Comparison of Heritability of Cystatin C‐ and Creatinine‐Based Estimates of Kidney Function and Their Relation to Heritability of Cardiovascular Disease

BACKGROUND: Decreased renal function is an established risk factor for cardiovascular disease (CVD). Causal mechanisms between estimates of renal function and CVD are intricate and investigation of the relative importance of genetic and environmental factors for the variability of these phenotypes could provide new knowledge. METHODS AND RESULTS: Cystatin C and creatinine levels in 12 313 twins were analyzed. Uni‐ and bivariate heritability for these traits and CVD was estimated through structured equation modelling and genome‐wide complex trait analysis (GCTA) in order to independently confirm additive genetic effects. Twin model‐estimated heritability of Cystatin C was 0.55 (95% confidence interval [CI], 0.49 to 0.60) in men, 0.63 (0.59 to 0.66) in women, and 0.60 (0.56 to 0.63) in both sexes combined. For creatinine, heritability estimates were in the same range. Heritability of CVD was 0.39 (0.02 to 0.67) in men and 0.20 (0.00 to 0.61) in women. The phenotypic correlation between Cystatin C and CVD correlation was 0.16 (0.12 to 0.20) in men and 0.17 (0.13 to 0.21) in women, whereas the genetic correlation in males was 0.41 (0.21 to 0.62) while it was non‐significant in females. Trough GCTA, the heritability of Cystatin C and creatinine in both sexes combined was estimated to 0.40 (SE 0.07, P=8E(−9)) and 0.19 (SE 0.07, P=0.003), respectively. CONCLUSIONS: Twin model‐based heritability of Cystatin C was higher compared to previous studies. Co‐variation between Cystatin C and CVD in males was partly explained by additive genetic components, indicating that Cystatin C and CVD share genetic influences. The GCTA provided independent evidence for significant contribution of additive genetics to trait variance of Cystatin C.