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

Chong, Michael; Mohammadi-Shemirani, Pedrum; Perrot, Nicolas; Nelson, William H.; Morton, Robert W.; Narula, Sukrit; Lali, Ricky; Khan, Irfan; Khan, Mohammad Daud; Judge, Conor; Machipisa, Tafadzwa; Cawte, Nathan; O’Donnell, Martin; Pigeyre, Marie; Akhabir, Loubna; Paré, Guillaume

doi:10.7554/elife.70382

Cited by 75 publications

(62 citation statements)

References 77 publications

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“…The minor allele associates with higher ANKLE1 expression (Consortium et al 2020). E) The minor rs56069439 allele associates with reduced mitochondrial DNA copy number (Chong et al 2022). F) Over 50% of the genome-wide significant GWAS variants for mtDNA correlate with ANKLE1 eQTL in the expected direction (higher ANKLE1 associates with lower mtDNA).…”

Section: Resultsmentioning

confidence: 99%

“…Colocalization analysis indicates that the most significant mtDNA-CN GWAS variants are also eQTLs for ANKLE1 (Figure 4C); moreover, the direction of effect is consistent with a role of ANKLE1 in digesting mitochondrial DNA. Higher ANKLE1 expression alleles (Figure 4D) associate with lower mtDNA-CN (Figure 4E) (Chong et al 2022). The majority of genome-wide significant alleles have an inverse correlation relationship between ANKLE1 expression and mtDNA-CN (Figure 4F).…”

Section: Resultsmentioning

confidence: 99%

“…GWAS data were obtained from published metaanalysis summary statistics (Chong et al 2022; Zhang et al 2020). Expression QTL data were obtained from GTEx GCS bucket (https://console.cloud.google.com/storage/browser/gtex-resources): dbGaP accession number phs000424.v8.p2 (Consortium et al 2020).…”

Section: Methodsmentioning

confidence: 99%

“…Since the molecular biology and genetic data indicate that ANKLE1 function is mediated through the mitochondria in normal and disease states, we hypothesized that ANKLE1 overexpression would lead to changes in expression of en- icance is specific to the TNBC breast cancer subtype. C) Integrative analysis of eQTL data from GTEx (Consortium et al 2020) and mtDNA copy number GWAS (Chong et al 2022) show that the GWAS alleles associated with lower mtDNA are associated with higher ANKLE1 expression (Drivas et al 2021). D) The lead SNP for mtDNA copy number is an eQTL for ANKLE1.…”

Section: Expression Of Ankle1 In Normal Tissue Is Limited To Erythrob...mentioning

confidence: 99%

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ANKLE1 cleaves mitochondrial DNA and contributes to cancer risk by promoting apoptosis resistance and metabolic dysregulation

Przanowski

Przanowska

Guertin

2021

Preprint

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Alleles within the chr19p13.1 locus are associated with increased risk of both ovarian and breast cancer and increased expression of the ANKLE1 gene. ANKLE1 is molecularly characterized as an endonuclease that efficiently cuts branched DNA and shuttles between the nucleus and cytoplasm. However, the role of ANKLE1 in mammalian development and homeostasis remains unknown. In normal development ANKLE1 expression is limited to the erythroblast lineage and we found that ANKLE1’s role is to cleave the mitochondrial genome during erythropoiesis. We show that ectopic expression of ANKLE1 in breast epithelial-derived cells leads to genome instability and mitochondrial DNA (mtDNA) cleavage. mtDNA degradation then leads to mitophagy and causes a shift from oxidative phosphorylation to glycolysis (Warburg effect). Moreover, mtDNA degradation activates STAT1 and expression of epithelial-mesenchymal transition (EMT) genes. Reduction in mitochondrial content contributes to apoptosis resistance, which may allow precancerous cells to avoid apoptotic checkpoints and proliferate. These findings provide evidence that ANKLE1 is the causal cancer susceptibility gene in the chr19p13.1 locus and describe mechanisms by which higher ANKLE1 expression promotes cancer risk.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Expression Of Ankle1 In Normal Tissue Is Limited To Erythrob...mentioning

confidence: 99%

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ANKLE1 cleaves mitochondrial DNA and contributes to cancer risk by promoting apoptosis resistance and metabolic dysregulation

Przanowski

Przanowska

Guertin

2021

Preprint

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“…MR is a method that estimates the causal effect of an exposure on an outcome by using genetic variants as a proxy for the exposure administered as an intervention in a randomized control trial. Recent GWAS studies considered the genetic regulation of mtDNAcn in blood cells [31,37,42]. These studies could facilitate PRS and MR analyses within AD and other neurodegenerative disease datasets and assess causal relationships between mtDNAcn and AD more critically.…”

Section: Narrativementioning

confidence: 99%

The Role of Mitochondrial genome abundance in Alzheimer’s Disease

Harerimana

Paliwali

Romero‐Molina

et al. 2022

Preprint

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Mitochondrial dysfunction is an early and prominent feature of Alzheimer's disease (AD), with impaired energy metabolism preceding the onset of clinical symptoms. Here we propose an update to the mitochondrial dysfunction hypothesis of AD based on recent results examining the role of mitochondrial genome abundance in AD. In a large post-mortem study, we show that lower brain mitochondrial genome abundance is associated with a greater odds of AD neuropathological change and worse cognitive performance. We hypothesize that lower mitochondrial genome abundance impairs mitochondrial function by reducing mitochondrial bioenergetics, thereby impacting neuronal and glial cell function. However, it remains to be determined if mitochondrial dysfunction causes, mediates, or is a by-product of AD pathogenesis. Additional support for this hypothesis will be generated by linking peripheral blood mitochondrial genome abundance to AD and establishing clinical trials of compounds that upregulate total mitochondrial genome abundance or boost mitochondrial mass.

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Surrogate Adiposity Markers and Mortality

Khan,

Chong,

et al. 2023

JAMA Netw Open

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ImportanceBody mass index (BMI) is an easily obtained adiposity surrogate. However, there is variability in body composition and adipose tissue distribution between individuals with the same BMI, and there is controversy regarding the BMI associated with the lowest mortality risk.ObjectiveTo evaluate which of BMI, fat mass index (FMI), and waist-to-hip (WHR) has the strongest and most consistent association with mortality.Design, Setting, and ParticipantThis cohort study used incident deaths from the UK Biobank (UKB; 2006-2022), which includes data from 22 clinical assessment centers across the United Kingdom. UKB British participants of British White ancestry (N = 387 672) were partitioned into a discovery cohort (n = 337 078) and validation cohort (n = 50 594), with the latter consisting of 25 297 deaths and 25 297 controls. The discovery cohort was used to derive genetically determined adiposity measures while the validation cohort was used for analyses. Exposure-outcome associations were analyzed through observational and mendelian randomization (MR) analyses.ExposuresBMI, FMI, and WHR.Main Outcomes and MeasuresAll-cause and cause-specific (cancer, cardiovascular disease [CVD], respiratory disease, or other causes) mortality.ResultsThere were 387 672 and 50 594 participants in our observational (mean [SD] age, 56.9 [8.0] years; 177 340 [45.9%] male, 210 332 [54.2%], female), and MR (mean [SD] age, 61.6 [6.2] years; 30 031 [59.3%] male, 20 563 [40.6%], female) analyses, respectively. Associations between measured BMI and FMI with all-cause mortality were J-shaped, whereas the association of WHR with all-cause mortality was linear using the hazard ratio (HR) scale (HR per SD increase of WHR, 1.41 [95% CI, 1.38-1.43]). Genetically determined WHR had a stronger association with all-cause mortality than BMI (odds ratio [OR] per SD increase of WHR, 1.51 [95% CI, 1.32-1.72]; OR per SD increase of BMI, 1.29 [95% CI, 1.20-1.38]; P for heterogeneity = .02). This association was stronger in male than female participants (OR, 1.89 [95% CI, 1.54-2.32]; P for heterogeneity = .01). Unlike BMI or FMI, the genetically determined WHR–all-cause mortality association was consistent irrespective of observed BMI.Conclusions and RelevanceIn this cohort study, WHR had the strongest and most consistent association with mortality irrespective of BMI. Clinical recommendations should consider focusing on adiposity distribution compared with mass.

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

Cited by 75 publications

References 77 publications

ANKLE1 cleaves mitochondrial DNA and contributes to cancer risk by promoting apoptosis resistance and metabolic dysregulation

ANKLE1 cleaves mitochondrial DNA and contributes to cancer risk by promoting apoptosis resistance and metabolic dysregulation

The Role of Mitochondrial genome abundance in Alzheimer’s Disease

Surrogate Adiposity Markers and Mortality

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