eMERGE Phenome-Wide Association Study (PheWAS) identifies clinical associations and pleiotropy for stop-gain variants
Date
2016
Journal Title
Journal ISSN
Volume Title
Publisher
BioMed Central
Abstract
Background: We explored premature stop-gain variants to test the hypothesis that variants, which are likely to
have a consequence on protein structure and function, will reveal important insights with respect to the
phenotypes associated with them. We performed a phenome-wide association study (PheWAS) exploring the
association between a selected list of functional stop-gain genetic variants (variation resulting in truncated proteins
or in nonsense-mediated decay) and an extensive group of diagnoses to identify novel associations and uncover
potential pleiotropy.
Results: In this study, we selected 25 stop-gain variants: 5 stop-gain variants with previously reported phenotypic
associations, and a set of 20 putative stop-gain variants identified using dbSNP. For the PheWAS, we used data
from the electronic MEdical Records and GEnomics (eMERGE) Network across 9 sites with a total of 41,057
unrelated patients. We divided all these samples into two datasets by equal proportion of eMERGE site, sex, race,
and genotyping platform. We calculated single effect associations between these 25 stop-gain variants and ICD-9
defined case-control diagnoses. We also performed stratified analyses for samples of European and African ancestry.
Associations were adjusted for sex, site, genotyping platform and the first three principal components to account
for global ancestry. We identified previously known associations, such as variants in LPL associated with
hyperglyceridemia indicating that our approach was robust. We also found a total of three significant associations
with p < 0.01 in both datasets, with the most significant replicating result being LPL SNP rs328 and ICD-9 code 272.
1 “Disorder of Lipoid metabolism” (pdiscovery = 2.59x10-6, preplicating = 2.7x10-4). The other two significant replicated
associations identified by this study are: variant rs1137617 in KCNH2 gene associated with ICD-9 code category 244
“Acquired Hypothyroidism” (pdiscovery = 5.31x103, preplicating = 1.15x10-3) and variant rs12060879 in DPT gene
associated with ICD-9 code category 996 “Complications peculiar to certain specified procedures” (pdiscovery = 8.
65x103, preplicating = 4.16x10-3).
Description
CITATION: Verma, A., et al. 2016. eMERGE Phenome-Wide Association Study (PheWAS) identifies clinical associations and pleiotropy for stop-gain variants. BMC Medical Genomics, 9:32, doi:10.1186/s12920-016-0191-8.
The original publication is available at https://bmcmedgenomics.biomedcentral.com
The original publication is available at https://bmcmedgenomics.biomedcentral.com
Keywords
Medical records and genomics network, Phenome-Wide Association Study, Phenotypes, Pleiotropy
Citation
Verma, A., et al. 2016. eMERGE Phenome-Wide Association Study (PheWAS) identifies clinical associations and pleiotropy for stop-gain variants. BMC Medical Genomics, 9:32, doi:10.1186/s12920-016-0191-8