Heritability and family-based GWAS analyses of the N-acyl ethanolamine and ceramide plasma lipidome.
McGurk KA., Williams SG., Guo H., Watkins H., Farrall M., Cordell HJ., Nicolaou A., Keavney BD.
Signalling lipids of the N-acyl ethanolamine (NAE) and ceramide (CER) classes have emerged as potential biomarkers of cardiovascular disease (CVD). We sought to establish the heritability of plasma NAEs (including the endocannabinoid anandamide) and CERs, to identify common DNA variants influencing the circulating concentrations of the heritable lipids, and assess causality of these lipids in CVD using 2-sample Mendelian randomisation (2SMR). Nine NAEs and sixteen CERs were analysed in plasma samples from 999 members of 196 British Caucasian families, using targeted mass spectrometry (UPLC-MS/MS). All 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 < 5x10-8) with four NAEs (DHEA, PEA, LEA, VEA). For CERs, rs680379 in the SPTLC3 gene, which encodes a subunit of the rate-limiting enzyme in CER biosynthesis, associated with a range of species (e.g. CER[N(24)S(19)]; P = 4.82x10-27). We observed three novel associations between SNPs at the CD83, SGPP1, and DEGS1 loci, and plasma CER traits (P < 5x10-8). 2SMR in the CARDIoGRAMplusC4D cohorts (60 801 cases; 123 504 controls) and in the DIAGRAM cohort (26 488 cases; 83 964 controls), using the genetic instruments from our family-based GWAS, did not reveal association between genetically determined differences in CER levels and CVD or diabetes. Two of the novel GWAS loci, SGPP1 and DEGS1, suggested a casual association between CERs and a range of haematological phenotypes, through 2SMR in the UK Biobank, INTERVAL, and UKBiLEVE cohorts (n = 110 000-350 000).