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

Table 2 Mendelian randomization estimates between genetically predicted mtDNA copy number and the risk of cardiometabolic disease

Exposure	Outcome	No. of SNPs	Methods	OR^a	Lower 95% CI	Upper 95% CI	P	MR-Egger intercept (P value)	Cochran’s Q test (I²)	P	Outliers from MR-PRESSO
mtDNA-CN	Obesity	54	IVW	0.859	0.699	1.055	0.148	0.018	104.092 (69.09%)	< 0.001	rs72660908
			WM	0.939	0.736	1.198	0.613
			MR-Egger	1.414	0.906	2.206	0.133
			MRPRESSO	0.790	0.644	0.969	0.028
mtDNA-CN	Hypertension	15	IVW	0.941	0.782	1.131	0.515	0.357	18.223 (23.17%)	0.197	NA
			WM	1.066	0.851	1.336	0.578
			MR-Egger	1.091	0.764	1.557	0.640
			MRPRESSO	0.941	0.756	1.125	0.525
mtDNA-CN	Dyslipidemia	54	IVW	0.968	0.828	1.132	0.684	0.324	68.710 (22.86%)	0.072	NA
			WM	1.037	0.845	1.273	0.726
			MR-Egger	0.824	0.579	1.174	0.289
			MRPRESSO	0.968	0.812	1.124	0.686
mtDNA-CN	T2DM	55	IVW	0.962	0.822	1.127	0.631	0.209	72.880 (25.90%)	0.044	NA
			WM	0.950	0.782	1.154	0.608
			MR-Egger	0.770	0.528	1.123	0.180
			MRPRESSO	0.928	0.773	1.083	0.351
mtDNA-CN	CAD	57	IVW	0.901	0.768	1.056	0.199	0.114	114.772 (53.82%)	< 0.001	NA
			WM	0.889	0.722	1.095	0.269
			MR-Egger	1.198	0.818	1.754	0.357
			MRPRESSO	0.901	0.742	1.060	0.245
mtDNA-CN	Stroke	55	IVW	0.917	0.775	1.086	0.314	0.390	95.959 (43.7%)	< 0.001	rs1760940, rs2263663
			WM	0.844	0.690	1.032	0.099
			MR-Egger	0.786	0.534	1.158	0.229
			MRPRESSO	0.920	0.767	1.074	0.296
mtDNA-CN	Ischemic stroke	54	IVW	0.962	0.822	1.127	0.631	0.209	89.620 (40.90%)	0.001	NA
			WM	0.950	0.778	1.162	0.620
			MR-Egger	0.770	0.528	1.123	0.180
			MRPRESSO	0.962	0.804	1.120	0.633
mtDNA-CN	Heart failure	57	IVW	1.021	0.917	1.135	0.708	0.378	89.620 (40.86%)	0.001	NA
			WM	1.014	0.861	1.194	0.868
			MR-Egger	1.127	0.884	1.437	0.340
			MRPRESSO	1.021	0.916	1.125	0.705

CAD coronary artery disease, T2DM type 2 diabetes mellitus, PRESSO Pleiotropy Residual Sum and Outlier
^aOdds ratios for associations between genetically predicted mtDNA copy number and cardiometabolic disease. The ORs represent the odds ratios per 1-standardized unit (in SD unit) increase in the mtDNA copy number. The random-effects inverse variance-weighted method was used as the primary approach, while other methods including MR-Egger, weighted median-based, MR-PRESSO were used as sensitivity analyses. The MR-PRESSO global test and MR-Egger regression were adopted to detect the pleiotropic effects. The MR-Egger regression method was to detect the effect of genetic instruments on the exposure which is plotted against its effect on the outcome, and an intercept distinct can be used to identify whether there are pleiotropic effects (MR-Egger regression test: p < 0.01). MR-PRESSO was used to calculate the outlier-corrected MR estimates if the horizontal pleiotropy was present (MR-PRESSO global test: p < 0.01). The q values derived from the Cochran’s Q statistics were used to reflect heterogeneity between the SNP-specific estimates, and the weighted median-based results should be highlighted if significant heterogeneity was observed

ISSN: 1475-2840