Meta-Analysis

.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

Peter K Joshi¹, Nicola Pirastu², Katherine A Kentistou^{2 3}, Krista Fischer⁴, Edith Hofer^{5 6}, Katharina E Schraut^{2 3}, David W Clark², Teresa Nutile⁷, Catriona L K Barnes², Paul R H J Timmers², Xia Shen^{2 8}, Ilaria Gandin^{9 10}, Aaron F McDaid^{11 12}, Thomas Folkmann Hansen^{13 14}, Scott D Gordon¹⁵, Franco Giulianini¹⁶, Thibaud S Boutin¹⁷, Abdel Abdellaoui¹⁸, Wei Zhao¹⁹, Carolina Medina-Gomez^{20 21}, Traci M Bartz²², Stella Trompet^{23 24}, Leslie A Lange²⁵, Laura Raffield²⁶, Ashley van der Spek²¹, Tessel E Galesloot²⁷, Petroula Proitsi²⁸, Lisa R Yanek²⁹, Lawrence F Bielak¹⁹, Antony Payton³⁰, Federico Murgia³¹, Maria Pina Concas³², Ginevra Biino³³, Salman M Tajuddin³⁴, Ilkka Seppälä³⁵, Najaf Amin²¹, Eric Boerwinkle³⁶, Anders D Børglum^{14 37 38}, Archie Campbell³⁹, Ellen W Demerath⁴⁰, Ilja Demuth^{41 42 43}, Jessica D Faul⁴⁴, Ian Ford⁴⁵, Alessandro Gialluisi⁴⁶, Martin Gögele³¹, MariaElisa Graff⁴⁷, Aroon Hingorani⁴⁸, Jouke-Jan Hottenga¹⁸, David M Hougaard^{14 49}, Mikko A Hurme⁵⁰, M Arfan Ikram²¹, Marja Jylhä⁵¹, Diana Kuh²⁸, Lannie Ligthart¹⁸, Christina M Lill⁵², Ulman Lindenberger^{53 54}, Thomas Lumley⁵⁵, Reedik Mägi⁴, Pedro Marques-Vidal⁵⁶, Sarah E Medland¹⁵, Lili Milani⁴, Reka Nagy¹⁷, William E R Ollier⁵⁷, Patricia A Peyser¹⁹, Peter P Pramstaller³¹, Paul M Ridker^{16 58}, Fernando Rivadeneira^{20 21}, Daniela Ruggiero⁷, Yasaman Saba⁵⁹, Reinhold Schmidt⁵, Helena Schmidt⁵⁹, P Eline Slagboom⁶⁰, Blair H Smith⁶¹, Jennifer A Smith^{19 44}, Nona Sotoodehnia⁶², Elisabeth Steinhagen-Thiessen⁴¹, Frank J A van Rooij²¹, André L Verbeek²⁷, Sita H Vermeulen²⁷, Peter Vollenweider⁵⁶, Yunpeng Wang^{14 63}, Thomas Werge^{13 14}, John B Whitfield¹⁵, Alan B Zonderman³⁴, Terho Lehtimäki³⁵, Michele K Evans³⁴, Mario Pirastu³², Christian Fuchsberger³¹, Lars Bertram^{64 65}, Neil Pendleton⁶⁶, Sharon L R Kardia¹⁹, Marina Ciullo^{7 46}, Diane M Becker²⁹, Andrew Wong²⁸, Bruce M Psaty^{67 68}, Cornelia M van Duijn²¹, James G Wilson⁶⁹, J Wouter Jukema²⁴, Lambertus Kiemeney²⁷, André G Uitterlinden^{20 21}, Nora Franceschini⁴⁷, Kari E North⁴⁷, David R Weir⁴⁴, Andres Metspalu⁴, Dorret I Boomsma¹⁸, Caroline Hayward¹⁷, Daniel Chasman^{16 58}, Nicholas G Martin¹⁵, Naveed Sattar⁷⁰, Harry Campbell², Tōnu Esko^{4 71}, Zoltán Kutalik^{11 12}, James F Wilson^{2 17}

Affiliations

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.

PMID:29030599
PMCID: PMC5715013
DOI: 10.1038/s41467-017-00934-5

Meta-Analysis

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

Peter K Joshi et al. Nat Commun.2017.

.2017 Oct 13;8(1):910.

doi: 10.1038/s41467-017-00934-5.

Authors

Affiliations

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.

PMID:29030599
PMCID: PMC5715013
DOI: 10.1038/s41467-017-00934-5

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.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing financial interests.

Figures

**Fig. 1**
Genome-wide associations with parental lifespan. Association analysis was carried out using imputed allelic dosages.a Manhattan plot for LifeGen European ancestry, with both parents combined;b Q−Q plot comparing the expected (under the null hypothesis) and actual (observed) –log₁₀p-values for results ina;c Manhattan plot of meta-analysis of LifeGen Europeans (both parents combined) with CHARGE-EU 90+ published summary statistics. The meta-analysis usedZ-scores and equal weights, as suggested by the near equality (9.5/9.4, LifeGen, CHARGE) ofZ-test statistics at rs4420638. The additional (just) GW significant SNP lies between the two chromosome 6 hits ina;d Manhattan plot for LifeGen African fathers only. In Manhattan plots, they-axis has been restricted to 15 to aid legibility

**Fig. 2**
Locus zoom plots for four genome-wide significant associations with lifespan. Results from the meta-analysis of subjects of European ancestry analysis, for both parents combined. The displayedp-value corresponds to that of a two-sided test of association between the SNP and parent lifespan under the Cox model.a The rs34831921 variant, at the HLA-DQA1/DRB1 locus,P = 4.18E-08.b The rs55730499 variant, at the LPA locus,P = 8.67E-11.c The rs8042849 variant, at the CHRNA3/5 locus,P = 3.75E-14.d The rs429358 variant, at the APOE locus,P = 1.44E-27

**Fig. 3**
Validation of associations reported elsewhere by lookup in LifeGen. A search of recent literature suggested the gene regions shown here were most likely to harbour associations with lifespan, beyond the four loci identified in Table 2, which are further explored in the Discussion. The most powerful LifeGen analysis (i.e., European ancestry, father and mother combined) was used for validation. The odds ratio (OR) for extreme long-livedness is presented for the reported life-shortening allele (i.e., the OR for long-livedness < 1) in the original study, but not necessarily in LifeGen. The LifeGen OR of being long-lived was estimated empirically on the assumption that the relationship between the LifeGen observed hazard ratio (HR) and the OR is stable across allelic effects, with APOE results from LifeGen and CHARGE-EU 90+ 6 being used to estimate the ratio of ln HR to ln OR (−4.7). These estimates will only fully align with the published ORs if the shape of the effect on lifespan is similar to APOE, as is true under the proportional hazards assumption, nonetheless the pattern is suggestive. Further details are shown in Supplementary Data 3

**Fig. 4**
Age-specific and sex-specific effects of the 4 GWS associations in LifeGen and the validated candidate loci. The four GWS and three suggestive replicated loci were analysed for age-specific and sex-specific effects on lifespan.a The variants at APOE and CHRNA3/5 exhibit sexually dimorphic effects on parental mortality, while all other variants exhibit more modest often non-significant sex-specific differences.b The effects of each gene on male and female lifespan were meta-analysed and studied in the cases that died aged between 40 and 75 or after 75. APOE exerts a much greater effect in the older age group, while most of the other genes exhibit the opposite effect. FOXO3 appears neutral, if not positive, in the earlier age group.c Effects on mortality were studied in both age groups for both sexes. APOE has the strongest effect on females aged 75+, CHRNA3/5 acts on males aged 40−75 and all other genes display more ambiguous trends

**Fig. 5**
Genetic correlations between trait clusters that associate with mortality. The upper panel shows whole genetic correlations, the lower panel, partial correlations. T2D, type 2 diabetes; BP, blood pressure; BC, breast cancer; CAD, coronary artery disease; Edu, educational attainment; RA, rheumatoid arthritis; AM, age at menarche; DL/WHR Dyslipidaemia/Waist-Hip ratio; BP, blood pressure

See this image and copyright information in PMC

References

1. Herskind AM, et al. The heritability of human longevity: a population-based study of 2872 Danish twin pairs born 1870-1900. Hum. Genet. 1996;97:319–323. doi: 10.1007/BF02185763. - DOI - PubMed
1. Deelen J, et al. Genome-wide association study identifies a single major locus contributing to survival into old age; the APOE locus revisited. Aging Cell. 2011;10:686–698. doi: 10.1111/j.1474-9726.2011.00705.x. - DOI - PMC - PubMed
1. Broer L, et al. GWAS of longevity in CHARGE consortium confirms APOE and FOXO3 candidacy. J. Gerontol. A Biol. Sci. Med. Sci. 2015;70:110–118. doi: 10.1093/gerona/glu166. - DOI - PMC - PubMed
1. Joshi PK, et al. Variants near CHRNA3/5 and APOE have age- and sex-related effects on human lifespan. Nat. Commun. 2016;7:11174. doi: 10.1038/ncomms11174. - DOI - PMC - PubMed
1. Pilling LC, et al. Human longevity is influenced by many genetic variants: evidence from 75,000 UK Biobank participants. Aging. 2016;8:547–560. doi: 10.18632/aging.100930. - DOI - PMC - PubMed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

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References

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LinkOut - more resources

Full Text Sources

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