Lundby A, Rossin EJ, Steffensen AB, Acha MR, Newton-Cheh C, Pfeufer A, Lynch SN; QT Interval International GWAS Consortium (QT-IGC), Olesen SP, Brunak S, Ellinor PT, Jukema JW, Trompet S, Ford I, Macfarlane PW, Krijthe BP, Hofman A, Uitterlinden AG, Stricker BH, Nathoe HM, Spiering W, Daly MJ, Asselbergs FW, van der Harst P, Milan DJ, de Bakker PI, Lage K, Olsen JV.
Nat Methods. 2014 Aug;11(8):868-74. doi: 10.1038/nmeth.2997. Epub 2014 Jun 22.
Genome-wide association studies (GWAS) have identified thousands of loci associated with complex traits, but it is challenging to pinpoint causal genes in these loci and to exploit subtle association signals. We used tissue-specific quantitative interaction proteomics to map a network of five genes involved in the Mendelian disorder long QT syndrome (LQTS). We integrated the LQTS network with GWAS loci from the corresponding common complex trait, QT-interval variation, to identify candidate genes that were subsequently confirmed in Xenopus laevis oocytes and zebrafish. We used the LQTS protein network to filter weak GWAS signals by identifying single-nucleotide polymorphisms (SNPs) in proximity to genes in the network supported by strong proteomic evidence. Three SNPs passing this filter reached genome-wide significance after replication genotyping. Overall, we present a general strategy to propose candidates in GWAS loci for functional studies and to systematically filter subtle association signals using tissue-specific quantitative interaction proteomics.
http://www.nature.com/nmeth/journal/v11/n8/full/nmeth.2997.htmlUniversity of Copenhagen, The Danish National Research Foundation Centre for Cardiac Arrhythmia, The Broad Institute of Harvard and MIT, Massachusetts General Hospital, Harvard Medical School, Technical University of Munich, Technical University of Denmark, Leiden University Medical Center, ICIN - Netherlands Heart Institute, University of Glasgow, Netherlands Consortium for Healthy Aging, Erasmus Medical Center, University Medical Center Utrecht, University College London, University of Groningen,
United States
