Causal associations between mitochondrial DNA copy number and gastrointestinal diseases: A Mendelian randomization study

We conducted a Mendelian randomization (MR) study to examine the associations of mitochondrial DNA copy number (mtDNA-cn) with 27 gastrointestinal diseases (GDs). To investigate the causal relationship between mtDNA-cn and the risk of 27 GDs, a two-sample MR analytic framework was used. A series of quality-control procedures were followed in order to select eligible instrumental variables that were strongly associated with mtDNA-cn. This two-sample MR study employed 2 cohorts of European ancestry with mtDNA-cn genome-wide association study summary statistics: the UK Biobank (395,718 samples) and the combined Cohorts for Heart and Aging Research in Genomic Epidemiology and UK Biobank dataset (465,809 samples). Genetic associations with 27 GDs were obtained from FinnGen and other large consortia. We conducted MR analyses separately in the 2 cohorts, followed by a meta-analysis. The Cochran Q test and MR-Egger intercept test were used to assess heterogeneity, horizontal pleiotropy, and the stability of single-nucleotide polymorphisms in GDs. The results of the discovery cohort showed that mtDNA-cn was significantly associated with ulcerative colitis (UC) after false discovery rate correction, and a suggestive association with an increased risk of diverticular disease of the intestine was noted for genetically predicted mtDNA-cn. However, the validation cohort did not find any causal relationship between mtDNA-cn and 27 GDs. Results from 2 cohorts were combined using the fixed-effect model; in the meta-analysis, the causal associations remained the same as in the discovery cohort. Our findings summarize the role of mtDNA-cn for 27 GDs. Findings may support a causal effect of mtDNA-cn in the development of UC and diverticular disease of the intestine. These findings have implications for mtDNA-cn as a biomarker of UC and diverticular disease in clinical practice.