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 ... -  《-》

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》

The role of mitochondrial DNA copy number in cardiometabolic disease: a bidirectional two-sample mendelian randomization study.

This study used a bidirectional 2-sample Mendelian randomization study to investigate the potential causal links between mtDNA copy number and cardiometabolic disease (obesity, hypertension, hyperlipidaemia, type 2 diabetes [T2DM], coronary artery disease [CAD], stroke, ischemic stroke, and heart failure). Genetic associations with mtDNA copy number were obtained from a genome-wide association study (GWAS) summary statistics from the UK biobank (n = 395,718) and cardio-metabolic disease were from largest available GWAS summary statistics. Inverse variance weighting (IVW) was conducted, with weighted median, MR-Egger, and MR-PRESSO as sensitivity analyses. We repeated this in the opposite direction using instruments for cardio-metabolic disease. Genetically predicted mtDNA copy number was not associated with risk of obesity (P = 0.148), hypertension (P = 0.515), dyslipidemia (P = 0.684), T2DM (P = 0.631), CAD (P = 0.199), stroke (P = 0.314), ischemic stroke (P = 0.633), and heart failure (P = 0.708). Regarding the reverse directions, we only found that genetically predicted dyslipidemia was associated with decreased levels of mtDNA copy number in the IVW analysis (β= - 0.060, 95% CI - 0.044 to - 0.076; P = 2.416e-14) and there was suggestive of evidence for a potential causal association between CAD and mtDNA copy number (β= - 0.021, 95% CI - 0.003 to - 0.039; P = 0.025). Sensitivity and replication analyses showed the stable findings. Findings of this Mendelian randomization study did not support a causal effect of mtDNA copy number in the development of cardiometabolic disease, but found dyslipidemia and CAD can lead to reduced mtDNA copy number. These findings have implications for mtDNA copy number as a biomarker of dyslipidemia and CAD in clinical practice.

Qin P ，Qin T ，Liang L ，Li X ，Jiang B ，Wang X ，Ma J ，Hu F ，Zhang M ，Hu D ... -  《Cardiovascular Diabetology》

Mitochondrial DNA copy number and cancer risks: A comprehensive Mendelian randomization analysis.

Cai X ，Liang C ，Zhang M ，Dong Z ，Weng Y ，Yu W ... -  《-》

Assessment of Bidirectional Relationships between Frailty and Mental Disorders: A Bidirectional Mendelian Randomization Study.

Although observational studies have reported the association between frailty and mental disorders, the causality remains unclear. We aimed to evaluate the bidirectional causal association between frailty levels and mental disorders using a 2-sample Mendelian randomization (MR) analysis. A bidirectional, 2-sample Mendelian randomization (MR) analysis. Instrumental variables were obtained from large-scale genome-wide association study (GWAS) of a European-descent population for frailty index (FI, n = 175,226), Fried Frailty Score (FFS, n = 386,565), major depressive disorder (MDD, n = 674,452), bipolar disorder (n = 353,899), anxiety and stress-related disorder (ASRD, n = 31,880), and schizophrenia (n = 127,906). Two-sample MR analyses were conducted using inverse variance-weighted method, with sensitivity analyses using MR-Egger, weighted median, and simple median methods. Per SD increase in genetically predicted FI and FFS increased the risk of MDD [odds ratio (OR) 1.56, 95% CI 1.27-1.94, P = 3.65 × 10-5, and OR 1.67, 95% CI 1.26-2.20, P = 3.02 × 10-4, respectively]. Per-SD increase in genetically predicted FI also increased the risk of ASRD (OR 2.76, 95% CI 1.36-5.60, P = .005). No significant effect was observed for frailty levels on the risk of bipolar disorder and schizophrenia. In the reverse direction, genetically predicted MDD was associated with higher FI (β 0.182, 95% CI 0.087-0.277, P = 1.79 × 10-4) and FFS (β 0.121, 95% CI 0.087-0.155, P = 4.43 × 10-12). No reliable evidence supported the effects of genetically predicted bipolar disorder, ASRD, or schizophrenia on frailty levels. A bidirectionally causal association exists between frailty levels and MDD, and higher FI is associated with a higher risk of ASRD. No reliable evidence suggested the causal associations of other mental disorders with frailty. Our findings provided evidence for introduction of psychological-related strategies in management of frailty.

Ma T ，Chen M ，Cheng X ，Bai Y ... -  《-》