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

Abstract

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. Targeted lipidomic profiling was performed on 4,492 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: BMI, HDL-C, LDL-C, triglycerides, total cholesterol, waist-hip ratio, systolic blood pressure, and diastolic blood pressure. We report heritabilities and genetic correlations of new lipid species/subclasses, including acylcarnitine (AC), 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 (h2: 0.14–0.50). The monohexosylceramide and AC classes had the highest median heritabilities (h2 = 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 4,768 lipid species-CVD trait genetic correlations were statistically significant after correction for multiple comparisons. 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 SNP and whole-genome sequencing data.

Integrating lipidomics and genomics: emerging tools to understand cardiovascular diseases

“…Despite the expected influence of dietary intake on the circulatory lipids, contribution of genetic factors in endogenous regulation of lipid metabolism is well recognized. Studies using pedigree information and genetic data have shown that 10−60% of the variation in plasma levels of circulatory lipid species is contributed by the genetic factors, with considerable variation across lipid categories [ 12 , 75 – 77 ]. For example, in general, sphingolipids have higher heritability than glycerophospholipids, with ceramides having highest estimated SNP-based heritability (35–40%) and phosphatidylinositols with the least heritability (11–31%) [ 12 ].…”

Heritability and family-based GWAS analyses of the N-acyl ethanolamine and ceramide plasma lipidome

“…Narrow-sense heritability for CERs in previous studies has been estimated at between 9 and 51% ( 18 , 19 ). Here, we have assessed a more extensive array of species to show that further CER[NS] and CER[NDS] are significantly heritable.…”

“…CER[N(16)S(18)]) have been suggested as novel biomarkers of cardiovascular death ( 16 ), type-2 diabetes and insulin resistance ( 17 ). The contribution of genetic factors to plasma variation in some CER species has been investigated ( 5 , 6 , 18 , 19 ).…”

Sphingolipids in the Heart: From Cradle to Grave

“…In another study, the serum of patients with a clinical diagnosis of HF with preserved ejection fraction (HFpEF), the most common form of HF and also strongly associated with diabetes, in The Alberta Heart Failure Etiology and Analysis Research Team (HEART) project showed reduced SM compared to non-HF controls ( 136 ). These sphingolipids seemed to have no relationship to conventional risk factors such as diastolic blood pressure, systolic blood pressure, BMI and waist-hip ratio, suggesting they may be used as more specific markers to identify high-risk patients especially likely to have CVD ( 137 – 140 ).…”