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

Abstract

Signalling lipids of the N-acyl ethanolamine (NAE) and ceramide (CER) classes are emerging as novel cardiovascular disease biomarkers. We sought to establish the heritability of plasma NAEs (including the endocannabinoid anandamide) and CERs, and identify common DNA variants influencing the circulating concentrations of the heritable lipid species. Nine NAE and sixteen CER species were analysed in plasma samples from 999 members of 196 British Caucasian families, using targeted mass spectrometry (UPLC-MS/MS). Heritability was estimated and GWAS analyses were undertaken; all target lipids were significantly heritable (h² = 36%-62%). A missense variant (rs324420) in the gene encoding the enzyme fatty acid amide hydrolase (FAAH), which degrades NAEs, associated at GWAS significance (P<2.15×10⁻⁸) with four NAEs (DHEA, PEA, LEA, VEA). The A allele of this SNP was associated with a 0.23 SD per-allele increase in plasma NAE species. Additionally, we found association between rs680379 in the SPTLC3 gene, which encodes a subunit of the rate limiting enzyme in CER biosynthesis, and a range of CER species (e.g. CER[N(24)S(19)]; P =4.82×10⁻²⁷). We also observed three novel associations (CD83, SGPP1, FBXO28-DEGS1) influencing plasma CER traits, two of which (SGPP1 and DEGS1) implicate CER species in haematological phenotypes. NAE and CER are substantially heritable bioactive lipids, influenced by SNPs in key metabolic enzymes.