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., Leach IM., 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., Neerincx PBT., Elbers CC., Francesco Palamara P., Pe’er I., Abdellaoui A., Kloosterman WP., van Oven M., Vermaat M., Li M., Laros JFJ., Stoneking M., de Knijff P., Kayser M., Veldink JH., van den Berg LH., Byelas H., den Dunnen JT., Dijkstra M., Amin N., Joeri van der Velde K., van Setten J., Kattenberg M., van Schaik BDC., Bot J., Nijman IJ., Mei H., Koval V., Ye K., Lameijer E-W., Moed MH., Hehir-Kwa JY., Handsaker RE., Sunyaev SR., Sohail M., Hormozdiari F., Marschall T., Schönhuth A., Guryev V., Suchiman HED., Wolffenbuttel BH., Platteel M., Pitts SJ., Potluri S., Cox DR., Li Q., Li Y., Du Y., Chen R., Cao H., Li N., Cao S., Wang J., Bovenberg JA., 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.
AbstractVariants 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.