Genetic and environmental determinants of variation in the plasma lipidome of older Australian twins

The critical role of blood lipids in a broad range of health and disease states is well recognised, while an understanding of the complex genetic regulation of lipid homeostasis is emerging. Traditional blood lipids (LDL-C, HDL-C and triglycerides) are known to be substantially regulated by genetic variation. Less well explored is the interplay of genetics and environment within the broader blood lipidome. Here we use the twin model to examine heritability of the plasma lipidome among healthy older aged twins and explore gene expression and epigenetic (DNA methylation) associations of these lipids. Heritability of 209 plasma lipids quantified by liquid chromatography coupled mass spectrometry (LC-MS) was assessed in 75 monozygotic and 55 dizygotic twin pairs enrolled in the Older Australian Twins Study (OATS), aged 69-93 years. Only 27/209 lipids (13.3%) were significantly heritable under the classical ACE twin model ( h 2 = 0.28-0.59). Ceramides (Cer) and triglycerides (TG) were most heritable, while sphingomyelins (SM) and most phospholipids, especially lysophospholipids, were not significantly heritable. Lipid levels correlated with 3731 transcripts. Relative to non-significantly heritable TGs, heritable TGs had a greater number of associations with gene transcripts, which were not directly associated with lipid metabolism, but with immune function, signalling and transcriptional regulation. Genome-wide average DNA methylation (GWAM) levels accounted for a proportion of variability in some non-heritable lipids, especially lysophosphatidylcholine (LPC). We found a complex interplay of genetic and environmental influences on the ageing plasma lipidome, with most of the variation controlled by unique environmental influences.