Abstract
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.
Competing Interest Statement
VKM is an advisor to and receives compensation or equity from Janssen Pharmaceuticals, 5am Ventures, and Raze Therapeutics. BMN is a member of the scientific advisory board at Deep Genomics and RBNC Therapeutics. BMN is a consultant for Camp4 Therapeutics, Takeda Pharmaceutical and Biogen. KJK is a consultant for Vor Biopharma.
Footnotes
In this manuscript update, we added a new analysis of proxies of aging, continuing to observe nucleus enrichment with little signal elsewhere (F4), as well as phenotypic correlation analysis between tested traits (F1B). We also clarified parts of the discussion and removed an analysis for which sufficient power had not been achieved.