Dataset Information

Variants near FOXE1 are associated with hypothyroidism and other thyroid conditions: using electronic medical records for genome- and phenome-wide studies.

ABSTRACT: 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.

SUBMITTER: Denny JC

PROVIDER: S-EPMC3188836 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Variants near FOXE1 are associated with hypothyroidism and other thyroid conditions: using electronic medical records for genome- and phenome-wide studies.

Denny Joshua C JC Crawford Dana C DC Ritchie Marylyn D MD Bielinski Suzette J SJ Basford Melissa A MA Bradford Yuki Y Chai High Seng HS Bastarache Lisa L Zuvich Rebecca R Peissig Peggy P Carrell David D Ramirez Andrea H AH Pathak Jyotishman J Wilke Russell A RA Rasmussen Luke L Wang Xiaoming X Pacheco Jennifer A JA Kho Abel N AN Hayes M Geoffrey MG Weston Noah N Matsumoto Martha M Kopp Peter A PA Newton Katherine M KM Jarvik Gail P GP Li Rongling R Manolio Teri A TA Kullo Iftikhar J IJ Chute Christopher G CG Chisholm Rex L RL Larson Eric B EB McCarty Catherine A CA Masys Daniel R DR Roden Dan M DM de Andrade Mariza M

American journal of human genetics 20111001 4

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% ...[more]

PMID: 21981779

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Project description:ImportanceLarge-scale DNA sequencing identifies incidental rare variants in established Mendelian disease genes, but the frequency of related clinical phenotypes in unselected patient populations is not well established. Phenotype data from electronic medical records (EMRs) may provide a resource to assess the clinical relevance of rare variants.ObjectiveTo determine the clinical phenotypes from EMRs for individuals with variants designated as pathogenic by expert review in arrhythmia susceptibility genes.Design, setting, and participantsThis prospective cohort study included 2022 individuals recruited for nonantiarrhythmic drug exposure phenotypes from October 5, 2012, to September 30, 2013, for the Electronic Medical Records and Genomics Network Pharmacogenomics project from 7 US academic medical centers. Variants in SCN5A and KCNH2, disease genes for long QT and Brugada syndromes, were assessed for potential pathogenicity by 3 laboratories with ion channel expertise and by comparison with the ClinVar database. Relevant phenotypes were determined from EMRs, with data available from 2002 (or earlier for some sites) through September 10, 2014.ExposuresOne or more variants designated as pathogenic in SCN5A or KCNH2.Main outcomes and measuresArrhythmia or electrocardiographic (ECG) phenotypes defined by International Classification of Diseases, Ninth Revision (ICD-9) codes, ECG data, and manual EMR review.ResultsAmong 2022 study participants (median age, 61 years [interquartile range, 56-65 years]; 1118 [55%] female; 1491 [74%] white), a total of 122 rare (minor allele frequency <0.5%) nonsynonymous and splice-site variants in 2 arrhythmia susceptibility genes were identified in 223 individuals (11% of the study cohort). Forty-two variants in 63 participants were designated potentially pathogenic by at least 1 laboratory or ClinVar, with low concordance across laboratories (Cohen κ = 0.26). An ICD-9 code for arrhythmia was found in 11 of 63 (17%) variant carriers vs 264 of 1959 (13%) of those without variants (difference, +4%; 95% CI, -5% to +13%; P = .35). In the 1270 (63%) with ECGs, corrected QT intervals were not different in variant carriers vs those without (median, 429 vs 439 milliseconds; difference, -10 milliseconds; 95% CI, -16 to +3 milliseconds; P = .17). After manual review, 22 of 63 participants (35%) with designated variants had any ECG or arrhythmia phenotype, and only 2 had corrected QT interval longer than 500 milliseconds.Conclusions and relevanceAmong laboratories experienced in genetic testing for cardiac arrhythmia disorders, there was low concordance in designating SCN5A and KCNH2 variants as pathogenic. In an unselected population, the putatively pathogenic genetic variants were not associated with an abnormal phenotype. These findings raise questions about the implications of notifying patients of incidental genetic findings.

Dataset Information

Variants near FOXE1 are associated with hypothyroidism and other thyroid conditions: using electronic medical records for genome- and phenome-wide studies.

Publications

Variants near FOXE1 are associated with hypothyroidism and other thyroid conditions: using electronic medical records for genome- and phenome-wide studies.

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