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》

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 ... -  《-》

Effects of childhood obesity on heart failure and its associated risk factors in the European population: A Mendelian randomization study.

Kong R ，Li S 《-》

Causal Association Between Anemia and Cardiovascular Disease: A 2-Sample Bidirectional Mendelian Randomization Study.

Gan T ，Hu J ，Liu W ，Li C ，Xu Q ，Wang Y ，Lu S ，Aledan AKO ，Wang Y ，Wang Z ... -  《Journal of the American Heart Association》

Association Between Whole Blood-Derived Mitochondrial DNA Copy Number, Low-Density Lipoprotein Cholesterol, and Cardiovascular Disease Risk.

Liu X ，Sun X ，Zhang Y ，Jiang W ，Lai M ，Wiggins KL ，Raffield LM ，Bielak LF ，Zhao W ，Pitsillides A ，Haessler J ，Zheng Y ，Blackwell TW ，Yao J ，Guo X ，Qian Y ，Thyagarajan B ，Pankratz N ，Rich SS ，Taylor KD ，Peyser PA ，Heckbert SR ，Seshadri S ，Boerwinkle E ，Grove ML ，Larson NB ，Smith JA ，Vasan RS ，Fitzpatrick AL ，Fornage M ，Ding J ，Carson AP ，Abecasis G ，Dupuis J ，Reiner A ，Kooperberg C ，Hou L ，Psaty BM ，Wilson JG ，Levy D ，Rotter JI ，Bis JC ，TOPMed mtDNA Working Group in NHLBI Trans‐Omics for Precision Medicine (TOPMed) Consortium ，Satizabal CL ，Arking DE ，Liu C ... -  《Journal of the American Heart Association》