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Elife. 2019 Jan 15;8. pii: e39856. doi: 10.7554/eLife.39856.

Genomics of 1 million parent lifespans implicates novel pathways and common diseases and distinguishes survival chances.

Timmers PR1, Mounier N2,3, Lall K4,5, Fischer K4,5, Ning Z6, Feng X7, Bretherick AD8, Clark DW1; eQTLGen Consortium, Agbessi M9, Ahsan H10, Alves I9, Andiappan A11, Awadalla P9, Battle A12, Bonder MJ13, Boomsma D14, Christiansen M15, Claringbould A13, Deelen P13, van Dongen J14, Esko T16, Favé M9, Franke L13, Frayling T17, Gharib SA18, Gibson G19, Hemani G20, Jansen R14, Kalnapenkis A16, Kasela S16, Kettunen J21, Kim Y12, Kirsten H22, Kovacs P23, Krohn K24, Kronberg-Guzman J16, Kukushkina V16, Kutalik Z25, Kähönen M26, Lee B11, Lehtimäki T27, Loeffler M28, Marigorta U19, Metspalu A16, van Meurs J29, Milani L16, Müller-Nurasyid M30, Nauck M31, Nivard M14, Penninx B14, Perola M32, Pervjakova N16, Pierce B10, Powell J33, Prokisch H34, Psaty BM35, Raitakari O36, Ring S37, Ripatti S21, Rotzschke O11, Ruëger S25, Saha A12, Scholz M38, Schramm K30, Seppälä I27, Stumvoll M39, Sullivan P6, Teumer A40, Thiery J41, Tong L10, Tönjes A39, Verlouw J29, Visscher PM33, Võsa U42, Völker U43, Yaghootkar H17, Yang J33, Zeng B19, Zhang F33, Agbessi M9, Ahsan H10, Alves I9, Andiappan A11, Awadalla P9, Battle A12, Bonder MJ13, Boomsma D14, Christiansen M15, Claringbould A13, Deelen P13, van Dongen J14, Esko T16, Favé M9, Franke L13, Frayling T17, Gharib SA18, Gibson G19, Hemani G20, Jansen R14, Kalnapenkis A16, Kasela S16, Kettunen J21, Kim Y12, Kirsten H22, Kovacs P23, Krohn K24, Kronberg-Guzman J16, Kukushkina V16, Kutalik Z25, Kähönen M26, Lee B11, Lehtimäki T27, Loeffler M28, Marigorta U19, Metspalu A16, van Meurs J29, Milani L16, Müller-Nurasyid M30, Nauck M31, Nivard M14, Penninx B14, Perola M32, Pervjakova N16, Pierce B10, Powell J33, Prokisch H34, Psaty BM35, Raitakari O36, Ring S37, Ripatti S21, Rotzschke O11, Ruëger S25, Saha A12, Scholz M38, Schramm K30, Seppälä I27, Stumvoll M39, Sullivan P6, Teumer A40, Thiery J41, Tong L10, Tönjes A39, Verlouw J29, Visscher PM33, Võsa U42, Völker U43, Yaghootkar H17, Yang J33, Zeng B19, Zhang F33, Shen X1,6,7, Esko T4,44, Kutalik Z2,3, Wilson JF1,8, Joshi PK1,2.

Author information

1
Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, United Kingdom.
2
Institute of Social and Preventive Medicine, University Hospital of Lausanne, Lausanne, Switzerland.
3
Swiss Institute of Bioinformatics, Lausanne, Switzerland.
4
Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia.
5
Institute of Mathematics and Statistics, University of Tartu, Tartu, Estonia.
6
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
7
State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
8
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
9
Ontario Institute for Cancer Research, Toronto, Canada.
10
Department of Public Health Sciences, University of Chicago, Chicago, United States.
11
Singapore Immunology Network, Agency for Science, Technology and Research, Singapore, Singapore.
12
Department of Computer Science, Johns Hopkins University, Baltimore, United States.
13
Department of Genetics University, Medical Centre Groningen, Groningen, The Netherlands.
14
Vrije Universiteit, Amsterdam, The Netherlands.
15
Cardiovascular Health Research Unit, University of Washington, Seattle, United States.
16
Estonian Genome Center, University of Tartu, Tartu, Estonia.
17
Exeter Medical School, University of Exeter, Exeter, United Kingdom.
18
Department of Medicine, University of Washington, Seattle, United States.
19
School of Biological Sciences, Georgia Institute of Technology, Atlanta, United States.
20
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.
21
University of Helsinki, Helsinki, Finland.
22
Institut für Medizinische Informatik, Statistik und Epidemiologie, LIFE - Leipzig ResearchCenter for Civilization Diseases, Universität Leipzig, Leipzig, Germany.
23
IFB Adiposity Diseases, Universität Leipzig, Leipzig, Germany.
24
Interdisciplinary Center for Clinical Research, Faculty of Medicine, Universität Leipzig, Leipzig, Germany.
25
Lausanne University Hospital, Lausanne, Switzerland.
26
Department of Clinical Physiology and Faculty of Medicine and Life Sciences, Tampere University Hospital and University of Tampere, Tampere, Finland.
27
Department of Clinical Chemistry, Fimlab Laboratories and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.
28
Institut für Medizinische Informatik, Statistik und Epidemiologie, LIFE - Leipzig Research Center for Civilization Diseases, Universität Leipzig, Leipzig, Germany.
29
Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands.
30
Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
31
Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
32
National Institute for Health and Welfare, University of Helsinki, Helsinki, Finland.
33
Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia.
34
Institute of Human Genetics, Helmholtz Zentrum München, München, Germany.
35
Departments of Epidemiology, Medicine, and Health Services, Cardiovascular Health Research Unit, University of Washington, Seattle, United States.
36
Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital and University of Turku, Turku, Finland.
37
School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
38
Institut für Medizinische InformatiK, Statistik und Epidemiologie, LIFE - Leipzig Research Center for Civilization Diseases, Universität Leipzig, Leipzig, Germany.
39
Department of Medicine, Universität Leipzig, Leipzig, Germany.
40
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
41
Institute for Laboratory Medicine, LIFE - Leipzig Research Center for Civilization Diseases, Universität Leipzig, Leipzig, Germany.
42
Department of Genetics, University Medical Centre Groningen, Groningen, The Netherlands.
43
Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
44
Broad Institute of Harvard and MIT, Cambridge, United States.

Abstract

We use a genome-wide association of 1 million parental lifespans of genotyped subjects and data on mortality risk factors to validate previously unreplicated findings near CDKN2B-AS1, ATXN2/BRAP, FURIN/FES, ZW10, PSORS1C3, and 13q21.31, and identify and replicate novel findings near ABO, ZC3HC1, and IGF2R. We also validate previous findings near 5q33.3/EBF1 and FOXO3, whilst finding contradictory evidence at other loci. Gene set and cell-specific analyses show that expression in foetal brain cells and adult dorsolateral prefrontal cortex is enriched for lifespan variation, as are gene pathways involving lipid proteins and homeostasis, vesicle-mediated transport, and synaptic function. Individual genetic variants that increase dementia, cardiovascular disease, and lung cancer - but not other cancers - explain the most variance. Resulting polygenic scores show a mean lifespan difference of around five years of life across the deciles.

Editorial note:

This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

KEYWORDS:

complex trait; genetics; genomics; human; lifespan; longevity

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