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J Gerontol A Biol Sci Med Sci. 2015 Jan;70(1):110-8. doi: 10.1093/gerona/glu166. Epub 2014 Sep 8.

GWAS of longevity in CHARGE consortium confirms APOE and FOXO3 candidacy.

Author information

1
Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands. Netherlands Consortium for Healthy Ageing, Leiden University Medical Center, The Netherlands. Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
2
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois.
3
Netherlands Consortium for Healthy Ageing, Leiden University Medical Center, The Netherlands. Department of Molecular Epidemiology, Leiden University Medical Center, The Netherlands.
4
California Pacific Medical Center Research Institute, San Francisco.
5
Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor.
6
Department of Biostatistics, Boston University School of Public Health, Massachusetts. NHLBI's and Boston Univesity's Framingham Heart Study, Massachusetts.
7
Department of Biostatistics, Boston University School of Public Health, Massachusetts.
8
Department of Epidemiology, University of Michigan, Ann Arbor.
9
Icelandic Heart Association, Kopavogur, Iceland. Department of Medicine, University of Iceland, Reykjavik.
10
Translational Gerontology Branch, National Institute on Aging, Baltimore, Maryland.
11
Department of Biostatistics, University of Washington, Seattle.
12
NHLBI's and Boston Univesity's Framingham Heart Study, Massachusetts. Department of Medicine, Sections of Preventive Medicine and Cardiology, Boston University School of Medicine, Massachusetts. Department of Epidemiology, Boston University School of Public Health, Massachusetts.
13
Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts. Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts.
14
Icelandic Heart Association, Kopavogur, Iceland.
15
Rush Institute for Healthy Aging and Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois.
16
Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, Maryland.
17
Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands. Netherlands Consortium for Healthy Ageing, Leiden University Medical Center, The Netherlands.
18
Department of Epidemiology and Population Health, Albert Einstein College, Bronx, New York.
19
Harvard Medical School, Boston, Massachusetts. Institute for Aging Research, Hebrew SeniorLife, Harvard Medical School Department of Medicine, Boston, Massachusetts. Division of Gerontology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
20
School of Medicine, Oregon Health and Science University, Portland.
21
Department of Medicine, University of Washington, Seattle. Deparment of Epidemiology, University of Washington, Seattle. Department of Health Services, University of Washington, Seattle. Group Health Research Institute, Group Health Cooperative, Seattle, Washington.
22
Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands. Institute for Aging Research, Hebrew SeniorLife, Harvard Medical School Department of Medicine, Boston, Massachusetts.
23
Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California.
24
Department of Biostatistics, Boston University School of Public Health, Massachusetts. Department of Neurology, Boston University School of Medicine, Massachusetts.
25
Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland.
26
Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands. Netherlands Consortium for Healthy Ageing, Leiden University Medical Center, The Netherlands. Department of Child and Adolescent Psychiatry, Erasmus MC and Sophia Children's Hospital, Rotterdam, The Netherlands.
27
Geriatric Unit, Azienda Sanitaria Firenze, Florence, Italy.
28
Institute for Aging Research, Hebrew SeniorLife, Harvard Medical School Department of Medicine, Boston, Massachusetts. Faculty of Medicine in The Galilee, Bar-Ilan University, Safed, Israel.
29
Section of Geriatrics, Boston University School of Medicine and Boston Medical Center, Massachusetts.
30
California Pacific Medical Center Research Institute, San Francisco. Department of Epidemiology and Biostatistics, University of California, San Francisco.
31
Department of Epidemiology, University of Pittsburgh, Pennsylvania. *These authors contributed equally to this work.
32
Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands. Netherlands Consortium for Healthy Ageing, Leiden University Medical Center, The Netherlands. *These authors contributed equally to this work.
33
NHLBI's and Boston Univesity's Framingham Heart Study, Massachusetts. Department of Medicine, Section of General Internal Medicine, Boston University School of Medicine, Massachusetts. *These authors contributed equally to this work. murabito@bu.edu.

Abstract

BACKGROUND:

The genetic contribution to longevity in humans has been estimated to range from 15% to 25%. Only two genes, APOE and FOXO3, have shown association with longevity in multiple independent studies.

METHODS:

We conducted a meta-analysis of genome-wide association studies including 6,036 longevity cases, age ≥90 years, and 3,757 controls that died between ages 55 and 80 years. We additionally attempted to replicate earlier identified single nucleotide polymorphism (SNP) associations with longevity.

RESULTS:

In our meta-analysis, we found suggestive evidence for the association of SNPs near CADM2 (odds ratio [OR] = 0.81; p value = 9.66 × 10(-7)) and GRIK2 (odds ratio = 1.24; p value = 5.09 × 10(-8)) with longevity. When attempting to replicate findings earlier identified in genome-wide association studies, only the APOE locus consistently replicated. In an additional look-up of the candidate gene FOXO3, we found that an earlier identified variant shows a highly significant association with longevity when including published data with our meta-analysis (odds ratio = 1.17; p value = 1.85×10(-10)).

CONCLUSIONS:

We did not identify new genome-wide significant associations with longevity and did not replicate earlier findings except for APOE and FOXO3. Our inability to find new associations with survival to ages ≥90 years because longevity represents multiple complex traits with heterogeneous genetic underpinnings, or alternatively, that longevity may be regulated by rare variants that are not captured by standard genome-wide genotyping and imputation of common variants.

KEYWORDS:

APOE.; FOXO3; GWAS; Longevity

PMID:
25199915
PMCID:
PMC4296168
DOI:
10.1093/gerona/glu166
[Indexed for MEDLINE]
Free PMC Article

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