Common variants on 9q22.33 and 14q13.3 predispose to thyroid cancer in European populations.
In order to search for sequence variants conferring risk of thyroid cancer we conducted a genome-wide association study in 192 and 37,196 Icelandic cases and controls, respectively, followed by a replication study in individuals of European descent. Here we show that two common variants, located on 9q22.33 and 14q13.3, are associated with the disease. Overall, the strongest association signals were observed for rs965513 on 9q22.33 (OR = 1.75; P = 1.7 x 10(-27)) and rs944289 on 14q13.3 (OR = 1.37; P = 2.0 x 10(-9)). The gene nearest to the 9q22.33 locus is FOXE1 (TTF2) and NKX2-1 (TTF1) is among the genes located at the 14q13.3 locus. Both variants contribute to an increased risk of both papillary and follicular thyroid cancer. Approximately 3.7% of individuals are homozygous for both variants, and their estimated risk of thyroid cancer is 5.7-fold greater than that of noncarriers. In a study on a large sample set from the general population, both risk alleles are associated with low concentrations of thyroid stimulating hormone (TSH), and the 9q22.33 allele is associated with low concentration of thyroxin (T(4)) and high concentration of triiodothyronine (T(3)).
Gudmundsson
Julius
J
deCODE Genetics, Sturlugata 8, Reykjavik, Iceland. julius.gudmundsson@decode.is
Sulem
Patrick
P
Gudbjartsson
Daniel F
DF
Jonasson
Jon G
JG
Sigurdsson
Asgeir
A
Bergthorsson
Jon T
JT
He
Huiling
H
Blondal
Thorarinn
T
Geller
Frank
F
Jakobsdottir
Margret
M
Magnusdottir
Droplaug N
DN
Matthiasdottir
Sigurborg
S
Stacey
Simon N
SN
Skarphedinsson
Oskar B
OB
Helgadottir
Hafdis
H
Li
Wei
W
Nagy
Rebecca
R
Aguillo
Esperanza
E
Faure
Eduardo
E
Prats
Enrique
E
Saez
Berta
B
Martinez
Mariano
M
Eyjolfsson
Gudmundur I
GI
Bjornsdottir
Unnur S
US
Holm
Hilma
H
Kristjansson
Kristleifur
K
Frigge
Michael L
ML
Kristvinsson
Hoskuldur
H
Gulcher
Jeffrey R
JR
Jonsson
Thorvaldur
T
Rafnar
Thorunn
T
Hjartarsson
Hannes
H
Mayordomo
Jose I
JI
de la Chapelle
Albert
A
Hrafnkelsson
Jon
J
Thorsteinsdottir
Unnur
U
Kong
Augustine
A
Stefansson
Kari
K
D002874:Chromosome Mapping; D002894:Chromosomes, Human, Pair 4; D002899:Chromosomes, Human, Pair 9; D004268:DNA-Binding Proteins / Q000235:genetics; D005060:Europe / Q000453:epidemiology; D051858:Forkhead Transcription Factors / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation; D006801:Humans; D013964:Thyroid Neoplasms / Q000453:epidemiology* / Q000235:genetics*; D013972:Thyrotropin / Q000097:blood; D013974:Thyroxine / Q000097:blood; D014157:Transcription Factors; D014284:Triiodothyronine / Q000097:blood
D004268:DNA-Binding Proteins; C106894:FOXE1 protein, human; D051858:Forkhead Transcription Factors; C504003:TTF1 protein, human; D014157:Transcription Factors; D014284:Triiodothyronine; D013972:Thyrotropin; D013974:Thyroxine