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

Abstract

Certain signalling lipids of the N-acyl ethanolamine (NAE) and ceramide (CER) classes are emerging as novel biomarkers of cardiovascular disease. We sought to establish the heritability of plasma NAEs (including endocannabinoid anandamide) and CERs, and identify common DNA variants influencing the circulating concentrations of the heritable lipid species. Eleven NAEs and thirty CERs were analysed in plasma samples from 999 members of 196 British Caucasian families, using targeted mass spectrometry-based lipidomics (UPLC-MS/MS). Family-based heritability was estimated and GWAS analyses were undertaken. All lipids were significantly heritable over a wide range (h2 = 18%-87%). A missense variant (rs324420) in the gene encoding the enzyme fatty acid amide hydrolase (FAAH), which degrades NAEs, associated at GWAS significance (P<5×10-8) with four NAEs (DHEA, PEA, LEA, VEA). This SNP, previously reported to be associated with addictive behaviour, was associated with an approximately 10% per-allele difference in mean plasma NAE species. Additionally, we have extended the previously described association between rs680379 in the gene encoding the rate limiting step of CER biosynthesis (SPTLC3) and CERs to a wider range of species (e.g. CER[N(24)S(19)] and rs680379 (P =4.82×10-27)). We have shown three novel associations (CD83, SGPP1, FBXO28-DEGS1) influencing plasma CER traits, two of which (SGPP1 and DEGS1) implicate CER species in haematological phenotypes. This first genetic analysis of plasma NAE species, and a wide range of CER mediators, highlights these bioactive lipids as substantially heritable and influenced by SNPs in key metabolic enzymes.

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

“…By contrast, our study found high heritability of ceramides, and no significantly heritable SMs and virtually zero heritability of LPCs. A more recent publication of a Finnish population based study (FINRISK) reported SNP-based heritability of lipid species to be in the range 0.10–0.54 ( Tabassum et al, 2019 ), and found Cer to be the most heritable species, corroborating findings from the present study and others ( McGurk et al, 2017 ; McGurk et al, 2019 ), though heritability of some other lipid classes, such as LPC was markedly higher than reported in the present study. We have summarised our findings against the backdrop of previous literature in Table 5 .…”

Genetic and environmental influences on serum oxylipins, endocannabinoids, bile acids and steroids

“…Similarly, TwinsUK reported varied estimates for steroids and BAs [1]. McGurk et al [22] reported heritability estimates ranging 45-82% for 11 plasma N-acylethanolamide (NAE) analytes in 196 families. In this study lower heritability estimates are reported for 7 NAEs (AEA, PEA, OEA, DHEA, SEA, LEA, POEA), possibly due to different biofluids and modelling methodology.…”

Omega‐3 carboxylic acids and fenofibrate differentially alter plasma lipid mediators in patients with non‐alcoholic fatty liver disease

“…Extraction and analysis of endocannabinoids, NAE, 2-monoacylglycerols (MAG), ceramides, phosphorylated ceramides, free and phosphorylated sphingoid bases were performed as described previously. 21,45,46 Briefly, plasma (1 ml) was spiked with a mixture of deuterated internal standards (20 ng of AEA-d8, 40 ng of 2-AG-d8 and 50 pmol of Cer/Sph Mixture I; Cayman Chemicals, Ann Arbour, MI, USA; Avanti Polar Lipids, USA) and lipids were extracted with ice-cold chloroform:methanol (2:1, v/v). Lipid extracts were analyzed by UPLC-MS/MS using a C18 column (50 × 2.1 mm, 1.7 μm; Acquity UPLC BEH; Waters) for NAE and 2-MAG, and a C8 column (100 × 2.1 mm, 1.7 μm; Acquity UPLC BEH; Waters) for ceramides.…”