| Title: |
Genome-wide analysis of mitochondrial DNA copy number reveals loci implicated in nucleotide metabolism, platelet activation, and megakaryocyte proliferation |
| Authors: |
Longchamps, RJ; Yang, SY; Castellani, CA; Shi, W; Lane, J; Grove, ML; Bartz, TM; Sarnowski, C; Liu, C; Burrows, K; Guyatt, AL; Gaunt, TR; Kacprowski, T; Yang, J; De Jager, PL; Yu, L; Bergman, A; Xia, R; Fornage, M; Feitosa, MF; Wojczynski, MK; Kraja, AT; Province, MA; Amin, N; Rivadeneira, F; Tiemeier, H; Uitterlinden, AG; Broer, L; Van Meurs, JBJ; Van Duijn, CM; Raffield, LM; Lange, L; Rich, SS; Lemaitre, RN; Goodarzi, MO; Sitlani, CM; Mak, ACY; Bennett, DA; Rodriguez, S; Murabito, JM; Lunetta, KL; Sotoodehnia, N; Atzmon, G; Ye, K; Barzilai, N; Brody, JA; Psaty, BM; Taylor, KD; Rotter, JI; Boerwinkle, E; Pankratz, N; Arking, DE |
| Source: |
Human Genetics, vol 141, iss 1 |
| Publisher Information: |
eScholarship, University of California |
| Publication Year: |
2022 |
| Collection: |
University of California: eScholarship |
| Subject Terms: |
31 Biological Sciences (for-2020); 3105 Genetics (for-2020); Biotechnology (rcdc); Hematology (rcdc); Human Genome (rcdc); Genetics (rcdc); Aging (rcdc); 2.1 Biological and endogenous factors (hrcs-rac); 1.1 Normal biological development and functioning (hrcs-rac); Cardiovascular (hrcs-hc); Generic health relevance (hrcs-hc); Aged (mesh); Cell Proliferation (mesh); DNA Copy Number Variations (mesh); DNA; Mitochondrial (mesh); Female (mesh); Genetic Predisposition to Disease (mesh); Genome-Wide Association Study (mesh); Humans (mesh); Male (mesh); Megakaryocytes (mesh); Middle Aged (mesh); Mitochondria (mesh); Nucleotides (mesh); Phenotype (mesh); Platelet Activation (mesh); Polymorphism; Single Nucleotide (mesh) |
| Subject Geographic: |
127 - 146 |
| Description: |
Mitochondrial DNA copy number (mtDNA-CN) measured from blood specimens is a minimally invasive marker of mitochondrial functionthatexhibits both inter-individual and intercellular variation. To identify genes involved in regulating mitochondrial function, we performed a genome-wide association study (GWAS) in 465,809White individuals from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and theUK 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). |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
unknown |
| Relation: |
qt9dr6s9ck; https://escholarship.org/uc/item/9dr6s9ck; https://escholarship.org/content/qt9dr6s9ck/qt9dr6s9ck.pdf |
| DOI: |
10.1007/s00439-021-02394-w |
| Availability: |
https://escholarship.org/uc/item/9dr6s9ck; https://escholarship.org/content/qt9dr6s9ck/qt9dr6s9ck.pdf; https://doi.org/10.1007/s00439-021-02394-w |
| Rights: |
CC-BY |
| Accession Number: |
edsbas.6986F676 |
| Database: |
BASE |