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

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

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.