Meta-analysis of 49 549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels.
van Leeuwen EM., Sabo A., Bis JC., Huffman JE., Manichaikul A., Smith AV., Feitosa MF., Demissie S., Joshi PK., Duan Q., Marten J., van Klinken JB., Surakka I., Nolte IM., Zhang W., Mbarek H., Li-Gao R., Trompet S., Verweij N., Evangelou E., Lyytikäinen L-P., Tayo BO., Deelen J., van der Most PJ., van der Laan SW., Arking DE., Morrison A., Dehghan A., Franco OH., Hofman A., Rivadeneira F., Sijbrands EJ., Uitterlinden AG., Mychaleckyj JC., Campbell A., Hocking LJ., Padmanabhan S., Brody JA., Rice KM., White CC., Harris T., Isaacs A., Campbell H., Lange LA., Rudan I., Kolcic I., Navarro P., Zemunik T., Salomaa V., LifeLines Cohort Study None., Kooner AS., Kooner JS., Lehne B., Scott WR., Tan S-T., de Geus EJ., Milaneschi Y., Penninx BWJH., Willemsen G., de Mutsert R., Ford I., Gansevoort RT., Segura-Lepe MP., Raitakari OT., Viikari JS., Nikus K., Forrester T., McKenzie CA., de Craen AJM., de Ruijter HM., CHARGE Lipids Working Group None., Pasterkamp G., Snieder H., Oldehinkel AJ., Slagboom PE., Cooper RS., Kähönen M., Lehtimäki T., Elliott P., van der Harst P., Jukema JW., Mook-Kanamori DO., Boomsma DI., Chambers JC., Swertz M., Ripatti S., Willems van Dijk K., Vitart V., Polasek O., Hayward C., Wilson JG., Wilson JF., Gudnason V., Rich SS., Psaty BM., Borecki IB., Boerwinkle E., Rotter JI., Cupples LA., van Duijn CM.
BACKGROUND: So far, more than 170 loci have been associated with circulating lipid levels through genome-wide association studies (GWAS). These associations are largely driven by common variants, their function is often not known, and many are likely to be markers for the causal variants. In this study we aimed to identify more new rare and low-frequency functional variants associated with circulating lipid levels. METHODS: We used the 1000 Genomes Project as a reference panel for the imputations of GWAS data from ∼60 000 individuals in the discovery stage and ∼90 000 samples in the replication stage. RESULTS: Our study resulted in the identification of five new associations with circulating lipid levels at four loci. All four loci are within genes that can be linked biologically to lipid metabolism. One of the variants, rs116843064, is a damaging missense variant within the ANGPTL4 gene. CONCLUSIONS: This study illustrates that GWAS with high-scale imputation may still help us unravel the biological mechanism behind circulating lipid levels.