Variants near FOXE1 are associated with hypothyroidism and other thyroid conditions

Using electronic medical records for genome- and phenome-wide studies

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 & 14 others Martha Matsumoto, Peter A. Kopp, Katherine M. Newton, Gail P. Jarvik, Rongling Li, Teri A. Manolio, Iftikhar Jan Kullo, Christopher G. Chute, Rex L. Chisholm, Eric B. Larson, Catherine A. McCarty, Daniel R. Masys, Dan M. Roden, Mariza De Andrade

Research output: Contribution to journalArticle

157 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)529-542
Number of pages14
JournalAmerican Journal of Human Genetics
Volume89
Issue number4
DOIs
StatePublished - Oct 7 2011

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Electronic Health Records
Hypothyroidism
Thyroid Gland
Odds Ratio
Genome
Thyroiditis
Thyrotoxicosis
Genome-Wide Association Study
Graves Disease
Thyroid Diseases
Linkage Disequilibrium
Goiter
Genetic Association Studies
Genomics
Thyroid Neoplasms
Single Nucleotide Polymorphism
Genotype
Phenotype
Costs and Cost Analysis

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Variants near FOXE1 are associated with hypothyroidism and other thyroid conditions : Using electronic medical records for genome- and phenome-wide studies. / Denny, Joshua C.; Crawford, Dana C.; Ritchie, Marylyn D.; Bielinski, Suzette J; Basford, Melissa A.; Bradford, Yuki; Chai, High Seng; Bastarache, Lisa; Zuvich, Rebecca; Peissig, Peggy; Carrell, David; Ramirez, Andrea H.; Pathak, Jyotishman; Wilke, Russell A.; Rasmussen, Luke; Wang, Xiaoming; Pacheco, Jennifer A.; Kho, Abel N.; Hayes, M. Geoffrey; Weston, Noah; Matsumoto, Martha; Kopp, Peter A.; Newton, Katherine M.; Jarvik, Gail P.; Li, Rongling; Manolio, Teri A.; Kullo, Iftikhar Jan; Chute, Christopher G.; Chisholm, Rex L.; Larson, Eric B.; McCarty, Catherine A.; Masys, Daniel R.; Roden, Dan M.; De Andrade, Mariza.

In: American Journal of Human Genetics, Vol. 89, No. 4, 07.10.2011, p. 529-542.

Research output: Contribution to journalArticle

Denny, JC, Crawford, DC, Ritchie, MD, Bielinski, SJ, Basford, MA, Bradford, Y, Chai, HS, Bastarache, L, Zuvich, R, Peissig, P, Carrell, D, Ramirez, AH, Pathak, J, Wilke, RA, Rasmussen, L, Wang, X, Pacheco, JA, Kho, AN, Hayes, MG, Weston, N, Matsumoto, M, Kopp, PA, Newton, KM, Jarvik, GP, Li, R, Manolio, TA, Kullo, IJ, Chute, CG, Chisholm, RL, Larson, EB, McCarty, CA, Masys, DR, Roden, DM & De Andrade, M 2011, 'Variants near FOXE1 are associated with hypothyroidism and other thyroid conditions: Using electronic medical records for genome- and phenome-wide studies', American Journal of Human Genetics, vol. 89, no. 4, pp. 529-542. https://doi.org/10.1016/j.ajhg.2011.09.008
Denny, Joshua C. ; Crawford, Dana C. ; Ritchie, Marylyn D. ; Bielinski, Suzette J ; Basford, Melissa A. ; Bradford, Yuki ; Chai, High Seng ; Bastarache, Lisa ; Zuvich, Rebecca ; Peissig, Peggy ; Carrell, David ; Ramirez, Andrea H. ; Pathak, Jyotishman ; Wilke, Russell A. ; Rasmussen, Luke ; Wang, Xiaoming ; Pacheco, Jennifer A. ; Kho, Abel N. ; Hayes, M. Geoffrey ; Weston, Noah ; Matsumoto, Martha ; Kopp, Peter A. ; Newton, Katherine M. ; Jarvik, Gail P. ; Li, Rongling ; Manolio, Teri A. ; Kullo, Iftikhar Jan ; Chute, Christopher G. ; Chisholm, Rex L. ; Larson, Eric B. ; McCarty, Catherine A. ; Masys, Daniel R. ; Roden, Dan M. ; De Andrade, Mariza. / Variants near FOXE1 are associated with hypothyroidism and other thyroid conditions : Using electronic medical records for genome- and phenome-wide studies. In: American Journal of Human Genetics. 2011 ; Vol. 89, No. 4. pp. 529-542.
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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.",
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T1 - Variants near FOXE1 are associated with hypothyroidism and other thyroid conditions

T2 - Using electronic medical records for genome- and phenome-wide studies

AU - Denny, Joshua C.

AU - Crawford, Dana C.

AU - Ritchie, Marylyn D.

AU - Bielinski, Suzette J

AU - Basford, Melissa A.

AU - Bradford, Yuki

AU - Chai, High Seng

AU - Bastarache, Lisa

AU - Zuvich, Rebecca

AU - Peissig, Peggy

AU - Carrell, David

AU - Ramirez, Andrea H.

AU - Pathak, Jyotishman

AU - Wilke, Russell A.

AU - Rasmussen, Luke

AU - Wang, Xiaoming

AU - Pacheco, Jennifer A.

AU - Kho, Abel N.

AU - Hayes, M. Geoffrey

AU - Weston, Noah

AU - Matsumoto, Martha

AU - Kopp, Peter A.

AU - Newton, Katherine M.

AU - Jarvik, Gail P.

AU - Li, Rongling

AU - Manolio, Teri A.

AU - Kullo, Iftikhar Jan

AU - Chute, Christopher G.

AU - Chisholm, Rex L.

AU - Larson, Eric B.

AU - McCarty, Catherine A.

AU - Masys, Daniel R.

AU - Roden, Dan M.

AU - De Andrade, Mariza

PY - 2011/10/7

Y1 - 2011/10/7

N2 - 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.

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