TY - JOUR TI - Human genetic analyses of organelles highlight the nucleus in age-related trait heritability AU - Gupta, Rahul AU - Karczewski, Konrad J AU - Howrigan, Daniel AU - Neale, Benjamin M AU - Mootha, Vamsi K A2 - Hägg, Sara A2 - Kaeberlein, Matt A2 - Hägg, Sara A2 - Deelen, Joris VL - 10 PY - 2021 DA - 2021/09/01 SP - e68610 C1 - eLife 2021;10:e68610 DO - 10.7554/eLife.68610 UR - https://doi.org/10.7554/eLife.68610 AB - 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. KW - aging KW - mitochondria KW - transcription factors KW - haplosufficiency KW - enrichment KW - constraint JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -