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

Nat Methods
Authors
Keywords
Abstract

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.

Year of Publication
2014
Journal
Nat Methods
Volume
11
Issue
8
Pages
868-74
Date Published
2014 Aug
ISSN
1548-7105
URL
DOI
10.1038/nmeth.2997
PubMed ID
24952909
PubMed Central ID
PMC4117722
Links
Grant list
K24 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