• Open Access

Genome-wide association study identifies a single major locus contributing to survival into old age; the APOE locus revisited

Authors

  • Joris Deelen,

    1. Section of Molecular Epidemiology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands
    2. Netherlands Consortium for Healthy Ageing, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands
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    • These authors contributed equally to this work.

  • Marian Beekman,

    1. Section of Molecular Epidemiology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands
    2. Netherlands Consortium for Healthy Ageing, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands
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    • These authors contributed equally to this work.

  • Hae-Won Uh,

    1. Section of Medical Statistics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands
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  • Quinta Helmer,

    1. Section of Medical Statistics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands
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  • Maris Kuningas,

    1. Department of Epidemiology, Erasmus Medical Center, PO Box 2040, 3015 CE Rotterdam, The Netherlands
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  • Lene Christiansen,

    1. Department of Epidemiology, University of Southern Denmark, J.B. Winsløws Vej 9, DK-5000 Odense C, Denmark
    2. The Danish Aging Research Center, Institute of Public Health-Epidemiology, J.B. Winsløws Vej 9 B, st. tv, DK-5000 Odense C, Denmark
    3. Department of Clinical Genetics and Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, DK-5000 Odense C, Denmark
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  • Dennis Kremer,

    1. Section of Molecular Epidemiology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands
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  • Ruud van der Breggen,

    1. Section of Molecular Epidemiology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands
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  • H. Eka D. Suchiman,

    1. Section of Molecular Epidemiology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands
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  • Nico Lakenberg,

    1. Section of Molecular Epidemiology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands
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  • Erik B. van den Akker,

    1. Section of Molecular Epidemiology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands
    2. Department of Mediamatics, Delft Bioinformatics Lab, Delft University of Technology, PO Box 5031, 2600 GA Delft, The Netherlands
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  • Willemijn M. Passtoors,

    1. Section of Molecular Epidemiology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands
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  • Henning Tiemeier,

    1. Department of Epidemiology, Erasmus Medical Center, PO Box 2040, 3015 CE Rotterdam, The Netherlands
    2. Department of Child and Adolescent Psychiatry, Erasmus Medical Center and Sophia Children’s Hospital, PO Box 2040, 3015 CE Rotterdam, The Netherlands
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  • Diana van Heemst,

    1. Department of Gerontology and Geriatrics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands
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  • Anton J. de Craen,

    1. Department of Gerontology and Geriatrics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands
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  • Fernando Rivadeneira,

    1. Department of Epidemiology, Erasmus Medical Center, PO Box 2040, 3015 CE Rotterdam, The Netherlands
    2. Department of Internal Medicine, Erasmus Medical Center, PO Box 2040, 3015 CE Rotterdam, The Netherlands
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  • Eco J de Geus,

    1. Department of Biological Psychology, VU University Amsterdam, Van der Boechorststraat 1, 1081 BT Amsterdam, The Netherlands
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  • Markus Perola,

    1. National Institute for Health and Welfare, PO Box 30, 00271 Helsinki, Finland
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  • Frans J. van der Ouderaa,

    1. Netherlands Consortium for Healthy Ageing, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands
    2. Department of Gerontology and Geriatrics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands
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  • David A. Gunn,

    1. Unilever Discover, Colworth Science Park, Sharnbrook, Bedfordshire MK44 1LQ, UK
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  • Dorret I. Boomsma,

    1. Department of Biological Psychology, VU University Amsterdam, Van der Boechorststraat 1, 1081 BT Amsterdam, The Netherlands
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  • André G. Uitterlinden,

    1. Netherlands Consortium for Healthy Ageing, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands
    2. Department of Epidemiology, Erasmus Medical Center, PO Box 2040, 3015 CE Rotterdam, The Netherlands
    3. Department of Internal Medicine, Erasmus Medical Center, PO Box 2040, 3015 CE Rotterdam, The Netherlands
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  • Kaare Christensen,

    1. The Danish Aging Research Center, Institute of Public Health-Epidemiology, J.B. Winsløws Vej 9 B, st. tv, DK-5000 Odense C, Denmark
    2. Department of Clinical Genetics and Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, DK-5000 Odense C, Denmark
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  • Cornelia M. van Duijn,

    1. Netherlands Consortium for Healthy Ageing, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands
    2. Department of Epidemiology, Erasmus Medical Center, PO Box 2040, 3015 CE Rotterdam, The Netherlands
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  • Bastiaan T. Heijmans,

    1. Section of Molecular Epidemiology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands
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  • Jeanine J. Houwing-Duistermaat,

    1. Section of Medical Statistics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands
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  • Rudi G. J. Westendorp,

    1. Netherlands Consortium for Healthy Ageing, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands
    2. Department of Gerontology and Geriatrics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands
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  • P. Eline Slagboom

    1. Section of Molecular Epidemiology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands
    2. Netherlands Consortium for Healthy Ageing, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands
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Joris Deelen, Leiden University Medical Center, Section of Molecular Epidemiology, Zone S5-P, PO Box 9600, 2300 RC Leiden, The Netherlands. Tel.:+31 71 526 9729; fax: +31 71 526 8280; e-mail: j.deelen@lumc.nl

Summary

By studying the loci that contribute to human longevity, we aim to identify mechanisms that contribute to healthy aging. To identify such loci, we performed a genome-wide association study (GWAS) comparing 403 unrelated nonagenarians from long-living families included in the Leiden Longevity Study (LLS) and 1670 younger population controls. The strongest candidate SNPs from this GWAS have been analyzed in a meta-analysis of nonagenarian cases from the Rotterdam Study, Leiden 85-plus study, and Danish 1905 cohort. Only one of the 62 prioritized SNPs from the GWAS analysis (P < 1 × 10−4) showed genome-wide significance with survival into old age in the meta-analysis of 4149 nonagenarian cases and 7582 younger controls [OR = 0.71 (95% CI 0.65–0.77), P = 3.39 × 10−17]. This SNP, rs2075650, is located in TOMM40 at chromosome 19q13.32 close to the apolipoprotein E (APOE) gene. Although there was only moderate linkage disequilibrium between rs2075650 and the ApoE ε4 defining SNP rs429358, we could not find an APOE-independent effect of rs2075650 on longevity, either in cross-sectional or in longitudinal analyses. As expected, rs429358 associated with metabolic phenotypes in the offspring of the nonagenarian cases from the LLS and their partners. In addition, we observed a novel association between this locus and serum levels of IGF-1 in women (P = 0.005). In conclusion, the major locus determining familial longevity up to high age as detected by GWAS was marked by rs2075650, which tags the deleterious effects of the ApoE ε4 allele. No other major longevity locus was found.

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