Human genetic analyses of organelles highlight the nucleus in age-related trait heritability

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.

Precise modulation of transcription factor levels identifies features underlying dosage sensitivity

“…For instance, TFs are strongly enriched for haploinsufficient disease associations, resulting from the loss of one functional allele, and are depleted of loss-of-function variants in the general population 7 , 8 . Genome-wide association studies have revealed thousands of trait-associated variants, many of which likely act by modulating RE activity and gene expression levels 9 , 10 ; trait-associated variants are also highly enriched around TF genes 11 , 12 . Both experimental and population-level data suggest that such common variants show per-allele effects on gene expression of up to 10–15% (refs.…”

Dissecting reprogramming heterogeneity at single-cell resolution using scTF-seq

“…Numerous studies have emphasized the transformative impact of adjusting the TF dose on molecular and cellular states 9,13,15,64–67 . The significant degree of cellular heterogeneity typically observed upon TF overexpression in ex vivo experiments contrasts however with the precise control of cell fate alterations observed in vivo .…”

Nuclear genetic control of mtDNA copy number and heteroplasmy in humans

“…Published mtscATACseq data used for chrM:302 analysis can be obtained via approval from dbGaP. Gene-sets for enrichment analyses can be obtained using COMPARTMENTS (https://compartments.jensenlab.org) and MitoCarta 2.0 (https://www.broadinstitute.org/files/shared/metabolism/mitocarta/human.mitocarta2.0.html ) as described previously (Gupta et al, 2021). The GRCh37 and GRCh38 reference genomes as well as other standard reference data are available via the GATK resource bundle: https://gatk.broadinstitute.org/hc/en-us/articles/360035890811-Resource-bundle.…”

“…Telomerase (TERT) is in the vicinity of one locus, however fine-mapping did not provide additional evidence for its causality (Supplementary table 3). We next tested mtCNcorr for heritability enrichment in genes associated with organelles or organs using stratified LD-score regression (S-LDSC, Finucane et al, 2015Finucane et al, , 2018Gupta et al, 2021), Methods). Encouragingly, the most significant organelle enrichment was seen for the mitochondrion (Supplementary figure 4C).…”

“…Stratified linkage disequilibrium score regression (S-LDSC, Finucane et al, 2015) was used for heritability estimation and enrichment analyses for mtDNA copy number in UKB as performed previously (Gupta et al, 2021). In brief, we analyzed EUR summary statistics in UKB, restricting variants to those in HapMap3 (HM3).…”