Meta-analysis of 49 549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels

Elisabeth M. van Leeuwen, Aniko Sabo, Joshua C. Bis, Jennifer E. Huffman, Ani Manichaikul, Albert V. Smith, Mary F. Feitosa, Serkalem Demissie, Peter K. Joshi, Qing Duan, Jonathan Marten, Jan B. van Klinken, Ida Surakka, Ilja M. Nolte, Weihua Zhang, Hamdi Mbarek, Ruifang Li-Gao, Stella Trompet, Niek Verweij, Evangelos EvangelouLeo-Pekka Lyytikainen, Bamidele O. Tayo, Joris Deelen, Peter J. van der Most, Sander W. van der Laan, Dan E. Arking, Alanna Morrison, Abbas Dehghan, Oscar H. Franco, Albert Hofman, Fernando Rivadeneira, Eric J. Sijbrands, Andre G. Uitterlinden, Josyf C. Mychaleckyj, Archie Campbell, Lynne J. Hocking, Sandosh Padmanabhan, Jennifer A. Brody, Kenneth M. Rice, Charles C. White, Tamara Harris, Aaron Isaacs, Harry Campbell, Leslie A. Lange, Igor Rudan, Ivana Kolcic, Pau Navarro, Tatijana Zemunik, Veikko Salomaa, Angad S. Kooner, Jaspal S. Kooner, Benjamin Lehne, William R. Scott, Sian-Tsung Tan, Eco J. de Geus, Yuri Milaneschi, Brenda W. J. H. Penninx, Gonneke Willemsen, Renee de Mutsert, Ian Ford, Ron T. Gansevoort, Marcelo P. Segura-Lepe, Olli T. Raitakari, Jorma S. Viikari, Kjell Nikus, Terrence Forrester, Colin A. McKenzie, Anton J. M. de Craen, Hester M. de Ruijter, Gerard Pasterkamp, Harold Snieder, Albertine J. Oldehinkel, P. Eline Slagboom, Richard S. Cooper, Mika Kahonen, Terho Lehtimaki, Paul Elliott, Pim van der Harst, J. Wouter Jukema, Dennis O. Mook-Kanamori, Dorret I. Boomsma, John C. Chambers, Morris Swertz, Samuli Ripatti, Ko Willems van Dijk, Veronique Vitart, Ozren Polasek, Caroline Hayward, James G. Wilson, James F. Wilson, Vilmundur Gudnason, Stephen S. Rich, Bruce M. Psaty, Ingrid B. Borecki, Eric Boerwinkle, Jerome I. Rotter, L. Adrienne Cupples, Cornelia M. van Duijn*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

23 Citations (Web of Science)

Abstract

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.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.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.This study illustrates that GWAS with high-scale imputation may still help us unravel the biological mechanism behind circulating lipid levels.Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
Original languageEnglish
Pages (from-to)441-449
JournalJournal of Medical Genetics
Volume53
Issue number7
DOIs
Publication statusPublished - Jul 2016

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