Document Detail


Variants near FOXE1 are associated with hypothyroidism and other thyroid conditions: using electronic medical records for genome- and phenome-wide studies.
MedLine Citation:
PMID:  21981779     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
We repurposed existing genotypes in DNA biobanks across the Electronic Medical Records and Genomics network to perform a genome-wide association study for primary hypothyroidism, the most common thyroid disease. Electronic selection algorithms incorporating billing codes, laboratory values, text queries, and medication records identified 1317 cases and 5053 controls of European ancestry within five electronic medical records (EMRs); the algorithms' positive predictive values were 92.4% and 98.5% for cases and controls, respectively. Four single-nucleotide polymorphisms (SNPs) in linkage disequilibrium at 9q22 near FOXE1 were associated with hypothyroidism at genome-wide significance, the strongest being rs7850258 (odds ratio [OR] 0.74, p = 3.96 × 10(-9)). This association was replicated in a set of 263 cases and 1616 controls (OR = 0.60, p = 5.7 × 10(-6)). A phenome-wide association study (PheWAS) that was performed on this locus with 13,617 individuals and more than 200,000 patient-years of billing data identified associations with additional phenotypes: thyroiditis (OR = 0.58, p = 1.4 × 10(-5)), nodular (OR = 0.76, p = 3.1 × 10(-5)) and multinodular (OR = 0.69, p = 3.9 × 10(-5)) goiters, and thyrotoxicosis (OR = 0.76, p = 1.5 × 10(-3)), but not Graves disease (OR = 1.03, p = 0.82). Thyroid cancer, previously associated with this locus, was not significantly associated in the PheWAS (OR = 1.29, p = 0.09). The strongest association in the PheWAS was hypothyroidism (OR = 0.76, p = 2.7 × 10(-13)), which had an odds ratio that was nearly identical to that of the curated case-control population in the primary analysis, providing further validation of the PheWAS method. Our findings indicate that EMR-linked genomic data could allow discovery of genes associated with many diseases without additional genotyping cost.
Authors:
Joshua C Denny; Dana C Crawford; Marylyn D Ritchie; Suzette J Bielinski; Melissa A Basford; Yuki Bradford; High Seng Chai; Lisa Bastarache; Rebecca Zuvich; Peggy Peissig; David Carrell; Andrea H Ramirez; Jyotishman Pathak; Russell A Wilke; Luke Rasmussen; Xiaoming Wang; Jennifer A Pacheco; Abel N Kho; M Geoffrey Hayes; Noah Weston; Martha Matsumoto; Peter A Kopp; Katherine M Newton; Gail P Jarvik; Rongling Li; Teri A Manolio; Iftikhar J Kullo; Christopher G Chute; Rex L Chisholm; Eric B Larson; Catherine A McCarty; Daniel R Masys; Dan M Roden; Mariza de Andrade
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  American journal of human genetics     Volume:  89     ISSN:  1537-6605     ISO Abbreviation:  Am. J. Hum. Genet.     Publication Date:  2011 Oct 
Date Detail:
Created Date:  2011-10-10     Completed Date:  2011-12-12     Revised Date:  2014-09-24    
Medline Journal Info:
Nlm Unique ID:  0370475     Medline TA:  Am J Hum Genet     Country:  United States    
Other Details:
Languages:  eng     Pagination:  529-42     Citation Subset:  IM    
Copyright Information:
Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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MeSH Terms
Descriptor/Qualifier:
Aged
Algorithms
Female
Forkhead Transcription Factors / genetics*
Genetic Markers
Genetic Variation
Genome
Genome-Wide Association Study
Genotype
Humans
Hypothyroidism / genetics*
Male
Medical Records Systems, Computerized
Middle Aged
Phenotype
Predictive Value of Tests
Grant Support
ID/Acronym/Agency:
HG-004735/HG/NHGRI NIH HHS; P50CA102701/CA/NCI NIH HHS; R01 LM010685/LM/NLM NIH HHS; U01 HG004599/HG/NHGRI NIH HHS; U01 HG004603/HG/NHGRI NIH HHS; U01 HG004608/HG/NHGRI NIH HHS; U01 HG004609/HG/NHGRI NIH HHS; U01 HG004609-04/HG/NHGRI NIH HHS; U01 HG004610/HG/NHGRI NIH HHS; U01-HG-004599/HG/NHGRI NIH HHS; U01-HG-004603/HG/NHGRI NIH HHS; U01-HG-004608/HG/NHGRI NIH HHS; U01-HG-004609/HG/NHGRI NIH HHS; U01-HG-004610/HG/NHGRI NIH HHS
Chemical
Reg. No./Substance:
0/FOXE1 protein, human; 0/Forkhead Transcription Factors; 0/Genetic Markers
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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