Partitioning the Pleiotropy Between Coronary Artery Disease and Body Mass Index Reveals the Importance of Low Frequency Variants and Central Nervous System–Specific Functional Elements

Abstract

Background: The objective of this study is to investigate the extent and nature of pleiotropy between coronary artery disease (CAD) and body mass index (BMI). Methods: We examined the contribution of genome-wide single-nucleotide polymorphisms (minor allele frequency ≥0.01) to co-occurrence of CAD and BMI in a sample of genetically unrelated 8041 subjects (genetic resemblance ≤0.025) of European ancestry using mixed-linear-models. We further partitioned the estimated pleiotropy according to biological features to gain insight into the nature of pleiotropy between CAD and BMI. Results: We found significant (Pr_g=0.60). The estimated pleiotropy explained 68% of phenotypic correlation, and it was not proportionally distributed across the chromosomes; notably, chromosome 10 contributed more; whereas, chromosomes 11 and 14 contributed less to pleiotropy than expected given their chromosomal length. We noted that a large proportion (63%; P=0.002) of the pleiotropy is attributed to single-nucleotide polymorphisms with low allele frequency (minor allele frequency MC4R gene were found concordantly associated with (P–8) BMI and CAD with lead single-nucleotide polymorphism being rs663129 (combined P=2.7×10^–65). Finally, partitioning the pleiotropy according to functional elements pointed to the importance of superenhancers and notably brain-specific superenhancers. Conclusions: Genome-wide pleiotropy substantially contributes to co-occurrence of CAD and obesity, and it is highly enriched among low frequency variants and central nervous system–specific functional elements.