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 impacting each organelle contributes to age-related disease pathogenesis. Here, we evaluate if organelle-relevant loci 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 relevant to mitochondria 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 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 variation contributes to age-related organelle deterioration.

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