Genomics of 1 million parent lifespans implicates novel pathways and common diseases and distinguishes survival chances
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...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2019-01-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/39856 |
| _version_ | 1811253034528800768 |
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| author | Paul RHJ Timmers Ninon Mounier Kristi Lall Krista Fischer Zheng Ning Xiao Feng Andrew D Bretherick David W Clark eQTLGen Consortium Xia Shen Tõnu Esko Zoltán Kutalik James F Wilson Peter K Joshi |
| author_facet | Paul RHJ Timmers Ninon Mounier Kristi Lall Krista Fischer Zheng Ning Xiao Feng Andrew D Bretherick David W Clark eQTLGen Consortium Xia Shen Tõnu Esko Zoltán Kutalik James F Wilson Peter K Joshi |
| author_sort | Paul RHJ Timmers |
| collection | DOAJ |
| description | 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). |
| first_indexed | 2024-04-12T16:44:41Z |
| format | Article |
| id | doaj.art-e04fb6e4bc9e4bb982a2a7b59c749bb5 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T16:44:41Z |
| publishDate | 2019-01-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-e04fb6e4bc9e4bb982a2a7b59c749bb52022-12-22T03:24:39ZengeLife Sciences Publications LtdeLife2050-084X2019-01-01810.7554/eLife.39856Genomics of 1 million parent lifespans implicates novel pathways and common diseases and distinguishes survival chancesPaul RHJ Timmers0https://orcid.org/0000-0002-5197-1267Ninon Mounier1Kristi Lall2Krista Fischer3Zheng Ning4Xiao Feng5Andrew D Bretherick6David W Clark7eQTLGen ConsortiumXia Shen8https://orcid.org/0000-0003-4390-1979Tõnu Esko9https://orcid.org/0000-0003-1982-6569Zoltán Kutalik10James F Wilson11https://orcid.org/0000-0001-5751-9178Peter K Joshi12https://orcid.org/0000-0002-6361-5059Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, United KingdomInstitute of Social and Preventive Medicine, University Hospital of Lausanne, Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, SwitzerlandEstonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia; Institute of Mathematics and Statistics, University of Tartu, Tartu, EstoniaEstonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia; Institute of Mathematics and Statistics, University of Tartu, Tartu, EstoniaDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, SwedenState Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, ChinaMRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United KingdomCentre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, United KingdomCentre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, United Kingdom; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, ChinaEstonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia; Broad Institute of Harvard and MIT, Cambridge, United StatesInstitute of Social and Preventive Medicine, University Hospital of Lausanne, Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, SwitzerlandCentre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, United Kingdom; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United KingdomCentre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, United Kingdom; Institute of Social and Preventive Medicine, University Hospital of Lausanne, Lausanne, SwitzerlandWe 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).https://elifesciences.org/articles/39856genomicslongevitylifespancomplex trait |
| spellingShingle | Paul RHJ Timmers Ninon Mounier Kristi Lall Krista Fischer Zheng Ning Xiao Feng Andrew D Bretherick David W Clark eQTLGen Consortium Xia Shen Tõnu Esko Zoltán Kutalik James F Wilson Peter K Joshi Genomics of 1 million parent lifespans implicates novel pathways and common diseases and distinguishes survival chances eLife genomics longevity lifespan complex trait |
| title | Genomics of 1 million parent lifespans implicates novel pathways and common diseases and distinguishes survival chances |
| title_full | Genomics of 1 million parent lifespans implicates novel pathways and common diseases and distinguishes survival chances |
| title_fullStr | Genomics of 1 million parent lifespans implicates novel pathways and common diseases and distinguishes survival chances |
| title_full_unstemmed | Genomics of 1 million parent lifespans implicates novel pathways and common diseases and distinguishes survival chances |
| title_short | Genomics of 1 million parent lifespans implicates novel pathways and common diseases and distinguishes survival chances |
| title_sort | genomics of 1 million parent lifespans implicates novel pathways and common diseases and distinguishes survival chances |
| topic | genomics longevity lifespan complex trait |
| url | https://elifesciences.org/articles/39856 |
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