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Nat Commun. 2017 Oct 13;8(1):910. doi: 10.1038/s41467-017-00934-5.

Genome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity.

Joshi PK1, Pirastu N2, Kentistou KA2,3, Fischer K4, Hofer E5,6, Schraut KE2,3, Clark DW2, Nutile T7, Barnes CLK2, Timmers PRHJ2, Shen X2,8, Gandin I9,10, McDaid AF11,12, Hansen TF13,14, Gordon SD15, Giulianini F16, Boutin TS17, Abdellaoui A18, Zhao W19, Medina-Gomez C20,21, Bartz TM22, Trompet S23,24, Lange LA25, Raffield L26, van der Spek A21, Galesloot TE27, Proitsi P28, Yanek LR29, Bielak LF19, Payton A30, Murgia F31, Concas MP32, Biino G33, Tajuddin SM34, Seppälä I35, Amin N21, Boerwinkle E36, Børglum AD14,37,38, Campbell A39, Demerath EW40, Demuth I41,42,43, Faul JD44, Ford I45, Gialluisi A46, Gögele M31, Graff M47, Hingorani A48, Hottenga JJ18, Hougaard DM14,49, Hurme MA50, Ikram MA21, Jylhä M51, Kuh D28, Ligthart L18, Lill CM52, Lindenberger U53,54, Lumley T55, Mägi R4, Marques-Vidal P56, Medland SE15, Milani L4, Nagy R17, Ollier WER57, Peyser PA19, Pramstaller PP31, Ridker PM16,58, Rivadeneira F20,21, Ruggiero D7, Saba Y59, Schmidt R5, Schmidt H59, Slagboom PE60, Smith BH61, Smith JA19,44, Sotoodehnia N62, Steinhagen-Thiessen E41, van Rooij FJA21, Verbeek AL27, Vermeulen SH27, Vollenweider P56, Wang Y14,63, Werge T13,14, Whitfield JB15, Zonderman AB34, Lehtimäki T35, Evans MK34, Pirastu M32, Fuchsberger C31, Bertram L64,65, Pendleton N66, Kardia SLR19, Ciullo M7,46, Becker DM29, Wong A28, Psaty BM67,68, van Duijn CM21, Wilson JG69, Jukema JW24, Kiemeney L27, Uitterlinden AG20,21, Franceschini N47, North KE47, Weir DR44, Metspalu A4, Boomsma DI18, Hayward C17, Chasman D16,58, Martin NG15, Sattar N70, Campbell H2, Esko T4,71, Kutalik Z11,12, Wilson JF2,17.

Author information

1
Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, EH8 9AG, UK. peter.joshi@ed.ac.uk.
2
Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, EH8 9AG, UK.
3
Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, EH16 4TJ, Scotland.
4
Estonian Genome Center, University of Tartu, University of Tartu, Tartu, 51010, Estonia.
5
Clinical Division of Neurogeriatrics, Department of Neurology, Medical University of Graz, Graz, 8036, Austria.
6
Institute of Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, 8036, Austria.
7
Institute of Genetics and Biophysics "A. Buzzati-Traverso" - CNR, Naples, 80131, Italy.
8
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-171 77, Stockholm, Sweden.
9
Department of Medical Sciences, University of Trieste, Trieste, 34100, Italy.
10
Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, 34137, Italy.
11
Institute of Social and Preventive Medicine, Lausanne University Hospital, Lausanne, 1010, Switzerland.
12
Swiss Institute of Bioinformatics, Lausanne, 1015, Switzerland.
13
Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Mental Health Services Copenhagen, Roskilde, DK-4000, Denmark.
14
iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, DK-8000, Denmark.
15
QIMR Berghofer Institute of Medical Research, Brisbane, QLD, 4006, Australia.
16
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, 02215, USA.
17
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK.
18
Netherlands Twin Register, Department of Biological Psychology, Vrije Universiteit, Amsterdam, Amsterdam Public Health Institute (APH), Amsterdam, 1081BT, Netherlands.
19
Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, 48109, USA.
20
Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, 3015 CN, Netherlands.
21
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, 3015 CN, Netherlands.
22
Cardiovascular Health Research Unit, Departments of Biostatistics and Medicine, University of Washington, Seattle, WA, 98101, USA.
23
Section of Gerontology and Geriatrics, Department of Internal Medicine, Leiden University Medical Center, Leiden, 2300RC, The Netherlands.
24
Department of Cardiology, Leiden University Medical Center, Leiden, 2300RC, The Netherlands.
25
Department of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, 80045, USA.
26
Department of Genetics, University of North Carolina, Chapel Hill, NC, 27599, USA.
27
Department for Health Evidence, Radboud Institute for Health Sciences, Radboud university medical center, Nijmegen, 6500 HB, The Netherlands.
28
MRC Unit for Lifelong Health & Ageing at UCL, University College London, London, WC1B 5JU, UK.
29
Department of Medicine, GeneSTAR Research Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
30
Centre for Epidemiology, Division of Population Health, Health Services Research & Primary Care, The University of Manchester, Manchester, Greater, Manchester, M13 9PL, UK.
31
Center for Biomedicine, European Academy of Bozen/Bolzano (EURAC), (Affiliated Institute of the University of Lübeck, Lübeck, Germany), Bolzano, 39100, Italy.
32
Institute of Genetic and Biomedical Research - Support Unity, National Research Council of Italy, Sassari, 07100, Italy.
33
Institute of Molecular Genetics, National Research Council of Italy, Pavia, 27100, Italy.
34
Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore City, MD, 21224, USA.
35
Department of Clinical Chemistry, Fimlab Laboratories and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, 33014, Finland.
36
Health Science Center at Houston, UTHealth School of Public Health, University of Texas, Houston, TX, 77030, USA.
37
Department of Biomedicine-Human Genetics, Aarhus University, DK-8000, Aarhus C, Denmark.
38
Centre for Integrative Sequencing, iSEQ, Aarhus University, DK-8000, Aarhus C, Denmark.
39
Centre for Genomic & Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK.
40
Division of Epidemiology & Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, 55454, USA.
41
Charité Research Group on Geriatrics, Charité, Universitätsmedizin Berlin, Berlin, 13347, Germany.
42
Lipid Clinic at the Interdisciplinary Metabolism Center, Charité, Universitätsmedizin Berlin, Berlin, 13353, Germany.
43
Institute for Medical and Human Genetics, Charité, Universitätsmedizin Berlin, Berlin, 13353, Germany.
44
Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, 48014, USA.
45
Robertson Center for biostatistics, University of Glasgow, Glasgow, G12 8QQ, UK.
46
IRCCS Neuromed, Pozzilli (IS), 86077, Italy.
47
Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, 27514, USA.
48
Institute of Cardiovascular Science, University College London, London, WC1E 6BT, UK.
49
Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, 2300, Denmark.
50
Department of Microbiology and Immunology, Fimlab Laboratories and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, 33014, Finland.
51
Gerontology Research Center, Tampere, Finland, Faculty of Social Sciences, University of Tampere, Tampere, 33104, Finland.
52
Genetic and Molecular Epidemiology Group, Institute of Neurogenetics, University of Lübeck, 23562, Lübeck, Germany.
53
Center for Lifespan Psychology, Max Planck Institute for Human Development, Berlin, 14195, Germany.
54
Max Planck UCL Centre for Computational Psychiatry and Ageing Research, Berlin, 14195, Germany.
55
Department of Statistics, University of Auckland, Auckland, 1010, New Zealand.
56
Department of Medicine, Internal Medicine, Lausanne University Hospital, Lausanne, 1011, Switzerland.
57
Division of Population Health, Health Services Research & Primary Care, School of Health Sciences, Manchester Academic Health Science Centre, University of Manchester, Manchester, Greater Manchester, M13 9PL, UK.
58
TH Chan School of Public Health, Harvard Medical School, Boston, MA, 02115, USA.
59
Austrian Stroke Prevention Study, Institute of Molecular Biology and Biochemistry, Centre for Molecular Medicine, Medical University of Graz, Graz, 8010, Austria.
60
Section of Molecular Epidemiology, Department of medical statistics, Leiden University Medical Center, Leiden, 2300RC, The Netherlands.
61
Division of Population Health Sciences, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK.
62
Cardiovascular Health Research Unit, Division of Cardiology, University of Washington, Seattle, WA, 98101, USA.
63
NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, 0450, Norway.
64
Lübeck Interdisciplinary Platform for Genome Analytics, Institutes of Neurogenetics & Cardiogenetics, University of Lübeck, Lübeck, 23562, Germany.
65
Neuroepidemiology and Ageing Research Group, School of Public Health, Imperial College, London, W6 8RP, UK.
66
Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Manchester Academic Health Science Centre, University of Manchester, Manchester, Greater Manchester, M13 9PL, UK.
67
Cardiovascular Health Research Unit, Departments of Epidemiology, Medicine and Health Services, University of Washington, Seattle, WA, 98101, USA.
68
Kaiser Permanente Washington Health Research Institute, Seattle, WA, 98101, USA.
69
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, 39216, USA.
70
BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, G12 8TD, UK.
71
Program in Medical and Population Genetics, Broad Institute, Broad Institute, Cambridge, MA, 02142, USA.

Abstract

Genomic analysis of longevity offers the potential to illuminate the biology of human aging. Here, using genome-wide association meta-analysis of 606,059 parents' survival, we discover two regions associated with longevity (HLA-DQA1/DRB1 and LPA). We also validate previous suggestions that APOE, CHRNA3/5, CDKN2A/B, SH2B3 and FOXO3A influence longevity. Next we show that giving up smoking, educational attainment, openness to new experience and high-density lipoprotein (HDL) cholesterol levels are most positively genetically correlated with lifespan while susceptibility to coronary artery disease (CAD), cigarettes smoked per day, lung cancer, insulin resistance and body fat are most negatively correlated. We suggest that the effect of education on lifespan is principally mediated through smoking while the effect of obesity appears to act via CAD. Using instrumental variables, we suggest that an increase of one body mass index unit reduces lifespan by 7 months while 1 year of education adds 11 months to expected lifespan.Variability in human longevity is genetically influenced. Using genetic data of parental lifespan, the authors identify associations at HLA-DQA/DRB1 and LPA and find that genetic variants that increase educational attainment have a positive effect on lifespan whereas increasing BMI negatively affects lifespan.

PMID:
29030599
PMCID:
PMC5715013
DOI:
10.1038/s41467-017-00934-5
[Indexed for MEDLINE]
Free PMC Article

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