Nuclear and mitochondrial genetic variants associated with mitochondrial DNA copy number

• Published in: Scientific reports 2024-01, Vol.14 (1), p.2083-15, Article 2083
• Main Authors: Koller, Adriana, Filosi, Michele, Weissensteiner, Hansi, Fazzini, Federica, Gorski, Mathias, Pattaro, Cristian, Schönherr, Sebastian, Forer, Lukas, Herold, Janina M., Stark, Klaus J., Döttelmayer, Patricia, Hicks, Andrew A., Pramstaller, Peter P., Würzner, Reinhard, Eckardt, Kai-Uwe, Heid, Iris M., Fuchsberger, Christian, Lamina, Claudia, Kronenberg, Florian
• Format: Article
• Language: English
• Subjects: 631/208/1516; 631/208/205/2138; Copy number; DNA Copy Number Variations - genetics; DNA microarrays; DNA, Mitochondrial - genetics; Gasdermins; Genetic diversity; Genetic Loci; Genetic variance; Genome-wide association studies; Genome-Wide Association Study; Genomes; Humanities and Social Sciences; Humans; Mitochondria - genetics; Mitochondrial DNA; multidisciplinary; Phenotypes; Science; Science (multidisciplinary); Single-nucleotide polymorphism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-52373-0

Mitochondrial DNA copy number (mtDNA-CN) is a biomarker for mitochondrial dysfunction associated with several diseases. Previous genome-wide association studies (GWAS) have been performed to unravel underlying mechanisms of mtDNA-CN regulation. However, the identified gene regions explain only a small fraction of mtDNA-CN variability. Most of this data has been estimated from microarrays based on various pipelines. In the present study we aimed to (1) identify genetic loci for qPCR-measured mtDNA-CN from three studies (16,130 participants) using GWAS, (2) identify potential systematic differences between our qPCR derived mtDNA-CN measurements compared to the published microarray intensity-based estimates, and (3) disentangle the nuclear from mitochondrial regulation of the mtDNA-CN phenotype. We identified two genome-wide significant autosomal loci associated with qPCR-measured mtDNA-CN: at HBS1L (rs4895440, p = 3.39 × 10 –13 ) and GSDMA (rs56030650, p = 4.85 × 10 –08 ) genes. Moreover, 113/115 of the previously published SNPs identified by microarray-based analyses were significantly equivalent with our findings. In our study, the mitochondrial genome itself contributed only marginally to mtDNA-CN regulation as we only detected a single rare mitochondrial variant associated with mtDNA-CN. Furthermore, we incorporated mitochondrial haplogroups into our analyses to explore their potential impact on mtDNA-CN. However, our findings indicate that they do not exert any significant influence on our results.