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...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2021-09-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/68610 |
| _version_ | 1811180630283649024 |
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| author | Rahul Gupta Konrad J Karczewski Daniel Howrigan Benjamin M Neale Vamsi K Mootha |
| author_facet | Rahul Gupta Konrad J Karczewski Daniel Howrigan Benjamin M Neale Vamsi K Mootha |
| author_sort | Rahul Gupta |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-11T09:05:12Z |
| format | Article |
| id | doaj.art-a0b432e46f33418a8009ba769c998035 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T09:05:12Z |
| publishDate | 2021-09-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-a0b432e46f33418a8009ba769c9980352022-12-22T04:32:39ZengeLife Sciences Publications LtdeLife2050-084X2021-09-011010.7554/eLife.68610Human genetic analyses of organelles highlight the nucleus in age-related trait heritabilityRahul Gupta0https://orcid.org/0000-0001-8263-2455Konrad J Karczewski1https://orcid.org/0000-0003-2878-4671Daniel Howrigan2https://orcid.org/0000-0002-7721-4838Benjamin M Neale3https://orcid.org/0000-0003-1513-6077Vamsi K Mootha4https://orcid.org/0000-0001-9924-642XHoward Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, United States; Broad Institute of MIT and Harvard, Cambridge, United States; Analytic and Translational Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, United StatesBroad Institute of MIT and Harvard, Cambridge, United States; Analytic and Translational Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, United StatesBroad Institute of MIT and Harvard, Cambridge, United States; Analytic and Translational Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, United StatesBroad Institute of MIT and Harvard, Cambridge, United States; Analytic and Translational Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, United StatesHoward Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, United States; Broad Institute of MIT and Harvard, Cambridge, United StatesMost 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.https://elifesciences.org/articles/68610agingmitochondriatranscription factorshaplosufficiencyenrichmentconstraint |
| spellingShingle | Rahul Gupta Konrad J Karczewski Daniel Howrigan Benjamin M Neale Vamsi K Mootha Human genetic analyses of organelles highlight the nucleus in age-related trait heritability eLife aging mitochondria transcription factors haplosufficiency enrichment constraint |
| 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 | aging mitochondria transcription factors haplosufficiency enrichment constraint |
| url | https://elifesciences.org/articles/68610 |
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