Format

Send to

Choose Destination
Hum Mol Genet. 2014 Aug 15;23(16):4420-32. doi: 10.1093/hmg/ddu139. Epub 2014 Mar 31.

Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age.

Author information

1
Department of Molecular Epidemiology, Netherlands Consortium for Healthy Ageing.
2
Department of Medical Statistics and Bioinformatics.
3
Netherlands Consortium for Healthy Ageing, Department of Epidemiology and.
4
Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
5
Epidemiology, Institute of Public Health and Department of Clinical Genetics and.
6
Fondation Jean Dausset-CEPH, Paris 75010, France.
7
Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm SE-171 77, Sweden.
8
Estonian Genome Center and Institute of Molecular and Cell Biology, University of Tartu, Tartu 51010, Estonia.
9
Department of Cardiology and Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden 2300 RC, The Netherlands.
10
Population Genomics, deCODE Genetics, Reykjavík 101, Iceland.
11
Institute of Clinical Molecular Biology and.
12
Department of Biology, Ecology and Earth Science, University of Calabria, Rende 87036, Italy.
13
Estonian Genome Center and.
14
Department of Molecular Epidemiology, Delft Bioinformatics Lab, Delft University of Technology, Delft 2600 GA, The Netherlands.
15
Department of Cardiovascular Sciences, University of Leicester, Leicester LE3 9QP, UK National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester LE3 9QP, UK.
16
Human and Vertebrate Analysis and Annotation, The Wellcome Trust Sanger Institute, The Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
17
Epidemiology, Institute of Public Health and.
18
School of Medicine, Dentistry and Biomedical Science, Queens University Belfast, Belfast BT9 7BL, UK Department of Psychiatry, University of Iowa, Iowa City, IA 52242, USA.
19
Department of Molecular Epidemiology.
20
Institute of Medical Informatics and Statistics, Christian-Albrechts-University, Kiel 24105, Germany.
21
Department of Experimental, Diagnostic and Specialty Medicine and.
22
Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne NE4 5PL, UK.
23
Robertson Center for Biostatistics and.
24
Laboratory of Statistical Demography, Max Planck Institute for Demographic Research, Rostock 18057, Germany.
25
Department of Biological Psychology, VU University Amsterdam, Amsterdam 1081 BT, The Netherlands EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam 1081 BT, The Netherlands.
26
Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden 2300 RC, The Netherlands.
27
Department of Biological Psychology, VU University Amsterdam, Amsterdam 1081 BT, The Netherlands.
28
Geriatrics, Landspitali University Hospital, Reykjavik 101, Iceland Faculty of Medicine, University of Iceland, Reykjavik 101, Iceland.
29
Fondation Jean Dausset-CEPH, Paris 75010, France EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam 1081 BT, The Netherlands McGill University and Génome Québec Innovation Centre, Montréal, Québec, Canada H3A 1A4.
30
Institut de Génomique, CEA, Évry 91057, France.
31
School of Medicine, Dentistry and Biomedical Science, Queens University Belfast, Belfast BT9 7BL, UK Cytogenetics Laboratory, Belfast Health and Social Care Trust, Belfast BT8 8BH, UK.
32
Estonian Genome Center and Estonian Biocentre, Tartu 51010, Estonia.
33
Netherlands Consortium for Healthy Ageing, Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden 2300 RC, The Netherlands.
34
School of Medicine, Dentistry and Biomedical Science, Queens University Belfast, Belfast BT9 7BL, UK.
35
Section for Epidemiology, Department of Public Health, Aarhus University, Aarhus C DK-8000, Denmark Department of Gynecology and Obstetrics, Institute of Clinical Research, University of Southern Denmark, Odense C DK-5000, Denmark.
36
MRC Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, University of Bristol, Bristol BS8 2BN, UK.
37
Netherlands Consortium for Healthy Ageing, Department of Epidemiology and Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands.
38
School of Medicine, Dentistry and Biomedical Science, Queens University Belfast, Belfast BT9 7BL, UK Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
39
BHF Glasgow Cardiovascular Research Centre, Faculty of Medicine, University of Glasgow, Glasgow G12 8TA, UK.
40
Institute of Clinical Molecular Biology and PopGen Biobank, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Kiel 24105, Germany.
41
Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
42
Netherlands Consortium for Healthy Ageing, Department of Epidemiology and Department of Child and Adolescent Psychiatry, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam 3000 CA, The Netherlands.
43
Université Sorbonne Paris Cité-UREN (Unité de Recherche en Epidémiologie Nutritionnelle), U557 Inserm; U1125 Inra; Cnam; Université Paris 13, CRNH IdF, Bobigny 93017, France.
44
Novo Nordisk Foundation Center for Basic Metabolic Research, Section on Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N DK-2200, Denmark Institute of Preventive Medicine, Bispebjerg and Frederiksberg University Hospitals, Frederiksberg DK-2000, Denmark.
45
Department of Cardiology and Interuniversity Cardiology Institute of the Netherlands, Utrecht 3501 DG, The Netherlands.
46
Epidemiology, Institute of Public Health and Department of Clinical Genetics and Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense C DK-5000, Denmark.
47
Estonian Genome Center and Institute of Molecular and Cell Biology, University of Tartu, Tartu 51010, Estonia Estonian Biocentre, Tartu 51010, Estonia.
48
Department of Experimental, Diagnostic and Specialty Medicine and Interdepartmental Centre 'L. Galvani', University of Bologna, Bologna 40126, Italy IRCCS Institute of Neurological Science, Bellaria Hospital, Bologna 40139, Italy CNR-ISOF, Bologna 40129, Italy.
49
Department of Molecular Epidemiology, Netherlands Consortium for Healthy Ageing, p.slagboom@lumc.nl.

Abstract

The genetic contribution to the variation in human lifespan is ∼ 25%. Despite the large number of identified disease-susceptibility loci, it is not known which loci influence population mortality. We performed a genome-wide association meta-analysis of 7729 long-lived individuals of European descent (≥ 85 years) and 16 121 younger controls (<65 years) followed by replication in an additional set of 13 060 long-lived individuals and 61 156 controls. In addition, we performed a subset analysis in cases aged ≥ 90 years. We observed genome-wide significant association with longevity, as reflected by survival to ages beyond 90 years, at a novel locus, rs2149954, on chromosome 5q33.3 (OR = 1.10, P = 1.74 × 10(-8)). We also confirmed association of rs4420638 on chromosome 19q13.32 (OR = 0.72, P = 3.40 × 10(-36)), representing the TOMM40/APOE/APOC1 locus. In a prospective meta-analysis (n = 34 103), the minor allele of rs2149954 (T) on chromosome 5q33.3 associates with increased survival (HR = 0.95, P = 0.003). This allele has previously been reported to associate with low blood pressure in middle age. Interestingly, the minor allele (T) associates with decreased cardiovascular mortality risk, independent of blood pressure. We report on the first GWAS-identified longevity locus on chromosome 5q33.3 influencing survival in the general European population. The minor allele of this locus associates with low blood pressure in middle age, although the contribution of this allele to survival may be less dependent on blood pressure. Hence, the pleiotropic mechanisms by which this intragenic variation contributes to lifespan regulation have to be elucidated.

PMID:
24688116
PMCID:
PMC4103672
DOI:
10.1093/hmg/ddu139
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Silverchair Information Systems Icon for PubMed Central
Loading ...
Support Center