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Nat Methods DOI:10.1038/nmeth.2997

Annotation of loci from genome-wide association studies using tissue-specific quantitative interaction proteomics.

Publication TypeJournal Article
Year of Publication2014
AuthorsLundby, A, Rossin, EJ, Steffensen, AB, Acha, MRav, Newton-Cheh, C, Pfeufer, A, Lynch, SN, Olesen, S-P, Brunak, S, Ellinor, PT, J Jukema, W, 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, PIW, Lage, K, Olsen, JV
Corporate AuthorsQT Interval International GWAS Consortium (QT-IGC)
JournalNat Methods
Date Published2014 Aug
KeywordsAnimals, Genome-Wide Association Study, Humans, Long QT Syndrome, Proteomics, Xenopus laevis, Zebrafish

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.


Alternate JournalNat. Methods
PubMed ID24952909
PubMed Central IDPMC4117722
Grant ListK24 HL105780 / HL / NHLBI NIH HHS / United States
R01 HL092577 / HL / NHLBI NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
T32GM007753 / GM / NIGMS NIH HHS / United States
P01 HD068250 / HD / NICHD NIH HHS / United States