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

Alicia Lundby, Elizabeth J. Rossin, Annette B. Steffensen, Moshe Ray Acha, Christopher Newton-Cheh, Arne Pfeufer, Stacey N. Lyneh, Søren-Peter Olesen, Søren Brunak, Patrick T. Ellinor, J. Wouter Jukema, Stella Trompet, Ian Ford, Peter W. Macfarlane, Bouwe P. Krijthe, Albert Hofman, Andre G. Uitterlinden, Bruno H. Stricker, Hendrik M. Nathoe, Wilko SpieringMark J. Daly, Folkert W. Asselbergs, Pim van der Harst, David J. Milan, Paul I. W. de Bakker, Kasper Lage, Jesper V. Olsen

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    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 (LOTS). We integrated the LOTS 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 LOTS 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.
    Original languageEnglish
    JournalNature Methods
    Issue number8
    Pages (from-to)868-874
    Number of pages7
    Publication statusPublished - 2014

    Cite this

    Lundby, A., Rossin, E. J., Steffensen, A. B., Acha, M. R., Newton-Cheh, C., Pfeufer, A., Lyneh, S. N., Olesen, S-P., Brunak, S., Ellinor, P. T., Jukema, J. W., Trompet, S., Ford, I., Macfarlane, P. W., Krijthe, B. P., Hofman, A., Uitterlinden, A. G., Stricker, B. H., Nathoe, H. M., ... Olsen, J. V. (2014). Annotation of loci from genome-wide association studies using tissue-specific quantitative interaction proteomics. Nature Methods, 11(8), 868-874.