title: Genetic variants associated with serum thyroid stimulating hormone (TSH) levels in European Americans and African Americans from the eMERGE Network.
abstract: Thyroid stimulating hormone (TSH) hormone levels are normally tightly regulated within an individual; thus, relatively small variations may indicate thyroid disease. Genome-wide association studies (GWAS) have identified variants in PDE8B and FOXE1 that are associated with TSH levels. However, prior studies lacked racial/ethnic diversity, limiting the generalization of these findings to individuals of non-European ethnicities. The Electronic Medical Records and Genomics (eMERGE) Network is a collaboration across institutions with biobanks linked to electronic medical records (EMRs). The eMERGE Network uses EMR-derived phenotypes to perform GWAS in diverse populations for a variety of phenotypes. In this report, we identified serum TSH levels from 4,501 European American and 351 African American euthyroid individuals in the eMERGE Network with existing GWAS data. Tests of association were performed using linear regression and adjusted for age, sex, body mass index (BMI), and principal components, assuming an additive genetic model. Our results replicate the known association of PDE8B with serum TSH levels in European Americans (rs2046045 p = 1.85×10-17, β = 0.09). FOXE1 variants, associated with hypothyroidism, were not genome-wide significant (rs10759944: p = 1.08×10-6, β = -0.05). No SNPs reached genome-wide significance in African Americans. However, multiple known associations with TSH levels in European ancestry were nominally significant in African Americans, including PDE8B (rs2046045 p = 0.03, β = -0.09), VEGFA (rs11755845 p = 0.01, β = -0.13), and NFIA (rs334699 p = 1.50×10-3, β = -0.17). We found little evidence that SNPs previously associated with other thyroid-related disorders were associated with serum TSH levels in this study. These results support the previously reported association between PDE8B and serum TSH levels in European Americans and emphasize the need for additional genetic studies in more diverse populations.
authors.affiliation: Center for Human Genetics Research, Vanderbilt University, Nashville, TN, United States of America.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Malinowski
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University, Nashville, TN, United States of America; Department of Medicine, Vanderbilt University, Nashville, TN, United States of America.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Denny
authors.affiliation: Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, United States of America.
authors.forename: Suzette J
authors.initials: SJ
authors.lastname: Bielinski
authors.affiliation: Office of Research, Vanderbilt University, Nashville, TN, United States of America.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Basford
authors.affiliation: Center for Human Genetics Research, Vanderbilt University, Nashville, TN, United States of America.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Bradford
authors.affiliation: Biomedical Informatics Research Center, Marshfield Clinic Research Foundation, Marshfield, WI, United States of America.
authors.forename: Peggy L
authors.initials: PL
authors.lastname: Peissig
authors.affiliation: Group Health Research Institute, Seattle, WA, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Carrell
authors.affiliation: Departments of Medicine (Medical Genetics) and Genome Sciences, University of Washington, Seattle, WA, United States of America.
authors.forename: David R
authors.initials: DR
authors.lastname: Crosslin
authors.affiliation: Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, United States of America.
authors.forename: Jyotishman
authors.initials: J
authors.lastname: Pathak
authors.affiliation: Biomedical Informatics Research Center, Marshfield Clinic Research Foundation, Marshfield, WI, United States of America.
authors.forename: Luke
authors.initials: L
authors.lastname: Rasmussen
authors.affiliation: Department of Medicine, Northwestern University, Chicago, IL, United States of America.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Pacheco
authors.affiliation: Department of Medicine, Northwestern University, Chicago, IL, United States of America.
authors.forename: Abel
authors.initials: A
authors.lastname: Kho
authors.affiliation: Group Health Research Institute, Seattle, WA, United States of America.
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Newton
authors.affiliation: Division of Genomic Medicine, National Human Genome Research Institute, Bethesda, MD, United States of America.
authors.forename: Rongling
authors.initials: R
authors.lastname: Li
authors.affiliation: Division of Cardiovascular Diseases, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, United States of America.
authors.forename: Iftikhar J
authors.initials: IJ
authors.lastname: Kullo
authors.affiliation: Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, United States of America.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Chute
authors.affiliation: Center for Genetic Medicine, Northwestern University, Chicago, IL, United States of America.
authors.forename: Rex L
authors.initials: RL
authors.lastname: Chisholm
authors.affiliation: Departments of Medicine (Medical Genetics) and Genome Sciences, University of Washington, Seattle, WA, United States of America.
authors.forename: Gail P
authors.initials: GP
authors.lastname: Jarvik
authors.affiliation: Group Health Research Institute, Seattle, WA, United States of America.
authors.forename: Eric B
authors.initials: EB
authors.lastname: Larson
authors.affiliation: Essentia Institute of Rural Health, Duluth, MN, United States of America.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: McCarty
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University, Nashville, TN, United States of America.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Masys
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, TN, United States of America; Department of Pharmacology, Vanderbilt University, Nashville, TN, United States of America.
authors.forename: Dan M
authors.initials: DM
authors.lastname: Roden
authors.affiliation: Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, United States of America.
authors.forename: Mariza
authors.initials: M
authors.lastname: de Andrade
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University, Nashville, TN, United States of America; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, United States of America; Center for Human Genetics Research, Vanderbilt University, Nashville, TN, United States of America.
authors.forename: Marylyn D
authors.initials: MD
authors.lastname: Ritchie
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, United States of America; Center for Human Genetics Research, Vanderbilt University, Nashville, TN, United States of America.
authors.forename: Dana C
authors.initials: DC
authors.lastname: Crawford
mesh_terms: D000349:Africa / Q000208:ethnology; D001741:Black or African American / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D015992:Body Mass Index; D057286:Electronic Health Records; D005060:Europe / Q000208:ethnology; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D013959:Thyroid Diseases / Q000097:blood / Q000235:genetics; D013972:Thyrotropin / Q000097:blood*; D044465:White People / Q000235:genetics*
chemical_list: D013972:Thyrotropin