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Human genetic analyses of organelles highlight the nucleus in age-related trait heritability
Most age-related human diseases are accompanied by a decline in cellular organelle integrity, including impaired lysosomal proteostasis and defective mitochondrial oxidative phosphorylation. An open question, however, is the degree to which inherited variation in or near genes encoding each organell...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8476128/ https://www.ncbi.nlm.nih.gov/pubmed/34467851 http://dx.doi.org/10.7554/eLife.68610 |
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author | Gupta, Rahul Karczewski, Konrad J Howrigan, Daniel Neale, Benjamin M Mootha, Vamsi K |
author_facet | Gupta, Rahul Karczewski, Konrad J Howrigan, Daniel Neale, Benjamin M Mootha, Vamsi K |
author_sort | Gupta, Rahul |
collection | PubMed |
description | Most age-related human diseases are accompanied by a decline in cellular organelle integrity, including impaired lysosomal proteostasis and defective mitochondrial oxidative phosphorylation. An open question, however, is the degree to which inherited variation in or near genes encoding each organelle contributes to age-related disease pathogenesis. Here, we evaluate if genetic loci encoding organelle proteomes confer greater-than-expected age-related disease risk. As mitochondrial dysfunction is a ‘hallmark’ of aging, we begin by assessing nuclear and mitochondrial DNA loci near genes encoding the mitochondrial proteome and surprisingly observe a lack of enrichment across 24 age-related traits. Within nine other organelles, we find no enrichment with one exception: the nucleus, where enrichment emanates from nuclear transcription factors. In agreement, we find that genes encoding several organelles tend to be ‘haplosufficient,’ while we observe strong purifying selection against heterozygous protein-truncating variants impacting the nucleus. Our work identifies common variation near transcription factors as having outsize influence on age-related trait risk, motivating future efforts to determine if and how this inherited variation then contributes to observed age-related organelle deterioration. |
format | Online Article Text |
id | pubmed-8476128 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-84761282021-09-29 Human genetic analyses of organelles highlight the nucleus in age-related trait heritability Gupta, Rahul Karczewski, Konrad J Howrigan, Daniel Neale, Benjamin M Mootha, Vamsi K eLife Genetics and Genomics Most age-related human diseases are accompanied by a decline in cellular organelle integrity, including impaired lysosomal proteostasis and defective mitochondrial oxidative phosphorylation. An open question, however, is the degree to which inherited variation in or near genes encoding each organelle contributes to age-related disease pathogenesis. Here, we evaluate if genetic loci encoding organelle proteomes confer greater-than-expected age-related disease risk. As mitochondrial dysfunction is a ‘hallmark’ of aging, we begin by assessing nuclear and mitochondrial DNA loci near genes encoding the mitochondrial proteome and surprisingly observe a lack of enrichment across 24 age-related traits. Within nine other organelles, we find no enrichment with one exception: the nucleus, where enrichment emanates from nuclear transcription factors. In agreement, we find that genes encoding several organelles tend to be ‘haplosufficient,’ while we observe strong purifying selection against heterozygous protein-truncating variants impacting the nucleus. Our work identifies common variation near transcription factors as having outsize influence on age-related trait risk, motivating future efforts to determine if and how this inherited variation then contributes to observed age-related organelle deterioration. eLife Sciences Publications, Ltd 2021-09-01 /pmc/articles/PMC8476128/ /pubmed/34467851 http://dx.doi.org/10.7554/eLife.68610 Text en © 2021, Gupta et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Genetics and Genomics Gupta, Rahul Karczewski, Konrad J Howrigan, Daniel Neale, Benjamin M Mootha, Vamsi K Human genetic analyses of organelles highlight the nucleus in age-related trait heritability |
title | Human genetic analyses of organelles highlight the nucleus in age-related trait heritability |
title_full | Human genetic analyses of organelles highlight the nucleus in age-related trait heritability |
title_fullStr | Human genetic analyses of organelles highlight the nucleus in age-related trait heritability |
title_full_unstemmed | Human genetic analyses of organelles highlight the nucleus in age-related trait heritability |
title_short | Human genetic analyses of organelles highlight the nucleus in age-related trait heritability |
title_sort | human genetic analyses of organelles highlight the nucleus in age-related trait heritability |
topic | Genetics and Genomics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8476128/ https://www.ncbi.nlm.nih.gov/pubmed/34467851 http://dx.doi.org/10.7554/eLife.68610 |
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