Variants Near FOXE1 Are Associated with Hypothyroidism and Other Thyroid Conditions: Using Electronic Medical Records for Genome- and Phenome-wide Studies

被引：191

作者：

Denny, Joshua C. ^{[1
,2
]}

Crawford, Dana C. ^{[3
]}

Ritchie, Marylyn D. ^{[1
,3
,4
]}

Bielinski, Suzette J. ^{[5
]}

Basford, Melissa A. ^{[6
]}

Bradford, Yuki ^{[4
]}

Chai, High Seng ^{[7
]}

Bastarache, Lisa ^{[1
]}

Zuvich, Rebecca ^{[3
,4
]}

Peissig, Peggy ^{[8
]}

Carrell, David ^{[9
]}

Ramirez, Andrea H. ^{[2
]}

Pathak, Jyotishman ^{[7
]}

Wilke, Russell A. ^{[2
]}

Rasmussen, Luke ^{[8
]}

Wang, Xiaoming ^{[6
]}

Pacheco, Jennifer A. ^{[14
]}

Kho, Abel N. ^{[10
]}

Hayes, M. Geoffrey ^{[10
]}

Weston, Noah ^{[9
]}

Matsumoto, Martha ^{[7
]}

Kopp, Peter A. ^{[10
,14
]}

Newton, Katherine M. ^{[8
]}

Jarvik, Gail P. ^{[11
]}

Li, Rongling ^{[12
]}

Manolio, Teri A. ^{[12
]}

Kullo, Iftikhar J. ^{[13
]}

Chute, Christopher G. ^{[7
]}

Chisholm, Rex L. ^{[14
]}

Larson, Eric B. ^{[9
]}

McCarty, Catherine A. ^{[15
]}

Masys, Daniel R. ^{[1
]}

Roden, Dan M. ^{[2
,16
]}

de Andrade, Mariza ^{[7
]}

机构：

[1] Vanderbilt Univ, Dept Biomed Informat, Nashville, TN 37232 USA

[2] Vanderbilt Univ, Dept Med, Nashville, TN 37232 USA

[3] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA

[4] Vanderbilt Univ, Ctr Human Genet Res, Nashville, TN 37232 USA

[5] Mayo Clin, Dept Hlth Sci Res, Div Epidemiol, Rochester, MN 55905 USA

[6] Vanderbilt Univ, Res Off, Nashville, TN 37232 USA

[7] Mayo Clin, Div Biomed Stat & Informat, Dept Hlth Sci Res, Rochester, MN 55905 USA

[8] Marshfield Clin Res Fdn, Biomed Informat Res Ctr, Marshfield, WI 54449 USA

[9] Grp Hlth Res Inst, Seattle, WA 98101 USA

[10] Northwestern Univ, Dept Med, Chicago, IL 60611 USA

[11] Univ Washington, Med Ctr, Dept Med, Seattle, WA 98105 USA

[12] Natl Human Genome Res Inst, Off Populat Genom, Bethesda, MD 20892 USA

[13] Mayo Clin, Dept Med, Div Cardiovasc Dis, Rochester, MN 55905 USA

[14] Northwestern Univ, Dept Ctr Genet Med, Chicago, IL USA

[15] Marshfield Clin Res Fdn, Ctr Human Genet, Marshfield, WI 54449 USA

[16] Vanderbilt Univ, Dept Pharmacol, Nashville, TN 37232 USA

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2011年 / 89卷 / 04期

关键词：

PHYSICIAN ORDER ENTRY; SERUM TSH; CLEFT-PALATE; SUBCLINICAL HYPOTHYROIDISM; GENETIC SUSCEPTIBILITY; POPULATION; SCAN; LINKAGE; CANCER; HEALTH;

D O I：

10.1016/j.ajhg.2011.09.008

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 x 10(-9)). This association was replicated in a set of 263 cases and 1616 controls (OR = 0.60, p = 5.7 x 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 x 10(-5)), nodular (OR = 0.76, p = 3.1 x 10(-5)) and multinodular (OR = 0.69, p = 3.9 x 10(-5)) goiters, and thyrotoxicosis (OR = 0.76, p = 1.5 x 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 x 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.

引用

页码：529 / 542

页数：14