Whole-exome sequencing in 415,422 individuals identifies rare variants associated with mitochondrial DNA copy number.

Inter-individual variation in the number of copies of the mitochondrial genome, called mitochondrial DNA copy number (mtDNA-CN), reflects mitochondrial function and has been associated with various aging-related diseases. We examined 415,422 exomes of self-reported White ancestry individuals from the UK Biobank and tested the impact of rare variants, at the level of single variants and through aggregate variant-set tests, on mtDNA-CN. A survey across nine variant sets tested enrichment of putatively causal variants and identified 14 genes at experiment-wide significance and three genes at marginal significance. These included associations at known mtDNA depletion syndrome genes (mtDNA helicase TWNK, p = 1.1 × 10-30; mitochondrial transcription factor TFAM, p = 4.3 × 10-15; mtDNA maintenance exonuclease MGME1, p = 2.0 × 10-6) and the V617F dominant gain-of-function mutation in the tyrosine kinase JAK2 (p = 2.7 × 10-17), associated with myeloproliferative disease. Novel genes included the ATP-dependent protease CLPX (p = 8.4 × 10-9), involved in mitochondrial proteome quality, and the mitochondrial adenylate kinase AK2 (p = 4.7 × 10-8), involved in hematopoiesis. The most significant association was a missense variant in SAMHD1 (p = 4.2 × 10-28), found on a rare, 1.2-Mb shared ancestral haplotype on chromosome 20. SAMHD1 encodes a cytoplasmic host restriction factor involved in viral defense response and the mitochondrial nucleotide salvage pathway, and is associated with Aicardi-Goutières syndrome 5, a childhood encephalopathy and chronic inflammatory response disorder. Rare variants were enriched in Mendelian mtDNA depletion syndrome loci, and these variants implicated core processes in mtDNA replication, nucleoid structure formation, and maintenance. These data indicate that strong-effect mutations from the nuclear genome contribute to the genetic architecture of mtDNA-CN.

Pillalamarri V ，Shi W ，Say C ，Yang S ，Lane J ，Guallar E ，Pankratz N ，Arking DE ... -  《-》

GWAS and ExWAS of blood mitochondrial DNA copy number identifies 71 loci and highlights a potential causal role in dementia.

Mitochondrial DNA copy number (mtDNA-CN) is an accessible blood-based measurement believed to capture underlying mitochondrial (MT) function. The specific biological processes underpinning its regulation, and whether those processes are causative for disease, is an area of active investigation. We developed a novel method for array-based mtDNA-CN estimation suitable for biobank-scale studies, called 'automatic mitochondrial copy (AutoMitoC).' We applied AutoMitoC to 395,781 UKBiobank study participants and performed genome- and exome-wide association studies, identifying novel common and rare genetic determinants. Finally, we performed two-sample Mendelian randomization to assess whether genetically low mtDNA-CN influenced select MT phenotypes. Overall, genetic analyses identified 71 loci for mtDNA-CN, which implicated several genes involved in rare mtDNA depletion disorders, deoxynucleoside triphosphate (dNTP) metabolism, and the MT central dogma. Rare variant analysis identified SAMHD1 mutation carriers as having higher mtDNA-CN (beta = 0.23 SDs; 95% CI, 0.18-0.29; p=2.6 × 10-19), a potential therapeutic target for patients with mtDNA depletion disorders, but at increased risk of breast cancer (OR = 1.91; 95% CI, 1.52-2.40; p=2.7 × 10-8). Finally, Mendelian randomization analyses suggest a causal effect of low mtDNA-CN on dementia risk (OR = 1.94 per 1 SD decrease in mtDNA-CN; 95% CI, 1.55-2.32; p=7.5 × 10-4). Altogether, our genetic findings indicate that mtDNA-CN is a complex biomarker reflecting specific MT processes related to mtDNA regulation, and that these processes are causally related to human diseases. No funds supported this specific investigation. Awards and positions supporting authors include: Canadian Institutes of Health Research (CIHR) Frederick Banting and Charles Best Canada Graduate Scholarships Doctoral Award (MC, PM); CIHR Post-Doctoral Fellowship Award (RM); Wellcome Trust Grant number: 099313/B/12/A; Crasnow Travel Scholarship; Bongani Mayosi UCT-PHRI Scholarship 2019/2020 (TM); Wellcome Trust Health Research Board Irish Clinical Academic Training (ICAT) Programme Grant Number: 203930/B/16/Z (CJ); European Research Council COSIP Grant Number: 640580 (MO); E.J. Moran Campbell Internal Career Research Award (MP); CISCO Professorship in Integrated Health Systems and Canada Research Chair in Genetic and Molecular Epidemiology (GP).

Chong M ，Mohammadi-Shemirani P ，Perrot N ，Nelson W ，Morton R ，Narula S ，Lali R ，Khan I ，Khan M ，Judge C ，Machipisa T ，Cawte N ，O'Donnell M ，Pigeyre M ，Akhabir L ，Paré G ... -  《eLife》

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

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).

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 ... -  《-》

Mitochondrial genome copy number measured by DNA sequencing in human blood is strongly associated with metabolic traits via cell-type composition differences.

Ganel L ，Chen L ，Christ R ，Vangipurapu J ，Young E ，Das I ，Kanchi K ，Larson D ，Regier A ，Abel H ，Kang CJ ，Scott A ，Havulinna A ，Chiang CWK ，Service S ，Freimer N ，Palotie A ，Ripatti S ，Kuusisto J ，Boehnke M ，Laakso M ，Locke A ，Stitziel NO ，Hall IM ... -  《-》

Nuclear and mitochondrial genetic variants associated with mitochondrial DNA copy number.

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.

Koller A ，Filosi M ，Weissensteiner H ，Fazzini F ，Gorski M ，Pattaro C ，Schönherr S ，Forer L ，Herold JM ，Stark KJ ，Döttelmayer P ，Hicks AA ，Pramstaller PP ，Würzner R ，Eckardt KU ，Heid IM ，Fuchsberger C ，Lamina C ，Kronenberg F ... -  《Scientific Reports》