Genome of The Netherlands population-specific imputations identify an ABCA6 variant associated with cholesterol levels.
van Leeuwen EM., Karssen LC., Deelen J., Isaacs A., Medina-Gomez C., Mbarek H., Kanterakis A., Trompet S., Postmus I., Verweij N., van Enckevort DJ., Huffman JE., White CC., Feitosa MF., Bartz TM., Manichaikul A., Joshi PK., Peloso GM., Deelen P., van Dijk F., Willemsen G., de Geus EJ., Milaneschi Y., Penninx BWJH., Francioli LC., Menelaou A., Pulit SL., Rivadeneira F., Hofman A., Oostra BA., Franco OH., Mateo Leach I., Beekman M., de Craen AJM., Uh H-W., Trochet H., Hocking LJ., Porteous DJ., Sattar N., Packard CJ., Buckley BM., Brody JA., Bis JC., Rotter JI., Mychaleckyj JC., Campbell H., Duan Q., Lange LA., Wilson JF., Hayward C., Polasek O., Vitart V., Rudan I., Wright AF., Rich SS., Psaty BM., Borecki IB., Kearney PM., Stott DJ., Adrienne Cupples L., Genome of The Netherlands Consortium None., Jukema JW., van der Harst P., Sijbrands EJ., Hottenga J-J., Uitterlinden AG., Swertz MA., van Ommen G-JB., de Bakker PIW., Eline Slagboom P., Boomsma DI., Wijmenga C., van Duijn CM.
Variants associated with blood lipid levels may be population-specific. To identify low-frequency variants associated with this phenotype, population-specific reference panels may be used. Here we impute nine large Dutch biobanks (~35,000 samples) with the population-specific reference panel created by the Genome of The Netherlands Project and perform association testing with blood lipid levels. We report the discovery of five novel associations at four loci (P value <6.61 × 10(-4)), including a rare missense variant in ABCA6 (rs77542162, p.Cys1359Arg, frequency 0.034), which is predicted to be deleterious. The frequency of this ABCA6 variant is 3.65-fold increased in the Dutch and its effect (βLDL-C=0.135, βTC=0.140) is estimated to be very similar to those observed for single variants in well-known lipid genes, such as LDLR.