title: A genetic risk score for thyroid peroxidase antibodies associates with clinical thyroid disease in community-based populations.
abstract: BACKGROUND
  Antibodies against thyroid peroxidase (TPOAbs) are detected in 90% of all patients with Hashimoto thyroiditis, the most common cause of hypothyroidism. Hypothyroidism is associated with a range of adverse outcomes. The current knowledge of its genetic underpinnings is limited.
  
  
  OBJECTIVE
  The purpose of this study was to identify novel genetic variants associated with TPOAb concentrations and positivity using genome-wide association data and to characterize their association with thyroid function and disease.
  
  
  METHODS
  We studied European ancestry participants of 3 independent prospective population-based studies: Atherosclerosis Risk In Communities study (n = 7524), Study of Health in Pomerania (n = 3803), and Study of Health in Pomerania-TREND (n = 887).
  
  
  METHODS
  Single nucleotide polymorphisms (SNPs), individually and combined into a genetic risk score (GRS), were examined.
  
  
  RESULTS
  The main outcomes were TPOAb concentrations and positivity, thyroid hormone concentrations (TSH, free T4), and clinical thyroid diseases (subclinical and overt hypothyroidism and goiter).
  
  
  RESULTS
  Significantly associated single nucleotide polymorphisms (P < 5 · 10(-8)) mapped into 4 genomic regions not previously implicated for TPOAbs (RERE, extended HLA region) and into 5 previously described loci. A higher Genetic Risk Score (GRS) based on these 9 SNPs showed strong and graded associations with higher TPOAb, TSH, and lower free T4 concentrations (P < .001). Compared with individuals in the lowest GRS quartile, those in the highest quartile had 1.80-fold higher odds of subclinical hypothyroidism (95% confidence interval, 1.27-2.55) and 1.89-fold higher odds of overt hypothyroidism (95% confidence interval, 1.24-2.87).
  
  
  CONCLUSIONS
  The identification of 4 novel genetic loci associated with TPOAb concentrations and positivity gives further insight into the genetic underpinnings of hypothyroidism. A GRS showed strong and graded associations with markers of thyroid function and disease in independent population-based studies.
authors.affiliation: Renal Division (U.T.S., Y.L., A.K.), Department of Medicine IV, Medical Center, University of Freiburg, 79106 Freiburg, Germany; Department of Internal Medicine and Rotterdam Thyroid Center (M.M., L.C., A.G.U., R.P.P.) and Department of Epidemiology (L.C., A.H.), Erasmus Medical Center, 3015 GE Rotterdam, The Netherlands; Institute for Community Medicine (A.T., H.V.), Interfaculty Institute for Genetics and Functional Genomics (G.H.), and Institute of Clinical Chemistry and Laboratory Medicine (M.N.), University Medicine Greifswald, 17475 Greifswald, Germany; and Department of Epidemiology (N.D., E.S., A.K.), Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205.
authors.forename: Ulla T
authors.initials: UT
authors.lastname: Schultheiss
authors.forename: Alexander
authors.initials: A
authors.lastname: Teumer
authors.forename: Marco
authors.initials: M
authors.lastname: Medici
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.forename: Natalie
authors.initials: N
authors.lastname: Daya
authors.forename: Layal
authors.initials: L
authors.lastname: Chaker
authors.forename: Georg
authors.initials: G
authors.lastname: Homuth
authors.forename: Andre G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: Matthias
authors.initials: M
authors.lastname: Nauck
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Selvin
authors.forename: Henry
authors.initials: H
authors.lastname: Völzke
authors.forename: Robin P
authors.initials: RP
authors.lastname: Peeters
authors.forename: Anna
authors.initials: A
authors.lastname: Köttgen
mesh_terms: D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007453:Iodide Peroxidase / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012307:Risk Factors; D013959:Thyroid Diseases / Q000097:blood / Q000235:genetics* / Q000276:immunology*; D013972:Thyrotropin / Q000097:blood; D013974:Thyroxine / Q000097:blood
chemical_list: D013972:Thyrotropin; D007453:Iodide Peroxidase; D013974:Thyroxine