Portal de Periódicos da CAPES

Genome-wide analysis of mitochondrial DNA copy number reveals loci implicated in nucleotide metabolism, platelet activation, and megakaryocyte proliferation

2021; Springer Science+Business Media; Volume: 141; Issue: 1 Linguagem: Inglês

10.1007/s00439-021-02394-w

1432-1203

RJ Longchamps, Stephanie Yang, Christina A. Castellani, Wen Shi, Jon D. Lane, Megan L. Grove, T.M. Bartz, Chloé Sarnowski, C. Liu, Kimberley Burrows, Anna L. Guyatt, Tom R. Gaunt, Tim Kacprowski, Jingyun Yang, Philip L. De Jager, Lei Yu, Aviv Bergman, Rui Xia, Myriam Fornage, M.F. Feitosa, MK Wojczynski, Aldi T. Kraja, M. A. Province, Najaf Amin, Fernando Rivadeneira, Henning Tiemeier, André G. Uitterlinden, Linda Broer, Joyce B. J. van Meurs, Cornelia M. van Duijn, Laura M. Raffield, Leslie A. Lange, Stephen S. Rich, Rozenn N. Lemaître, Mark O. Goodarzi, C. M. Sitlani, Angel C. Y. Mak, David A. Bennett, Santiago Rodrı́guez, Joanne M. Murabito, Kathryn L. Lunetta, N Sotoodehnia, Gil Atzmon, Kenny Ye, Nir Barzilai, J. A. Brody, Bruce M. Psaty, Kent D. Taylor, Jerome I. Rotter, Eric Boerwinkle, Nathan Pankratz, Dan E. Arking,

Peroxisome Proliferator-Activated Receptors

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 ).