title: Meta-analysis of two genome-wide association studies identifies four genetic loci associated with thyroid function.
abstract: Thyroid hormones play key roles in cellular growth, development and metabolism. Although there is a strong genetic influence on thyroid hormone levels, the genes involved are widely unknown. The levels of circulating thyroid hormones are tightly regulated by thyrotropin (TSH), which also represents the most important diagnostic marker for thyroid function. Therefore, in order to identify genetic loci associated with TSH levels, we performed a discovery meta-analysis of two genome-wide association studies including two cohorts from Germany, KORA (n = 1287) and SHIP (n = 2449), resulting in a total sample size of 3736. Four genetic loci at 5q13.3, 1p36, 16q23 and 4q31 were associated with serum TSH levels. The lead single-nucleotide polymorphisms of these four loci were located within PDE8B encoding phosphodiesterase 8B, upstream of CAPZB that encodes the β-subunit of the barbed-end F-actin-binding protein, in a former 'gene desert' that was recently demonstrated to encode a functional gene (LOC440389) associated with thyroid volume, and upstream of NR3C2 encoding the mineralocorticoid receptor. The latter association for the first time suggests the modulation of thyroid function by mineral corticoids. All four loci were replicated in three additional cohorts: the HUNT study from Norway (n = 1487) and the two German studies CARLA (CARLA, n = 1357) and SHIP-TREND (n = 883). Together, these four quantitative trait loci accounted for ∼3.3% of the variance in TSH serum levels. These results contribute to our understanding of genetic factors and physiological mechanisms mediating thyroid function.
authors.affiliation: Institute of Genetic Epidemiology, Helmholtz Zentrum Mu¨nchen, 85764 Neuherberg, Germany. rajesh.rawal@helmholtz-muenchen.de
authors.forename: Rajesh
authors.initials: R
authors.lastname: Rawal
authors.forename: Alexander
authors.initials: A
authors.lastname: Teumer
authors.forename: Henry
authors.initials: H
authors.lastname: Völzke
authors.forename: Henri
authors.initials: H
authors.lastname: Wallaschofski
authors.forename: Till
authors.initials: T
authors.lastname: Ittermann
authors.forename: Bjørn O
authors.initials: BO
authors.lastname: Åsvold
authors.forename: Trine
authors.initials: T
authors.lastname: Bjøro
authors.forename: Karin H
authors.initials: KH
authors.lastname: Greiser
authors.forename: Daniel
authors.initials: D
authors.lastname: Tiller
authors.forename: Karl
authors.initials: K
authors.lastname: Werdan
authors.forename: Henriette E
authors.initials: HE
authors.lastname: Meyer zu Schwabedissen
authors.forename: Angela
authors.initials: A
authors.lastname: Doering
authors.forename: Thomas
authors.initials: T
authors.lastname: Illig
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.forename: Christa
authors.initials: C
authors.lastname: Meisinger
authors.forename: Georg
authors.initials: G
authors.lastname: Homuth
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D005260:Female; D056426:Genetic Loci; D005828:Genetics, Population; D055106:Genome-Wide Association Study; D005858:Germany; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D018161:Receptors, Mineralocorticoid / Q000235:genetics; D013961:Thyroid Gland / Q000378:metabolism*; D013963:Thyroid Hormones / Q000097:blood; D013972:Thyrotropin / Q000097:blood / Q000378:metabolism*; D044465:White People / Q000235:genetics*
chemical_list: C561839:NR3C2 protein, human; D018161:Receptors, Mineralocorticoid; D013963:Thyroid Hormones; D013972:Thyrotropin; D015105:3',5'-Cyclic-AMP Phosphodiesterases; C468781:PDE8B protein, human