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

Qin, Pei; Qin, Tianhang; Liang, Lei; Li, Xinying; Jiang, Bin; Wang, Xiaojie; Ma, Jianping; Hu, Fulan; Zhang, Ming; Hu, Dongsheng

doi:10.1186/s12933-023-02074-1

Cardiovascular Diabetology

Table 3 Reverse mendelian randomization estimates on associations of genetically predicted cardiometabolic disease and mtDNA copy number

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

Exposure	Outcome	No. of SNPs	Methods	β	SE	Lower 95% CI	Upper 95% CI	P	MR-Egger intercept (P value)	Cochran’s Q test (I²)	P	Outliers from MR-PRESSO
Obesity	mtDNA-CN	25	IVW	− 0.001	0.007	0.013	− 0.015	0.953	0.121	36.200 (36.5%)	0.039	rs7187776
			WM	− 0.007	0.008	0.009	− 0.023	0.432
			MR-Egger	− 0.029	0.019	0.008	− 0.066	0.142
			MRPRESSO	− 0.004	0.006	0.008	− 0.016	0.557
Hypertension	mtDNA-CN	34	IVW	0.007	0.009	0.025	− 0.011	0.457	0.817	25.148 (11.3%)	0.620	NA
			WM	0.010	0.012	0.034	− 0.014	0.417
			MR-Egger	0.031	0.028	0.086	− 0.024	0.284
			MRPRESSO	0.007	0.009	0.025	− 0.011	0.457
Dyslipidemia	mtDNA-CN	26	IVW	− 0.060	0.008	− 0.044	− 0.076	2.416e−14	0.017	46.840 (63.7%)	< 0.001	rs3005923, rs7412
			WM	− 0.069	0.008	− 0.053	− 0.085	5.872e−17
			MR-Egger	− 0.085	0.012	− 0.061	− 0.109	1.798e−06
			MRPRESSO	− 0.052	0.007	− 0.038	− 0.066	1.836e−06
T2DM	mtDNA-CN	149	IVW	− 0.0001	0.004	0.008	− 0.008	0.974	0.852	203.098 (38.5%)	< 0.001	rs10401969
			WM	0.007	0.005	0.017	− 0.003	0.153
			MR-Egger	0.001	0.008	0.017	− 0.015	0.880
			MRPRESSO	− 0.002	0.003	0.004	− 0.008	0.766
CAD	mtDNA-CN	41	IVW	− 0.021	0.009	− 0.003	− 0.039	0.025	0.895	218.390 (78.0%)	< 0.001	rs115654617, rs1412444, rs2519093, rs3918226, rs4420638, rs515135, rs56289821, rs7528419
			WM	− 0.013	0.008	0.003	− 0.029	0.122
			MR-Egger	− 0.023	0.022	0.020	− 0.066	0.286
			MRPRESSO	− 0.010	0.007	0.004	− 0.024	0.138
Stroke	mtDNA-CN	12	IVW	− 0.004	0.006	0.008	− 0.016	0.452	0.988	147. 600 (85.8%)	< 0.001	NA
			WM	− 0.006	0.004	0.002	− 0.014	0.138
			MR-Egger	0.016	0.026	0.067	− 0.035	0.557
			MRPRESSO	− 0.004	0.006	0.008	− 0.016	0.452
Ischemic stroke	mtDNA-CN	19	IVW	− 0.013	0.012	0.011	− 0.037	0.258	0.457	26.093 (34.8%)	0.073	NA
			WM	− 0.008	0.014	0.019	− 0.035	0.591
			MR-Egger	− 0.063	0.066	0.066	− 0.192	0.355
Heart failure	mtDNA-CN	12	IVW	− 0.048	0.034	0.019	− 0.115	0.160	0.378	51.956 (3.93%)	0.554	rs17042102, rs55730499, rs600038
			WM	0.012	0.023	0.057	− 0.033	0.608
			MR-Egger	− 0.059	0.105	0.147	− 0.265	0.588
			MRPRESSO	0.004	0.019	0.041	− 0.033	0.829

Odds ratios for associations between genetically predicted cardiometabolic disease and mtDNA copy number. 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
PRESSO Pleiotropy Residual Sum and Outlier

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ISSN: 1475-2840

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