Global multi-ancestry genome-wide analyses identify genes and biological pathways associated with thyroid cancer and benign thyroid diseases.
White SL., Brasher MS., Pattee J., Zhou W., Chapman S., Jee YH., Bell CC., Jamil TL., Barrio M., Arehart CH., Evans LM., Hirbo J., Cox NJ., Straub P., Namba S., Bertucci-Richter E., Guare L., Edris A., Morris S., Mulford AJ., Zhang H., Fennessy B., Tobin MD., Chen J., Williams AT., John C., van Heel DA., Mathur R., Finer S., Moksnes MR., Brumpton BM., Åsvold BO., Peculis R., Rovite V., Konrade I., Wang Y., Crooks K., Chavan S., Fisher MJ., Rafaels N., Lin M., Shortt JA., Sanders AR., Whiteman DC., MacGregor S., Medland SE., Thorsteinsdóttir U., Stefánsson K., Karaderi T., Egan KM., Bocklage T., McCrary HC., Riedlinger G., Salhia B., Shriver C., Phan MD., Farlow JL., Edge S., Kaur V., Churchman ML., Rounbehler RJ., Brock PL., Ringel MD., Pividori M., Schweppe R., Raeburn CD., Walters RG., Chen Z., Li L., Matsuda K., Okada Y., Zöllner S., Verma A., Penn Medicine BioBank ., Preuss MH., Kenny E., Hendricks AE., Fishbein L., Kraft P., Daly MJ., Neale BM., Virtual Thyroid Biopsy Consortium ., Colorado Center for Personalized Medicine ., Genes & Health Research Team ., BioBank Japan Project ., Martin AR., Cole JB., Haugen BR., Global Biobank Meta-analysis Initiative ., Gignoux CR., Pozdeyev N.
Thyroid diseases are common and highly heritable. We performed a meta-analysis of genome-wide association studies from 19 biobanks for five thyroid diseases: thyroid cancer (ThC), benign nodular goiter, Graves' disease, lymphocytic thyroiditis and primary hypothyroidism. We analyzed genetic association data from ~2.9 million genomes and identified 313 known and 570 new independent loci linked to thyroid diseases. We discovered genetic correlations between ThC, benign nodular goiter and autoimmune thyroid diseases (rg = 0.16-0.97). Telomere maintenance genes contributed to benign and malignant thyroid nodular disease risk, whereas cell cycle, DNA repair and damage response genes were associated with ThC. We propose a paradigm that explains genetic predisposition to benign and malignant thyroid nodules. We found polygenic risk score associations with ThC risk of structural disease recurrence, tumor size, multifocality, lymph node metastases and extranodal extension. Polygenic risk scores identified individuals with aggressive ThC in a biobank, creating an opportunity for genetically informed population screening.