Discovery and fine-mapping of loci associated with MUFAs through trans-ethnic meta-analysis in Chinese and European populations.
Hu Y., Tanaka T., Zhu J., Guan W., Wu JHY., Psaty BM., McKnight B., King IB., Sun Q., Richard M., Manichaikul A., Frazier-Wood AC., Kabagambe EK., Hopkins PN., Ordovas JM., Ferrucci L., Bandinelli S., Arnett DK., Chen Y-DI., Liang S., Siscovick DS., Tsai MY., Rich SS., Fornage M., Hu FB., Rimm EB., Jensen MK., Lemaitre RN., Mozaffarian D., Steffen LM., Morris AP., Li H., Lin X.
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 atFADS1/2andPKD2L1[log10(Bayes factor) ≥ 8.07] and for gondoic acid atFADS1/2andGCKR[log10(Bayes factor) ≥ 6.22], and also observed improved fine-mapping resolutions atFADS1/2andGCKRloci. The greatest improvement was observed atGCKR, 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 ofPKD2L1,FADS1/2,GCKR, andHIF1ANwith palmitoleic acid and ofFADS1/2andLPCAT3with 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.