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Heritability and family-based GWAS analyses of the N-acyl ethanolamine and ceramide lipidome reveal genetic influence over circulating lipids

K. McGurk,S. Williams,Hui Guo,H. Watkins,M. Farrall,H. Cordell,A. Nicolaou,B. Keavney

Published 2019 in bioRxiv

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.

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