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》

Association between blood mitochondrial DNA copy number and mental disorders: A bidirectional two-sample mendelian randomization study.

Mitochondria is essential for cellular energy production, oxidative stress, and apoptosis. Mitochondrial DNA (mtDNA) encodes essential proteins for mitochondrial function. Although several studies have explored the association between changes in mtDNA copy number (mtDNA-CN) and risk of mental disorders, the results remain debated. This study used a bidirectional two-sample Mendelian randomization (MR) analysis to examine the genetic causality between mtDNA-CN and mental disorders. Genome-wide association study (GWAS) data for mtDNA-CN were sourced from UK biobank, involving 383,476 European cases. GWAS data for seven mental disorders-attention deficit/hyperactivity disorder, autism spectrum disorder (ASD), schizophrenia, bipolar disorder, major depressive disorder, anxiety, and obsessive-compulsive disorder-were primarily obtained from the Psychiatric Genomics Consortium. Causal associations were assessed using inverse variance weighting, with sensitivity analyses via the weighted median and MR-Egger methods. Reverse MR considered the seven mental disorders as exposures. All analyses were replicated with additional mtDNA-CN GWAS data from 465,809 individuals in the Heart and Ageing Research in Genomic Epidemiology consortium and the UK Biobank. Forward MR observed a 27 % decrease in the risk of ASD per standard deviation increase in genetically determined blood mtDNA-CN (OR = 0.73, 95%CI: 0.58-0.92, p = 0.002), with no causal effects on other disorders. Additionally, reverse MR did not indicate a causal association between any of the mental disorders and mtDNA-CN. Validation analyses corroborated these findings, indicating their robustness. Our study supports the potential causal association between mtDNA-CN and the risk of ASD, suggesting that mtDNA-CN could serve as a promising biomarker for early screening of ASD.

Lu Y ，Han L ，Wang X ，Liu X ，Jia X ，Lan K ，Gao S ，Feng Z ，Yu L ，Yang Q ，Cui N ，Wei YB ，Liu JJ ... -  《-》

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 ... -  《-》

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 ... -  《-》

Assessing the causal role of epigenetic clocks in the development of multiple cancers: a Mendelian randomization study.

Epigenetic clocks have been associated with cancer risk in several observational studies. Nevertheless, it is unclear whether they play a causal role in cancer risk or if they act as a non-causal biomarker. We conducted a two-sample Mendelian randomization (MR) study to examine the genetically predicted effects of epigenetic age acceleration as measured by HannumAge (nine single-nucleotide polymorphisms (SNPs)), Horvath Intrinsic Age (24 SNPs), PhenoAge (11 SNPs), and GrimAge (4 SNPs) on multiple cancers (i.e. breast, prostate, colorectal, ovarian and lung cancer). We obtained genome-wide association data for biological ageing from a meta-analysis (N = 34,710), and for cancer from the UK Biobank (N cases = 2671-13,879; N controls = 173,493-372,016), FinnGen (N cases = 719-8401; N controls = 74,685-174,006) and several international cancer genetic consortia (N cases = 11,348-122,977; N controls = 15,861-105,974). Main analyses were performed using multiplicative random effects inverse variance weighted (IVW) MR. Individual study estimates were pooled using fixed effect meta-analysis. Sensitivity analyses included MR-Egger, weighted median, weighted mode and Causal Analysis using Summary Effect Estimates (CAUSE) methods, which are robust to some of the assumptions of the IVW approach. Meta-analysed IVW MR findings suggested that higher GrimAge acceleration increased the risk of colorectal cancer (OR = 1.12 per year increase in GrimAge acceleration, 95% CI 1.04-1.20, p = 0.002). The direction of the genetically predicted effects was consistent across main and sensitivity MR analyses. Among subtypes, the genetically predicted effect of GrimAge acceleration was greater for colon cancer (IVW OR = 1.15, 95% CI 1.09-1.21, p = 0.006), than rectal cancer (IVW OR = 1.05, 95% CI 0.97-1.13, p = 0.24). Results were less consistent for associations between other epigenetic clocks and cancers. GrimAge acceleration may increase the risk of colorectal cancer. Findings for other clocks and cancers were inconsistent. Further work is required to investigate the potential mechanisms underlying the results. FMB was supported by a Wellcome Trust PhD studentship in Molecular, Genetic and Lifecourse Epidemiology (224982/Z/22/Z which is part of grant 218495/Z/19/Z). KKT was supported by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme) and by the Hellenic Republic's Operational Programme 'Competitiveness, Entrepreneurship & Innovation' (OΠΣ 5047228). PH was supported by Cancer Research UK (C18281/A29019). RMM was supported by the NIHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol and by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). RMM is a National Institute for Health Research Senior Investigator (NIHR202411). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. GDS and CLR were supported by the Medical Research Council (MC_UU_00011/1 and MC_UU_00011/5, respectively) and by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). REM was supported by an Alzheimer's Society project grant (AS-PG-19b-010) and NIH grant (U01 AG-18-018, PI: Steve Horvath). RCR is a de Pass Vice Chancellor's Research Fellow at the University of Bristol.

Morales Berstein F ，McCartney DL ，Lu AT ，Tsilidis KK ，Bouras E ，Haycock P ，Burrows K ，Phipps AI ，Buchanan DD ，Cheng I ，PRACTICAL consortium ，Martin RM ，Davey Smith G ，Relton CL ，Horvath S ，Marioni RE ，Richardson TG ，Richmond RC ... -  《eLife》