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Title: Discovery and fine-mapping of loci associated with monounsaturated fatty acids through trans-ethnic meta-analysis in Chinese and European populations

Author
item HU, YAO - Chinese Academy Of Sciences
item TANAKA, TOSHIKO - National Institute On Aging (NIA, NIH)
item ZHU, JINGWEN - Chinese Academy Of Sciences
item GUAN, WEIHUA - University Of Minnesota
item WU, JASON - University Of Sydney
item PSATY, BRUCE - University Of Washington
item MCKNIGHT, BARBARA - University Of Washington
item KING, IRENA - University Of New Mexico
item SUN, QI - Harvard Medical School
item RICHARD, MELISSA - University Of Texas Health Science Center
item MANICHAIKUL, ANI - University Of Virginia
item FRAZIER-WOOD, ALEXIS - Children'S Nutrition Research Center (CNRC)
item KABAGAMBE, EDMOND - Vanderbilt University Medical Center
item HOPKINS, PAUL - University Of Utah
item ORDOVAS, JOSE - Tufts University
item FERRUCCI, LUIGI - National Institute On Aging (NIA, NIH)
item BANDINELLI, STEFANIA - Azienda Sanitaria Di Firenze
item ARNETT, DONNA - University Of Alabama
item CHEN, YII-DER - Harbor-Ucla Medical Center
item LIANG, SHUANG - University Of Minnesota
item SISCOVICK, DAVID - University Of Washington
item TSAI, MICHAEL - University Of Minnesota
item RICH, STEPHEN - University Of Virginia
item FORNAGE, MYRIAM - University Of Texas Health Science Center
item HU, FRANK - Harvard Medical School
item RIMM, ERIC - Harvard Medical School
item JENSEN, MAJKEN - Harvard Medical School
item LEMAITRE, ROZENN - University Of Washington
item MOZAFFARIAN, DARIUSH - Tufts University
item STEFFEN, LYN - University Of Minnesota
item MORRIS, ANDREW - Wellcome Trust Sanger Institute
item LI, HUAIXING - Chinese Academy Of Sciences
item LIN, XU - Chinese Academy Of Sciences

Submitted to: Journal of Lipid Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/10/2017
Publication Date: 3/15/2017
Citation: Hu, Y., Tanaka, T., Zhu, J., Guan, W., Wu, J.H., Psaty, B.M., McKnight, B., King, I.B., Sun, Q., Richard, M., Manichaikul, A., Frazier-Wood, A.C., Kabagambe, E.K., Hopkins, P.N., Ordovas, J.M., Ferrucci, L., Bandinelli, S., Arnett, D.K., Chen, Y.I., Liang, S., Siscovick, D.S., Tsai, M.Y., Rich, S.S., Fornage, M., Hu, F.B., Rimm, E.B., Jensen, M.K., Lemaitre, R.N., Mozaffarian, D., Steffen, L.M., Morris, A.P., Li, H., Lin, X. 2017. Discovery and fine-mapping of loci associated with monounsaturated fatty acids through trans-ethnic meta-analysis in Chinese and European populations. Journal of Lipid Research. doi:10.1194/jlr.P071860.

Interpretive Summary: Monounsaturated fatty acids (MUFAs) are synthesized both from dietary sources such as nuts, seeds and some oils and independently of dietary intake within the body. MUFA levels in the blood are associated with protection from cardiometabolic disorders including cardiovascular disease (CVD), type 2 diabetes (T2D) and metabolic syndrome (MS). If we understood why some individuals have naturally higher MUFA levels regardless of what they eat, we might be able to identify new pathways of protection from cardiometabolic risk. However, few studies have identified which genetic variants influence MUFA synthesis in the body, and any variants we do know have been identified in Caucasian individuals. To identify additional genetic variants associated with MUFA levels in the blood, we performed ethnic-specific genetic meta-analyses and meta-analyses across over 15,000 participants of Chinese- and European-ancestry using data from across the whole genome. As well as confirning previous gene-MUFA associations, we identified novel variant-MUFA associations in genes called FADS1/2, PKD2L1 and GCKR. The greatest improvement was observed at GCKR, where the number of variants in the 99% credible set was reduced from 16 (covering ~95kb) to five (covering ~20kb, including a missense variant rs1260326) after trans-ethnic meta-analysis. These results provided novel insight into the genetic basis of MUFA metabolism and may one day help us better understand why some individuals are more likely to get caridometabolic diseases than others.

Technical Abstract: Monounsaturated fatty acids (MUFAs) are unsaturated fatty acids with one double bond and are derived from endogenous synthesis and dietary intake. Accumulating evidence has suggested that plasma and erythrocyte MUFA levels were associated with cardiometabolic disorders including cardiovascular disease (CVD), type 2 diabetes (T2D) and metabolic syndrome (MS). Previous genome-wide association studies (GWAS) have identified seven loci for plasma and erythrocyte palmitoleic acid and oleic acid levels in populations of European origin. To identify additional MUFA-associated loci and the potential causal variant at each locus, we performed ethnic-specific GWAS meta-analyses and trans-ethnic meta-analyses in over 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)>=61619;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 ~95kb) to five (covering ~20kb, 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 trans-ethnic meta-analyses. Pathway-based analyses suggested that the identified loci were enriched in unsaturated fatty acids metabolism and signaling pathways. Our findings provided novel insight into the genetic basis relevant to MUFA metabolism and biology.