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.

Genetic effects on gene expression across human tissues

“…16). The 9q22 locus has previously been linked to multiple thyroid-specific diseases including goitre, hypothyroidism and thyroid cancer 48,49 , and loss-of- function mutations in a thyroid-specific transcription factor at this locus, FOXE1 , manifest as ectopic thyroid tissue or cleft palate in developing mice. However, the mechanism of any cis -effects of these trans -eVariants remains uncertain from the GTEx data; a post hoc analysis demonstrated that PEER correction removed broad regulatory signals from the 9q22 locus, and particularly from cis - and trans -eQTL signals for FOXE1 (Supplementary Information 17).…”

Evidence for Extensive Pleiotropy Among Pharmacogenes

“…We used the Illumina ® Absorption, Distribution, Metabolism and Elimination (ADME) Core Panel (CA, USA) [33] to genotype 6067 European-American and 762 AfricanAmerican patients linked to deidentified electronic health records (EHRs). The EHR is a source of highdimensional clinical data, well suited for studying pleiotropic effects across a wide spectrum of clinical phenotypes [34,35].…”

Integration of Complex Data Sources to Provide Biologic Insight into Pulmonary Vascular Disease (2015 Grover Conference Series)

“…Examples of discoveries using EMR-linked DNA biobanks include variants associated with PR segment duration on electrocardiography and variants associated with white blood cell count. [27][28][29] Most eMERGE sites have employed an "opt-in" approach to DNA collection, in which patients with targeted phenotypes are consented for blood collection. An advantage of this approach is that patient identifiers can be maintained, which allows recontact of patients (and potentially family members) for future studies.…”