Abstract
Mitochondrial DNA copy number (mtDNA-CN) measured from blood specimens is a minimally invasive marker of mitochondrial function that exhibits both inter-individual and intercellular variation. To identify genes involved in regulating mitochondrial function, we performed a genome-wide association study (GWAS) in 465,809 White individuals from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank (UKB). We identified 133 SNPs with statistically significant, independent effects associated with mtDNA-CN across 100 loci. A combination of fine-mapping, variant annotation, and co-localization analyses was used to prioritize genes within each of the 133 independent sites. Putative causal genes were enriched for known mitochondrial DNA depletion syndromes (p = 3.09 × 10–15) and the gene ontology (GO) terms for mtDNA metabolism (p = 1.43 × 10–8) and mtDNA replication (p = 1.2 × 10–7). A clustering approach leveraged pleiotropy between mtDNA-CN associated SNPs and 41 mtDNA-CN associated phenotypes to identify functional domains, revealing three distinct groups, including platelet activation, megakaryocyte proliferation, and mtDNA metabolism. Finally, using mitochondrial SNPs, we establish causal relationships between mitochondrial function and a variety of blood cell-related traits, kidney function, liver function and overall (p = 0.044) and non-cancer mortality (p = 6.56 × 10–4).
Highlights
Mitochondria are the cellular organelles primarily responsible for producing the chemical energy required for metabolism, as well as signaling the apoptotic process, maintaining homeostasis, and synthesizing several macromolecules such as lipids, heme and iron-sulfur clusters (Wallace 1992; Vakifahmetoglu-Norberg et al 2017)
The bulk of the DNA used for mtDNA-CN estimation was derived from the buffy coat (95.5%) while the rest was derived from peripheral leukocytes (2.2%), whole blood (2.3%), or brain (< 0.2%). mtDNA-CN estimated from Affymetrix genotyping arrays consisted of 97.9% of the data while the remainder was derived from qPCR (1.8%) and WGS (0.3%)
Given that > 90% of the samples come from the UK Biobank (UKB) study, and the challenge of interpreting effect size estimates from a random-effects model, downstream analyses all use effect size estimates from the UKB only analyses (Supplemental Table 6), which showed no evidence for population substructure inflating test statistics, with a genomic inflation factor of 1.09 (Supplemental Fig. 5). mtDNA-CN in the UKB dataset was significantly associated with known covariates such as age (p < 2 × 10–16) and sex (p < 2 × 10–16) in the expected directions, with older individuals having lower mtDNA-CN, and females having higher mtDNA-CN
Summary
Mitochondria are the cellular organelles primarily responsible for producing the chemical energy required for metabolism, as well as signaling the apoptotic process, maintaining homeostasis, and synthesizing several macromolecules such as lipids, heme and iron-sulfur clusters (Wallace 1992; Vakifahmetoglu-Norberg et al 2017). To further elucidate the genetic control over mtDNACN, several genome-wide association studies (GWAS) of mtDNA-CN have been published (Cai et al 2015; Workalemahu et al 2017; Guyatt et al 2019; Hägg et al 2020), including a study that was published while the current manuscript was in preparation, analyzing ~ 300,000 participants from the UK Biobank (UKB), and identifying 50 independent loci (Hägg et al 2020). MtDNA-SNPs are known to associate with altered risks of developing many diseases, and can modulate mitochondrial protein translation (Marom et al 2017; Cai et al 2021). We perform a PHEWAS and group our genome-wide significant SNPs into three clusters that represent distinct functional domains related to mtDNA-CN. We leverage mitochondrial SNPs to establish causality between mitochondrial function and mtDNA-CN associated traits
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