Genome of the Netherlands population-specific imputations identify an ABCA6 variant associated with cholesterol levels
Authors: van Leeuwen Elisabeth M. , Karssen Lennart C. , Deelen Joris , Isaacs Aaron , Medina-Gomez Carolina , Mbarek Hamdi , Kanterakis Alexandros , Trompet Stella , Postmus Iris , Verweij Niek , van Enckevort David J. , Huffman Jennifer E. , White Charles C. , Feitosa Mary F. , Bartz Traci M. , Manichaikul Ani , Joshi Peter K. , Peloso Gina M. , Deelen Patrick , van Dijk Freerk , Willemsen Gonneke , de Geus Eco J. , Milaneschi Yuri , Penninx Brenda W.J.H. , Francioli Laurent C. , Menelaou Androniki , Pulit Sara L. , Rivadeneira Fernando , Hofman Albert , Oostra Ben A. , Franco Oscar H. , Leach Irene Mateo , Beekman Marian , de Craen Anton J.M. , Uh Hae-Won , Trochet Holly , Hocking Lynne J. , Porteous David J. , Sattar Naveed , Packard Chris J. , Buckley Brendan M. , Brody Jennifer A. , Bis Joshua C. , Rotter Jerome I. , Mychaleckyj Josyf C. , Campbell Harry , Duan Qing , Lange Leslie A. , Wilson James F. , Hayward Caroline , Polasek Ozren , Vitart Veronique , Rudan Igor , Wright Alan F. , Rich Stephen S. , Psaty Bruce M. , Borecki Ingrid B. , Kearney Patricia M. , Stott David J. , Adrienne Cupples L. ,   The Genome of the Netherlands Consortium, Neerincx Pieter B.T. , Elbers Clara C. , Francesco Palamara Pier , Pe’er Itsik , Abdellaoui Abdel , Kloosterman Wigard P. , van Oven Mannis , Vermaat Martijn , Li Mingkun , Laros Jeroen F.J. , Stoneking Mark , de Knijff Peter , Kayser Manfred , Veldink Jan H. , van den Berg Leonard H. , Byelas Heorhiy , den Dunnen Johan T. , Dijkstra Martijn , Amin Najaf , Joeri van der Velde K. , van Setten Jessica , Kattenberg Mathijs , van Schaik Barbera D.C. , Bot Jan , Nijman Isaäc J. , Mei Hailiang , Koval Vyacheslav , Ye Kai , Lameijer Eric-Wubbo , Moed Matthijs H. , Hehir-Kwa Jayne Y. , Handsaker Robert E. , Sunyaev Shamil R. , Sohail Mashaal , Hormozdiari Fereydoun , Marschall Tobias , Schönhuth Alexander , Guryev Victor , Suchiman H. Eka D. , Wolffenbuttel Bruce H. , Platteel Mathieu , Pitts Steven J. , Potluri Shobha , Cox David R. , Li Qibin , Li Yingrui , Du Yuanping , Chen Ruoyan , Cao Hongzhi , Li Ning , Cao Sujie , Wang Jun , Bovenberg Jasper A. , Jukema J. Wouter , van der Harst Pim , Sijbrands Eric J. , Hottenga Jouke-Jan , Uitterlinden Andre G. , Swertz Morris A. , van Ommen Gert-Jan B. , de Bakker Paul I.W. , Eline Slagboom P. , Boomsma Dorret I. , Wijmenga Cisca , van Duijn Cornelia M. 
Published: March 2015

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.