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Human Longevity is Influenced by Many Genetic Variants: Evidence from 75,000 UK Biobank Participants

Luke C. Pilling, Janice L. Atkins, Kirsty Bowman, Samuel E. Jones, Jessica Tyrrell, Robin N. Beaumont, Katherine S. Ruth, Marcus A. Tuke, Hanieh Yaghootkar, Andrew R. Wood, Rachel M. Freathy, Anna Murray, Michael N. Weedon, Luting Xue, Kathryn Lunetta, Joanne M. Murabito, Lorna W. Harries, Jean-Marie Robine, Carol Brayne, George A. Kuchel, Luigi Ferrucci, Timothy M. Frayling, David Melzer
doi: https://doi.org/10.1101/038430
Luke C. Pilling
1Epidemiology and Public Health Group, University of Exeter Medical School, RILD Level 3, Royal Devon & Exeter Hospital, Barrack Road, Exeter, EX2 5DW, UK.
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Janice L. Atkins
1Epidemiology and Public Health Group, University of Exeter Medical School, RILD Level 3, Royal Devon & Exeter Hospital, Barrack Road, Exeter, EX2 5DW, UK.
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Kirsty Bowman
1Epidemiology and Public Health Group, University of Exeter Medical School, RILD Level 3, Royal Devon & Exeter Hospital, Barrack Road, Exeter, EX2 5DW, UK.
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Samuel E. Jones
2Genetics of Complex Traits, University of Exeter Medical School, RILD Level 3, Royal Devon & Exeter Hospital, Barrack Road, Exeter, EX2 5DW, UK.
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Jessica Tyrrell
2Genetics of Complex Traits, University of Exeter Medical School, RILD Level 3, Royal Devon & Exeter Hospital, Barrack Road, Exeter, EX2 5DW, UK.
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Robin N. Beaumont
2Genetics of Complex Traits, University of Exeter Medical School, RILD Level 3, Royal Devon & Exeter Hospital, Barrack Road, Exeter, EX2 5DW, UK.
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Katherine S. Ruth
2Genetics of Complex Traits, University of Exeter Medical School, RILD Level 3, Royal Devon & Exeter Hospital, Barrack Road, Exeter, EX2 5DW, UK.
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Marcus A. Tuke
2Genetics of Complex Traits, University of Exeter Medical School, RILD Level 3, Royal Devon & Exeter Hospital, Barrack Road, Exeter, EX2 5DW, UK.
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Hanieh Yaghootkar
2Genetics of Complex Traits, University of Exeter Medical School, RILD Level 3, Royal Devon & Exeter Hospital, Barrack Road, Exeter, EX2 5DW, UK.
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Andrew R. Wood
2Genetics of Complex Traits, University of Exeter Medical School, RILD Level 3, Royal Devon & Exeter Hospital, Barrack Road, Exeter, EX2 5DW, UK.
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Rachel M. Freathy
2Genetics of Complex Traits, University of Exeter Medical School, RILD Level 3, Royal Devon & Exeter Hospital, Barrack Road, Exeter, EX2 5DW, UK.
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Anna Murray
2Genetics of Complex Traits, University of Exeter Medical School, RILD Level 3, Royal Devon & Exeter Hospital, Barrack Road, Exeter, EX2 5DW, UK.
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Michael N. Weedon
2Genetics of Complex Traits, University of Exeter Medical School, RILD Level 3, Royal Devon & Exeter Hospital, Barrack Road, Exeter, EX2 5DW, UK.
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Luting Xue
3School of Public Health, Department of Biostatistics, Boston University, Boston, MA, USA
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Kathryn Lunetta
3School of Public Health, Department of Biostatistics, Boston University, Boston, MA, USA
4The Framingham Heart Study, 73 Mt. Wayte Ave. Suite #2, Framingham, MA 01702, USA
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Joanne M. Murabito
4The Framingham Heart Study, 73 Mt. Wayte Ave. Suite #2, Framingham, MA 01702, USA
5Section of General Internal Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA
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Lorna W. Harries
6Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, RILD Level 3, Royal Devon & Exeter Hospital, Barrack Road, Exeter, UK
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Jean-Marie Robine
7Institut National de la Sante et de la Recherché Medicale, Demographie et Santé du Departement de Biostatistiques, Montpellier, France
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Carol Brayne
8Cambridge Institute of Public Health, School of Clinical Medicine, University of Cambridge, Cambridge, UK
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George A. Kuchel
9Center on Aging, University of Connecticut, 263 Farmington Avenue, Farmington, CT 060305215, USA.
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Luigi Ferrucci
10National Institute on Aging, Baltimore, MD, United States.
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Timothy M. Frayling
2Genetics of Complex Traits, University of Exeter Medical School, RILD Level 3, Royal Devon & Exeter Hospital, Barrack Road, Exeter, EX2 5DW, UK.
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David Melzer
1Epidemiology and Public Health Group, University of Exeter Medical School, RILD Level 3, Royal Devon & Exeter Hospital, Barrack Road, Exeter, EX2 5DW, UK.
3School of Public Health, Department of Biostatistics, Boston University, Boston, MA, USA
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Abstract

Variation in human lifespan is 20 to 30% heritable but few genetic variants have been identified. We undertook a Genome Wide Association Study (GWAS) using age at death of parents of middle-aged UK Biobank participants of European decent (n=75,244 with father’s and/or mother’s data). Genetic risk scores for 19 phenotypes (n=777 proven variants) were also tested.

Genotyped variants (n=845,997) explained 10.2% (SD=1.3%) of combined parental longevity. In GWAS, a locus in the nicotine receptor CHRNA3 – previously associated with increased smoking and lung cancer - was associated with paternal age at death, with each protective allele (rs1051730[G]) being associated with 0.03 years later age at father’s death (p=3x10-8). Offspring of longer lived parents had more protective alleles (lower genetic risk scores) for coronary artery disease, systolic blood pressure, body mass index, cholesterol and triglyceride levels, type-1 diabetes, inflammatory bowel disease and Alzheimer’s disease. In candidate gene analyses, variants in the TOMM40/APOE locus were associated with longevity (including rs429358, p=3x10-5), but FOXO variants were not associated.

These results support a multiple protective factors model for achieving longer lifespans in humans, with a prominent role for cardiovascular-related pathways. Several of these genetically influenced risks, including blood pressure and tobacco exposure, are potentially modifiable.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted February 01, 2016.
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Human Longevity is Influenced by Many Genetic Variants: Evidence from 75,000 UK Biobank Participants
Luke C. Pilling, Janice L. Atkins, Kirsty Bowman, Samuel E. Jones, Jessica Tyrrell, Robin N. Beaumont, Katherine S. Ruth, Marcus A. Tuke, Hanieh Yaghootkar, Andrew R. Wood, Rachel M. Freathy, Anna Murray, Michael N. Weedon, Luting Xue, Kathryn Lunetta, Joanne M. Murabito, Lorna W. Harries, Jean-Marie Robine, Carol Brayne, George A. Kuchel, Luigi Ferrucci, Timothy M. Frayling, David Melzer
bioRxiv 038430; doi: https://doi.org/10.1101/038430
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Human Longevity is Influenced by Many Genetic Variants: Evidence from 75,000 UK Biobank Participants
Luke C. Pilling, Janice L. Atkins, Kirsty Bowman, Samuel E. Jones, Jessica Tyrrell, Robin N. Beaumont, Katherine S. Ruth, Marcus A. Tuke, Hanieh Yaghootkar, Andrew R. Wood, Rachel M. Freathy, Anna Murray, Michael N. Weedon, Luting Xue, Kathryn Lunetta, Joanne M. Murabito, Lorna W. Harries, Jean-Marie Robine, Carol Brayne, George A. Kuchel, Luigi Ferrucci, Timothy M. Frayling, David Melzer
bioRxiv 038430; doi: https://doi.org/10.1101/038430

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