Familial Co-aggregation and Shared Genetics of Cardiometabolic Disorders and Traits: Data from The Multi-Generational Lifelines Cohort Study

Background: It is unclear to what extent genetics explain the familial clustering and the co-occurrence of distinct cardiometabolic disorders in the general population. We aim to quantify the familial (co-)aggregation of various cardiometabolic disorders and to estimate the heritability of cardiometabolic traits and their genetic correlations.
Methods: We used baseline data of 162,416 participants from the multi-generational Lifelines Cohort Study. Cardiometabolic disorders including type 2 diabetes (T2D), cardiovascular diseases, hypertension, obesity, hypercholesterolemia, and metabolic syndrome (MetS), were defined in adult participants. Fifteen additional cardiometabolic traits indexing obesity, blood pressure, inflammation, glucose regulation, and lipid levels were measured in all included participants. Recurrence risk ratios (λR) for first-degree relatives (FDR) indexed familial (co-)aggregation of cardiometabolic disorders using modified conditional Cox proportional hazards models and were compared to those of spouses. Heritability (h2), shared environment, and genetic correlation (rg) were estimated using restricted maximum likelihood variance decomposition methods, adjusted for age, age2, and sex.
Results: Individuals with a first-degree relative with a cardiometabolic disorder had a higher risk of the same disorder, ranging from λFDR of 1.23 (95%CI: 1.20-1.25) for hypertension to λFDR of 2.48 (95%CI: 2.15-2.86) for T2D. Most of these were higher than in spouses (λSpouses<λFDR), except for obesity which was slightly higher in spouses. We found moderate heritability for cardiometabolic traits (from h2CRP: 0.26 to h2HDL: 0.50). Cardiometabolic disorders showed positive familial co-aggregation, particularly between T2D, MetS, and obesity (from λFDR obesity-MetS: 1.28 (95%CI: 1.24-1.32) to λFDR MetS-T2D: 1.61 (95%CI: 1.52-1.70)), consistent with the genetic correlations between their continuous traits (ranging from rg HDL-Triglycerides: -0.53 to rg LDL-ApoB: 0.94).
Conclusions: There is positive familial (co-)aggregation of cardiometabolic disorders. Cardiometabolic traits are moderately heritable with moderate genetic correlations between traits. These results indicate that shared genetics and a common genetic architecture underly various cardiometabolic disorders and traits.
Keywords: Cardiometabolic disorders, cardiometabolic traits, familial (co-)aggregation, genetic correlation, heritability.