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.
Keywords: aging; constraint; enrichment; genetics; genomics; haplosufficiency; human; mitochondria; transcription factors.
Getting older increases our risk of experiencing a wide range of diseases, such as diabetes, heart disease and neurodegenerative disease. The genetic variations that we inherit from our parents play a major role in predicting this risk. However, the biological networks involved in this process are extremely complex and remain challenging to decipher. Prior studies have suggested that specialised structures inside our body’s cells, called organelles, may have an important role to play in aging. Organelles represent self-contained biological factories inside each cell, designed to perform specific tasks. Examples include the nucleus, which harbours most of the cell’s genetic material, and mitochondria, which help provide cells with energy. Organelles tend to deteriorate and become dysfunctional with age, and mitochondria in particular are badly affected by the ageing process. A decline in organelle activity has been thought to explain ageing and the development of age-related diseases. However, this has never been systematically tested on a large scale at the inherited genetic level. Gupta et al. assessed whether common inherited genetic variation in genes associated with ten different organelles could affect the risk of age-related disease, using a database of DNA samples from more than 300,000 individuals. They considered 24 diseases and traits that become more common with advanced age. Gupta et al. discovered that inherited variants in or near genes associated with the nucleus were consistently linked to age-related disease risks. Most of this signal arose from genes encoding the nuclear transcription factors, proteins that help to control the rate at which genes are expressed. However, variants in genes associated with other organelles, including mitochondria, did not appear to be linked to age-related diseases. This research suggests that inherited variation in transcription factors in the nucleus could act as genetic levers that increase the risk of common, age-related diseases. It also suggests that common genetic variation in other cellular organelles may not be as heavily involved in the development of such diseases. Such insights into the cellular structures and biological pathways involved in ageing and age-related disease also establish new targets for drugs to prevent or treat disease.
© 2021, Gupta et al.