Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation

TY - JOUR

T1 - Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation

AU - Teumer, Alexander

AU - Chaker, Layal

AU - Groeneweg, Stefan

AU - Li, Yong

AU - Di Munno, Celia

AU - Barbieri, Caterina

AU - Ahluwalia, Tarunveer S

AU - Astrup, Arne

AU - Linneberg, Allan

AU - Pedersen, Oluf Borbye

AU - Sørensen, Thorkild I.A.

AU - ThyroidOmics Consortium

N1 - CURIS 2018 NEXS 364

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associatedwith these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves’ disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets.

AB - Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associatedwith these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves’ disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets.

KW - Faculty of Science

KW - Thyroid dysfunction

KW - Thyroid hormone regulation

KW - Genome-wide analysis

KW - Genetic variants

KW - Thyroid hormone transporter (SLC17A4)

KW - Metabolyzing hormone (AADAT)

U2 - 10.1038/s41467-018-06356-1

DO - 10.1038/s41467-018-06356-1

M3 - Journal article

C2 - 30367059

SN - 2041-1723

VL - 9

JO - Nature Communications

JF - Nature Communications

M1 - 4455

ER -