Heritability of 596 lipid species and genetic correlation with cardiovascular traits in the Busselton Family Heart Study

INTRODUCTION: Cardiovascular disease (CVD) is the leading cause of death worldwide, and genetic investigations into the human lipidome may provide insight into CVD risk. The aim of this study was to estimate the heritability of circulating lipid species and their genetic correlation with CVD traits. Methods: Targeted lipidomic profiling was performed on 4492 participants from the Busselton Family Heart Study to quantify the major fatty acids of 596 lipid species from 33 classes. We estimated narrow-sense heritabilities of lipid species/classes, and their genetic correlations with eight CVD traits - body mass index, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, triglycerides, total cholesterol, waist-hip-ratio, systolic blood pressure, and diastolic blood pressure. Results: We report heritabilities and genetic correlations of new lipid species/sub-classes, including acylcarnitine, ubiquinone, sulfatide, and oxidized cholesteryl esters. Over 99% of lipid species were significantly heritable (h2:0.06-0.50) and all lipid classes were significantly heritable (h(2):0.14-0.50). The monohexosylceramide and acylcarnitine classes had the highest median heritabilities (h(2)=0.43). The largest genetic correlation was between clinical triglycerides and total diacylglycerol (rg=0.88). We observed novel positive genetic correlations between clinical triglycerides and phosphatidylglycerol species (rg: 0.64-0.82), and HDL-C and alkenylphosphatidylcholine species (rg:0.45-0.74). Overall, 51% of the 4768 lipid species-CVD trait genetic correlations were statistically significant after correction for multiple comparisons. CONCLUSION: This is the largest lipidomic study to address the heritability of lipids, and their genetic correlation with CVD traits. Future work includes identifying putative causal genetic variants for lipid species and CVD using genome-wide single nucleotide polymorphism and whole genome sequencing data.