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.
Aging is associated with defects in many organelles, but an open question is whether the inherited risk for age-related disease is enriched within loci relevant to each organelle. Here, we begin with a focus on mitochondria, as mitochondrial dysfunction is a hallmark of age-related disease. We report a striking lack of enrichment of mitochondria-relevant loci across GWAS for 24 age-related traits. Analyses of nine additional organelles reveal enrichment only for the nucleus, particularly nuclear transcription factors. Consistent with these results, natural selection appears to exert stronger purifying selection against protein-truncating variants for transcription factors compared to mitochondrial pathways, underscoring the importance of inherited variation in gene-regulation in age-related traits.
Variation in traits can be owing to genetic factors or the environment – nature versus nurture – or more likely, a combination of both. It may be of interest, especially when a trait is detrimental, to localise the regions of the genome that contain the genes involved and beyond that, to map specific risk variants. Understanding the possible roles that genes may play in trait variation and, furthermore, estimating or modelling the genetic component are important first steps to inform subsequent genetic studies. There are many different study designs and genetic analysis techniques, each with their respective strengths and weaknesses for the identification of risk variants. Knowledge of disease susceptibility genes may help in the quest for new treatments and cures. Key Concepts Types of trait variation. The possible roles of genes in trait variation. The components of phenotypic variation. Study designs for the estimation of genetic effects and heritability. Genetic heterogeneity. Types of genetic study designs. Various analysis techniques used in genetic studies.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.