Heritability and family-based GWAS analyses to discover novel lipidomic biomarkers of cardiovascular disease

Abstract

Background: Genetic studies of lipids have shown that, while not DNA-encoded, their activities and metabolism are strongly influenced by DNA variants. Signalling lipids are emerging as novel biomarkers of cardiovascular disease (CVD). Those with a strong genetic influence (high heritability) are the strongest candidate species of which common DNA variants influencing lipid concentrations may be identified. Such DNA variants could then be used in Mendelian randomisation analyses to explore causality of each lipid species in CVD and other phenotypes. Methods: In this study, lipidomics, genome-wide association studies (GWAS), and two-sample Mendelian randomisation (2SMR) using the UK Biobank study, were carried out to identify heritable species of signalling plasma lipids and the common DNA variants that influence their concentration, to allow for assessment of their causality in CVD. A family cohort (196 families, 999 individuals) was collected through a proband with hypertension in each family to assess for common DNA associations with lipids in an exemplar British Caucasian population. Arrays of 83 eicosanoids and related species (Eico), 54 ceramides and related sphingolipids (CER), and 28 N-acyl ethanolamines including endocannabinoid anandamide (NAE), were analysed in a range finding study of 204 plasma samples (31 families) by targeted mass spectrometry-based lipidomics (LC-ESI-MS/MS) to identify the most heritable lipid classes for full-cohort analysis (999 samples). Heritability was estimated by pedigree-based QTDT and SNP/GREML-based GCTA software, and family-based GWAS were completed using GCTA software on Human Reference Consortium imputed genotyping data. Results and Interpretation: The range finding study of 31 families showed that NAE and CER lipid classes were more heritable than the Eico species; 9 NAE, 10 CER, and 4 Eico were significantly heritable. Variants in the gene encoding the rate- limiting step of CER biosynthesis (SPTLC3) were identified for 3 CER traits at this stage. The full cohort analysis of 999 plasma samples (196 families) of the NAE and CER classes showed the 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

Date of Award	1 Aug 2020
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Bernard Keavney (Supervisor) & Anna Nicolaou (Supervisor)