Journal article
Annotation of loci from genome-wide association studies using tissue-specific quantitative interaction proteomics
University of Copenhagen1
Erasmus University Medical Center2
The Netherlands Consortium for Healthy Ageing3
University Medical Centre Utrecht4
University College London5
University of Groningen6
Massachusetts General Hospital7
Massachusetts General Hospital/Harvard Medical School8
Technical University of Munich9
Department of Systems Biology, Technical University of Denmark10
Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark11
Leiden University12
Netherlands Heart Institute13
University of Glasgow14
...and 4 moreGenome-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.
Language: | English |
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Publisher: | Nature Publishing Group US |
Year: | 2014 |
Pages: | 868-874 |
Journal subtitle: | Techniques for Life Scientists and Chemists |
ISSN: | 15487105 and 15487091 |
Types: | Journal article |
DOI: | 10.1038/NMETH.2997 |
ORCIDs: | 0000-0002-1612-6041 , 0000-0003-0316-5866 , 0000-0002-4747-4938 , 0000-0002-2067-0533 , 0000-0002-2493-6407 and 0000-0001-7735-7858 |