA.
51
School of Public Health, Epidemiology, University of Michigan, Ann Arbor, MI, 48109, USA.
52
Institute of Epidemiology and Biobank PopGen, Kiel University, 24105, Kiel, Germany.
53
Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou, 311058, China.
54
Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
55
Research Unit of Gynecology and Obstetrics, Department of Clinical Research, University of Southern Denmark, 5000, Odense C, Denmark.
56
Bone and Mineral Unit, Oregon Health Sciences University, Portland, OR, 97239, USA.
57
Department of Medicine, Geriatrics Section, Boston Medical Center, Boston University School of Medicine, Boston, MA, 02118, USA.
58
Department of Epidemiology, University of Washington, Seattle, WA, 98101, USA.
59
Department of Health Services, University of Washington, Seattle, WA, 98101, USA.
60
Kaiser Permanente Washington Health Research Institute, Seattle, WA, 98101, USA.
61
Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, 20521, Turku, Finland.
62
Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, 20014, Turku, Finland.
63
CERMES3, UMR CNRS 8211-Unité Inserm 988-EHESS-Université Paris Descartes, 94801, Paris, France.
64
Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, 90502, USA.
65
Division of Genetic Outcomes, Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA, 90502, USA.
66
Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, and Department of Public Health, Section of Epidemiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen N, Denmark.
67
MRC Integrative Epidemiology Unit, Bristol University, BS8 2BN, Bristol, UK.
68
Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA, 90502, USA.
69
Department of Internal Medicine, Erasmus MC, 3000 CA, Rotterdam, The Netherlands.
70
Nuffield Department of Population Health, University of Oxford, Oxford, OX3 7LF, UK.
71
Department of Gerontology and Geriatrics, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands.
72
Max Planck Institute for Demographic Research, 18057, Rostock, Germany.
73
Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
74
Center for Healthy Aging and Development Studies, National School of Development and Raissun Institute for Advanced Studies, Peking University, 100871, Beijing, China.
75
Center for the Study of Aging and Human Development and Geriatrics Division, Medical School of Duke University, Durham, NC, 27710, USA.
76
Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, 02215, USA.
77
Broad Institute of MIT & Harvard, Cambridge, MA, 02142, USA.
78
Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands. P.Slagboom@lumc.nl.
79
NHLBI's and Boston University's Framingham Heart Study, Framingham, MA, 01702, USA. murabito@bu.edu.
80
Section of General Internal Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA, 02118, USA. murabito@bu.edu.

Abstract

Human longevity is heritable, but genome-wide association (GWA) studies have had limited success. Here, we perform two meta-analyses of GWA studies of a rigorous longevity phenotype definition including 11,262/3484 cases surviving at or beyond the age corresponding to the 90th/99th survival percentile, respectively, and 25,483 controls whose age at death or at last contact was at or below the age corresponding to the 60th survival percentile. Consistent with previous reports, rs429358 (apolipoprotein E (ApoE) ε4) is associated with lower odds of surviving to the 90th and 99th percentile age, while rs7412 (ApoE ε2) shows the opposite. Moreover, rs7676745, located near GPR78, associates with lower odds of surviving to the 90th percentile age. Gene-level association analysis reveals a role for tissue-specific expression of multiple genes in longevity. Finally, genetic correlation of the longevity GWA results with that of several disease-related phenotypes points to a shared genetic architecture between health and longevity.

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