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Aims We tested the hypothesis that mitochondrial DNA copy number (CN) is associated with cardiometabolic disease (CMD) traits. Methods and results We determined the cross-sectional association of mtDNA CN measured in whole blood with several CMD traits in 65,996 individuals (mean age 60, 54% women, and 79% European descent). Cohort- and ancestry/ethnicity-specific association analysis was performed adjusting for trait- and cohort-specific covariates. Age was slightly positively associated with age (0.03 s.d. / 10 years (95% CI=0.01, 0.05)) before 65 years, while every 10 years older age was associated with 0.14 s.d. lower level of mtDNA CN after 65 years (95% CI= -0.18, -0.10). In meta-analysis without adjustment for white blood cell (WBC) and differential count in participants of European descent (N=52,491), low mtDNA CN was associated with increased odds of obesity (OR with 95% CI=1.13 (1.11, 1.16), P=3.3e-30) and hypertension (OR=1.05 (1.03, 1.08), P=4.0e-07). Further adjusting for WBC and differential count in the same participants of European descent (N=44,035), associations became non-significant (P>0.05) for hypertension, attenuated for obesity (ORwithout cell count=1.15 (1.12, 1.18) versus ORcell count=1.06 (1.03, 1.08)) but strengthened for hyperlipidemia (ORwithout cell counts =1.03 (1.00, 1.06) versus ORcell counts =1.06 (1.03, 1.09)). The magnitude and directionality of most associations were consistent between participants of European descent and other ethnicity/ancestry origins. Conclusion Low levels of mtDNA CN in peripheral blood were associated with an increased risk of CMD diseases. Key words: mitochondrial DNA copy number, cardiometabolic disease, whole genome sequencing

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