Discovery and fine-mapping of loci associated with MUFAs through trans-ethnic meta-analysis in Chinese and European populations

Abstract

MUFAs are unsaturated FAs with one double bond and are derived from endogenous synthesis and dietary intake. Accumulating evidence has suggested that plasma and erythrocyte MUFA levels are associated with cardiometabolic disorders, including CVD, T2D, and metabolic syndrome (MS). Previous genome-wide association studies (GWASs) have identified seven loci for plasma and erythrocyte palmitoleic and oleic acid levels in populations of European origin. To identify additional MUFA-associated loci and the potential functional variant at each locus, we performed ethnic-specific GWAS meta-analyses and trans-ethnic meta-analyses in more than 15,000 participants of Chinese and European ancestry. We identified novel genome-wide significant associations for vaccenic acid at FADS1/2 and PKD2L1 [log10(Bayes factor) ≥ 8.07] and for gondoic acid at FADS1/2 and GCKR [log10(Bayes factor) ≥ 6.22], and also observed improved fine-mapping resolutions at FADS1/2 and GCKR loci. The greatest improvement was observed at GCKR, where the number of variants in the 99% credible set was reduced from 16 (covering 94.8 kb) to 5 (covering 19.6 kb, including a missense variant rs1260326) after trans-ethnic meta-analysis. We also confirmed the previously reported associations of PKD2L1, FADS1/2, GCKR, and HIF1AN with palmitoleic acid and of FADS1/2 and LPCAT3 with oleic acid in the Chinese-specific GWAS and the trans-ethnic meta-analyses. Pathway-based analyses suggested that the identified loci were in unsaturated FA metabolism and signaling pathways. Our findings provide novel insight into the genetic basis relevant to MUFA metabolism and biology.

Genome-wide analysis of blood lipid metabolites in over 5,000 South Asians reveals biological insights at cardiometabolic disease loci

“…Sphingomyelins have previously been shown to be associated with SGPP1 [41], but the associations of sphingomyelins with these other three loci are reported here for the first time. GCKR has been shown to be associated with total cholesterol and triglycerides (see Figure 2), and has also been associated with the plasma phospholipid fraction fatty acids 16:0 and 16:1 [42, 43]; most lipids that we found to be associated with GCKR (Supplementary Figure 6g) are likely to contain these particular fatty acids. It has been suggested that the glucokinase receptor, encoded by GCKR , affects the production of malonyl-CoA, an important substrate for de novo lipogenesis [42].…”

Integrating lipidomics and genomics: emerging tools to understand cardiovascular diseases

“…After chromatographic separation, the isolated lipids are ionized that are detected using a mass analyser [ 31 ]. GC–MS provides limited coverage of the lipidome and hence, is restricted to studies focused on specific lipid classes and fatty acids quantifications [ 43 – 45 ]. In recent times, shotgun lipidomics has gain popularity due to its relative simplicity of operation and short run times to quantify hundreds of lipids [ 32 – 34 ] and has been applied in several large-scale studies [ 12 , 46 , 47 ].…”

“…As epidemiological studies have demonstrated that distinct molecular species (e.g., TGs and PCs) have different or opposite effect on disease outcomes, genetic variants/loci could potentially have different effect on functionally diverse lipid species. To ascertain that, several genome-wide association studies have been performed with individual lipid species (Table 3 ) [ 12 , 38 – 45 , 83 – 100 ]. These studies have not only identified several new loci/genes contributing to lipid metabolism, but also provided novel mechanistic insights to the known loci identified for traditional lipids.…”

Linking of metabolomic biomarkers with cardiometabolic health in Chinese population

“…57,58 Moreover, a case-control study showed that the adverse effect of the rs3786897 polymorphism of peptidase D (PEPD) on T2D could be alleviated by a higher level of erythrocyte phospholipid n-3 FAs. 59 [60][61][62] Meanwhile, we demonstrated different effect sizes of FADS1 variants on PUFA levels between Chinese and Europeans, and a lower allele frequency of the rs3734398 polymorphism of ELOVL fatty acid elongase 2 (ELOVL2) for Chinese compared with Europeans in a transethnic analysis. 62 These findings suggest potential effects of different genetic backgrounds on PUFA metabolism, and highlight how important it is to establish dietary fat recommendations for the Chinese population based on evidence from Chinese studies.…”

“…Moreover, a case‐control study showed that the adverse effect of the rs3786897 polymorphism of peptidase D ( PEPD ) on T2D could be alleviated by a higher level of erythrocyte phospholipid n‐3 FAs . Recently, we identified 10 novel genetic loci, namely three for blood saturated FAs (LIM homeobox transcription factor 1 [ LMX1A ], AMP deaminase 3 [ AMPD3 ], ceramide synthase 4 [ CERS4 ]), three for blood monounsaturated FAs (fatty acid desaturase 1/2 [ FADS1/2 ], polycystin 2 like 1, transient receptor potential cation channel [ PKD2L1 ], glucokinase regulator [ GCKR ]) and four for blood PUFAs (MYB proto‐oncogene, transcription factor [ MYB ], 1‐acylglycerol‐3‐phosphate O ‐acyltransferase 4 [ AGPAT4 ], diacylglycerol O ‐acyltransferase 2 [ DGAT2 ], palmitoyl‐protein thioesterase 2 [ PPT2 ]), in our GWAS analysis in cooperation with the Cohorts from Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium . Meanwhile, we demonstrated different effect sizes of FADS1 variants on PUFA levels between Chinese and Europeans, and a lower allele frequency of the rs3734398 polymorphism of ELOVL fatty acid elongase 2 ( ELOVL2 ) for Chinese compared with Europeans in a transethnic analysis .…”