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

Paul RHJ Timmers; D. I. Boomsma; J. van Dongen; M. G. Nivard; B. Penninx; Peter K. Joshi; eQTLGen Consortium

doi:10.7554/eLife.39856

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

Paul RHJ Timmers, D. I. Boomsma, J. van Dongen, M. G. Nivard, B. Penninx, Peter K. Joshi, eQTLGen Consortium

Research output: Contribution to Journal › Article › Academic › peer-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 language	English
Article number	e39856
Pages (from-to)	1-40
Number of pages	40
Journal	eLife
Volume	8
DOIs	https://doi.org/10.7554/eLife.39856
Publication status	Published - 15 Jan 2019

Funding

We thank the UK Biobank Resource, approved under application 8304; we acknowledge funding from the UK Medical Research Council Human Genetics Unit, Wellcome Trust PhD Training Fellowship for Clinicians - the Edinburgh Clinical Academic Track (ECAT) programme (204979/Z/16/Z), the Medical Research Council Doctoral Training Programme in Precision Medicine (MR/N013166/1) and the AXA research fund. We thank Tom Haller of the University of Tartu, for tailoring RegScan so we could use it with compressed files (Haller et al., 2015). We would also like to thank the researchers, funders and participants of the LifeGen consortium (Joshi et al., 2017).

Funders	Funder number
Medical Research Council Human Genetics Unit
National Cancer Institute	K04CA001665
Wellcome Trust	204979/Z/16/Z
Medical Research Council	MR/N013166/1
AXA Research Fund

Keywords

complex trait
genetics
genomics
human
lifespan
longevity

Cohort Studies

Netherlands Twin Register (NTR)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.7554/eLife.39856

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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 Boomsma, {D. I.} 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 Nivard, {M. G.} 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}",

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doi = "10.7554/eLife.39856",

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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. I.

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. G.

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

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

M3 - Article

C2 - 30642433

SN - 2050-084X

VL - 8

SP - 1

EP - 40

JO - eLife

JF - eLife

M1 - e39856

ER -

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

Abstract

Funding

Keywords

Cohort Studies

UN SDGs

Access to Document

Persistent URL (handle)

Other files and links

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Cite this