GWAS of thyroid stimulating hormone highlights pleiotropic effects and inverse association with thyroid cancer

ZHOU, WEI; BRUMPTON, BEN; KABIL, OMER; GUDMUNDSSON, JULIUS; THORLEIFSSON, GUDMAR; WEINSTOCK, JOSH; ZAWISTOWSKI, MATTHEW; NIELSEN, JONAS B.; CHAKER, LAYAL; MEDICI, MARCO; TEUMER, ALEXANDER; NAITZA, SILVIA; SANNA, SERENA; SCHULTHEISS, ULLA T.; CAPPOLA, ANNE; KARJALAINEN, JUHA; KURKI, MITJA; ONEKA, MORGAN; TAYLOR, PETER; FRITSCHE, LARS G.; GRAHAM, SARAH E.; WOLFORD, BROOKE N.; OVERTON, WILLIAM; RASHEED, HUMAIRA; HAUG, EIRIN B.; GABRIELSEN, MAIKEN E.; SKOGHOLT, ANNE HEIDI; SURAKKA, IDA; DAVEY SMITH, GEORGE; PANDIT, ANITA; ROYCHOWDHURY, TANMOY; HORNSBY, WHITNEY E.; JONASSON, JON G.; SENTER, LEIGHA; LIYANARACHCHI, SANDYA; RINGEL, MATTHEW D.; XU, LI; KIEMENEY, LAMBERTUS A.; HE, HUILING; NETEA-MAIER, ROMANA T.; MAYORDOMO, JOSE I.; PLANTINGA, THEO S.; HRAFNKELSSON, JON; HJARTARSON, HANNES; STURGIS, ERICH M.; PALOTIE, AARNO; DALY, MARK; CITTERIO, CINTIA E.; ARVAN, PETER; BRUMMETT, CHAD M.; BOEHNKE, MICHAEL; DE LA CHAPELLE, ALBERT; STEFANSSON, KARI; HVEEM, KRISTIAN; WILLER, CRISTEN J.; ÅSVOLD, BJØRN OLAV

NATURE COMMUNICATIONS

Springer Nature

Año: 2020 vol. 11

2041-1723

Thyroid stimulating hormone (TSH) is critical for normal development and metabolism. To better understand the genetic contribution to TSH levels, we conduct a GWAS meta-analysis at 22.4 million genetic markers in up to 119,715 individuals and identify 74 genome-wide significant loci for TSH, of which 28 are previously unreported. Functional experiments show that the thyroglobulin protein-altering variants P118L and G67S impact thyroglobulin secretion. Phenome-wide association analysis in the UK Biobank demonstrates the pleiotropic effects of TSH-associated variants and a polygenic score for higher TSH levels is associated with a reduced risk of thyroid cancer in the UK Biobank and three other independent studies. Two-sample Mendelian randomization using TSH index variants as instrumental variables suggests a protective effect of higher TSH levels (indicating lower thyroid function) on risk of thyroid cancer and goiter. Our findings highlight the pleiotropic effects of TSH-associated variants on thyroid function and growth of malignant and benign thyroid tumors.