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

eQTLGen Consortium

Research output: Contribution to JournalArticleAcademicpeer-review

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).

Original languageEnglish
Article numbere39856
Pages (from-to)1-40
Number of pages40
JournaleLife
Volume8
DOIs
Publication statusPublished - 15 Jan 2019

Fingerprint

Genomics
Genes
Furin
Transport Vesicles
Peer Review
Synaptic Vesicles
Prefrontal Cortex
Dementia
Lung Neoplasms
Homeostasis
Cardiovascular Diseases
Genome
Lipids
Mortality
Brain
Neoplasms
Proteins

Keywords

  • complex trait
  • genetics
  • genomics
  • human
  • lifespan
  • longevity

Cite this

@article{e6f2b298466646989d52d42fd47a822d,
title = "Genomics of 1 million parent lifespans implicates novel pathways and common diseases and distinguishes survival chances",
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",
author = "Timmers, {Paul Rhj} and Ninon Mounier and Kristi Lall and Krista Fischer and Zheng Ning and Xiao Feng and Bretherick, {Andrew D.} and Clark, {David W.} and M. Agbessi and H. Ahsan and I. Alves and A. Andiappan and P. Awadalla and A. Battle and Bonder, {M. J.} and D. Boomsma and M. Christiansen and A. Claringbould and P. Deelen and {van Dongen}, J. and T. Esko and M. Fav{\'e} and L. Franke and T. Frayling and Gharib, {S. A.} and G. Gibson and G. Hemani and R. Jansen and A. Kalnapenkis and S. Kasela and J. Kettunen and Y. Kim and H. Kirsten and P. Kovacs and K. Krohn and J. Kronberg-Guzman and V. Kukushkina and Z. Kutalik and M. K{\"a}h{\"o}nen and B. Lee and T. Lehtim{\"a}ki and M. Loeffler and U. Marigorta and A. Metspalu and {van Meurs}, J. and L. Milani and M. M{\"u}ller-Nurasyid and M. Nauck and M. Nivard and B. Penninx and M. Perola and N. Pervjakova and B. Pierce and J. Powell and H. Prokisch and Psaty, {B. M.} and O. Raitakari and S. Ring and S. Ripatti and O. Rotzschke and S. Ru{\"e}ger and A. Saha and M. Scholz and K. Schramm and I. Sepp{\"a}l{\"a} and M. Stumvoll and P. Sullivan and A. Teumer and J. Thiery and L. Tong and A. T{\"o}njes and J. Verlouw and Visscher, {P. M.} and U. V{\~o}sa and U. V{\"o}lker and H. Yaghootkar and J. Yang and B. Zeng and P. Sullivan and Xia Shen and T{\~o}nu Esko and Zolt{\'a}n Kutalik and Wilson, {James F.} and Joshi, {Peter K.} and {eQTLGen Consortium}",
note = "{\circledC} 2019, Timmers et al.",
year = "2019",
month = "1",
day = "15",
doi = "10.7554/eLife.39856",
language = "English",
volume = "8",
pages = "1--40",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",

}

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

In: eLife, Vol. 8, e39856, 15.01.2019, p. 1-40.

Research output: Contribution to JournalArticleAcademicpeer-review

TY - JOUR

T1 - Genomics of 1 million parent lifespans implicates novel pathways and common diseases and distinguishes survival chances

AU - Timmers, Paul Rhj

AU - Mounier, Ninon

AU - Lall, Kristi

AU - Fischer, Krista

AU - Ning, Zheng

AU - Feng, Xiao

AU - Bretherick, Andrew D.

AU - Clark, David W.

AU - Agbessi, M.

AU - Ahsan, H.

AU - Alves, I.

AU - Andiappan, A.

AU - Awadalla, P.

AU - Battle, A.

AU - Bonder, M. J.

AU - Boomsma, D.

AU - Christiansen, M.

AU - Claringbould, A.

AU - Deelen, P.

AU - van Dongen, J.

AU - Esko, T.

AU - Favé, M.

AU - Franke, L.

AU - Frayling, T.

AU - Gharib, S. A.

AU - Gibson, G.

AU - Hemani, G.

AU - Jansen, R.

AU - Kalnapenkis, A.

AU - Kasela, S.

AU - Kettunen, J.

AU - Kim, Y.

AU - Kirsten, H.

AU - Kovacs, P.

AU - Krohn, K.

AU - Kronberg-Guzman, J.

AU - Kukushkina, V.

AU - Kutalik, Z.

AU - Kähönen, M.

AU - Lee, B.

AU - Lehtimäki, T.

AU - Loeffler, M.

AU - Marigorta, U.

AU - Metspalu, A.

AU - van Meurs, J.

AU - Milani, L.

AU - Müller-Nurasyid, M.

AU - Nauck, M.

AU - Nivard, M.

AU - Penninx, B.

AU - Perola, M.

AU - Pervjakova, N.

AU - Pierce, B.

AU - Powell, J.

AU - Prokisch, H.

AU - Psaty, B. M.

AU - Raitakari, O.

AU - Ring, S.

AU - Ripatti, S.

AU - Rotzschke, O.

AU - Ruëger, S.

AU - Saha, A.

AU - Scholz, M.

AU - Schramm, K.

AU - Seppälä, I.

AU - Stumvoll, M.

AU - Sullivan, P.

AU - Teumer, A.

AU - Thiery, J.

AU - Tong, L.

AU - Tönjes, A.

AU - Verlouw, J.

AU - Visscher, P. M.

AU - Võsa, U.

AU - Völker, U.

AU - Yaghootkar, H.

AU - Yang, J.

AU - Zeng, B.

AU - Sullivan, P.

AU - Shen, Xia

AU - Esko, Tõnu

AU - Kutalik, Zoltán

AU - Wilson, James F.

AU - Joshi, Peter K.

AU - eQTLGen Consortium

N1 - © 2019, Timmers et al.

PY - 2019/1/15

Y1 - 2019/1/15

N2 - 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).

AB - 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).

KW - complex trait

KW - genetics

KW - genomics

KW - human

KW - lifespan

KW - longevity

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U2 - 10.7554/eLife.39856

DO - 10.7554/eLife.39856

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VL - 8

SP - 1

EP - 40

JO - eLife

JF - eLife

SN - 2050-084X

M1 - e39856

ER -