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[Preprint]. 2025 May 16:2025.05.15.25327513.

doi: 10.1101/2025.05.15.25327513.

Global multi-ancestry genetic study elucidates genes and biological pathways associated with thyroid cancer and benign thyroid diseases

Samantha L White¹, Maizy S Brasher¹, Jack Pattee², Wei Zhou^{3

4

5}, Sinéad Chapman⁶, Yon Ho Jee⁷, Caitlin C Bell⁸, Taylor L Jamil⁹, Martin Barrio¹⁰, Jibril Hirbo^{11

12}, Nancy J Cox^{11

12}, Peter Straub^{13

12}, Shinichi Namba^{14

15

16}, Emily Bertucci-Richter¹⁷, Lindsay Guare¹⁸, Ahmed EdrisMohammed¹⁹, Sam Morris¹⁹, Ashley J Mulford²⁰, Haoyu Zhang¹, Brian Fennessy²¹, Martin D Tobin^{22

23}, Jing Chen²², Alexander T Williams²², Catherine John^{22

23}, David A van Heel²⁴, Rohini Mathur²⁵, Sarah Finer²⁵, Marta Riise Moksnes²⁶, Ben Brumpton²⁶, Bjørn Olav Åsvold²⁶, Raitis Peculis²⁷, Vita Rovite²⁷, Ilze Konrade²⁸, Ying Wang²⁹, Kristy Crooks³⁰, Sameer Chavan³⁰, Matthew J Fisher³⁰, Nicholas Rafaels³⁰, Meng Lin¹, Jonathan Shortt^{1

30}, Alan R Sanders^{20

31}, David Whiteman³², Stuart MacGregor³², Sarah Medland³², Unnur Thorsteinsdóttir^{33

34}, Kári Stefánsson^{33

34}, Tugce Karaderi³⁵, Kathleen M Egan^{36

37}, Therese Bocklage^{38

39}, Hilary C McCrary^{40

41}, Greg Riedlingeer⁴², Bodour Salhia^{43

44}, Craig Shriver^{45

46}, Minh D Phan^{47

48}, Janice L Farlow⁴⁹, Stephen Edge^{50

51}, Varinder Kaur^{52

53}, Michelle Churchman⁵⁴, Robert J Rounbehler⁵⁴, Pamela L Brock⁵⁵, Matthew D Ringel⁵⁵, Milton Pividori¹, Rebecca Schweppe^{8

56}, Christopher D Raeburn¹⁰, Robin Walters¹⁹, Zhengming Chen¹⁹, Liming Li^{57

58

59}, Koichi Matsuda^{60

61}, Yukinori Okada^{14

15

16}, Sebastian Zoellner¹⁷, Anurag Verma¹⁸, Michael Preuss²¹, Eimear Kenny²¹, Audrey Hendricks¹, Lauren Fishbein^{8

1

56

62}, Peter Kraft^{7

63}, Mark Daly^{29

64

65}, Benjamin Neale^{29

64

65}; biobank at the Colorado Center for Personalized Medicine; Genes & Health Research Team; BioBank Japan Project; Alicia Martin^{5

66

67}, Joanne B Cole^{1

68}, Bryan R Haugen^{8

56}, Christopher R Gignoux^{68

1

30

56}, Nikita Pozdeyev^{1

8

56

30}

Affiliations

¹ Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
² Center for Innovative Design & Analysis, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
³ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
⁴ Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
⁵ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
⁶ The Broad Institute, Cambridge, MA, USA.
⁷ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁸ Division of Endocrinology, Diabetes and Metabolism, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
⁹ Department of Otolaryngology, Head and Neck Surgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
¹⁰ Division of GI, Trauma, and Endocrine Surgery, Department of Surgery, University of Colorado School of Medicine, Aurora, CO, USA.
¹¹ Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
¹² Vanderbilt Genetic Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
¹³ Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USAz.
¹⁴ Department of Genome Informatics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
¹⁵ Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.
¹⁶ Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
¹⁷ Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
¹⁸ Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁹ Nuffield Department of Population Health, University of Oxford, Oxford, UK.
²⁰ Genomic Health Initiative, Endeavor Health Research Institute, Evanston, IL, USA.
²¹ The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²² Department of Population Health Sciences, University of Leicester, Leicester, UK.
²³ University Hospitals of Leicester NHS Trust, Leicester, LE15WW, UK.
²⁴ Blizard Institute, Queen Mary University of London, London E1 2AB, UK.
²⁵ Wolfson Institute of Population Health, Queen Mary University of London, London E1 2AB, UK.
²⁶ HUNT Research Centre, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Levanger, Norway.
²⁷ Latvian Biomedical Research and Study Centre, Ratsupites 1-1, Riga, LV-1067, Latvia.
²⁸ Department of Internal Medicine, Riga Stradins University, Dzirciema Str 16, LV-1007 Riga, Latvia.
²⁹ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³⁰ Colorado Center for Personalized Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
³¹ Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, USA.
³² QIMR Berghofer Medical Research Institute: Herston, QLD, AU.
³³ deCODE genetics/Amgen, Inc., Reykjavik, Iceland.
³⁴ Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
³⁵ Center for Health Data Science, Section for Health Data Science and Artificial Intelligence, Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
³⁶ Moffitt Cancer Center.
³⁷ Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
³⁸ University of Kentucky Markey Cancer Center.
³⁹ University of Kentucky-Department of Pathology and Laboratory Medicine, University of Kentucky-Chandler Medical Center, Lexington, KY, USA.
⁴⁰ University of Utah Huntsman Cancer Institute.
⁴¹ Department of Otolaryngology-Head and Neck Surgery, School of Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
⁴² Rutgers Cancer Institute of New Jersey Department of Medicine, Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
⁴³ Norris Comprehensive Cancer Center and Keck School of Medicine of University of Southern California.
⁴⁴ Department of Translational Genomics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
⁴⁵ Muthra Cancer Center.
⁴⁶ Murtha Cancer Center, Uniformed Services University/Walter Reed National Military Medical Center, Bethesda, MD, USA.
⁴⁷ University of Oklahoma Stephenson Cancer Center.
⁴⁸ Medical Oncology/Head and Neck Oncology, Stephenson Cancer Center, University of Oklahoma, Oklahoma City, Oklahoma, USA.
⁴⁹ Indiana University School of Medicine, Indianapolis, Indiana.
⁵⁰ Roswell Park Comprehensive Cancer Center.
⁵¹ Departments of Surgical Oncology and Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
⁵² University of Virginia Cancer Center.
⁵³ Department of Internal Medicine, Division of Hematology & Oncology, University of Virginia Health, Charlottesville, VA, USA.
⁵⁴ Aster Insights, Hudson, FL, USA.
⁵⁵ The Ohio State University Comprehensive Cancer Center and the Ohio State University College of Medicine, Columbus, OH, USA.
⁵⁶ University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
⁵⁷ Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China.
⁵⁸ Peking University Center for Public Health and Epidemic Preparedness and Response, Beijing, China.
⁵⁹ Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, Beijing 100191, China.
⁶⁰ Laboratory of Genome Technology, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
⁶¹ Laboratory of Clinical Genome Sequencing, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
⁶² Research Service, Rocky Mountain Regional VA Medical Center, Aurora, CO, USA.
⁶³ Transdivisional Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, MD, USA.
⁶⁴ Analytical and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁶⁵ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁶⁶ Stanley Center for Psychiatric Research and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁶⁷ Department of Medicine, Harvard Medical School, Boston, MA, USA.
⁶⁸ Human Medical Genetics and Genomics Program, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

PMID: 40463558
PMCID: PMC12132132
DOI: 10.1101/2025.05.15.25327513

Global multi-ancestry genetic study elucidates genes and biological pathways associated with thyroid cancer and benign thyroid diseases

Samantha L White et al. medRxiv. 2025.

[Preprint]. 2025 May 16:2025.05.15.25327513.

doi: 10.1101/2025.05.15.25327513.

Authors

Affiliations

¹ Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
² Center for Innovative Design & Analysis, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
³ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
⁴ Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
⁵ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
⁶ The Broad Institute, Cambridge, MA, USA.
⁷ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁸ Division of Endocrinology, Diabetes and Metabolism, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
⁹ Department of Otolaryngology, Head and Neck Surgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
¹⁰ Division of GI, Trauma, and Endocrine Surgery, Department of Surgery, University of Colorado School of Medicine, Aurora, CO, USA.
¹¹ Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
¹² Vanderbilt Genetic Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
¹³ Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USAz.
¹⁴ Department of Genome Informatics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
¹⁵ Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.
¹⁶ Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
¹⁷ Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
¹⁸ Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁹ Nuffield Department of Population Health, University of Oxford, Oxford, UK.
²⁰ Genomic Health Initiative, Endeavor Health Research Institute, Evanston, IL, USA.
²¹ The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²² Department of Population Health Sciences, University of Leicester, Leicester, UK.
²³ University Hospitals of Leicester NHS Trust, Leicester, LE15WW, UK.
²⁴ Blizard Institute, Queen Mary University of London, London E1 2AB, UK.
²⁵ Wolfson Institute of Population Health, Queen Mary University of London, London E1 2AB, UK.
²⁶ HUNT Research Centre, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Levanger, Norway.
²⁷ Latvian Biomedical Research and Study Centre, Ratsupites 1-1, Riga, LV-1067, Latvia.
²⁸ Department of Internal Medicine, Riga Stradins University, Dzirciema Str 16, LV-1007 Riga, Latvia.
²⁹ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³⁰ Colorado Center for Personalized Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
³¹ Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, USA.
³² QIMR Berghofer Medical Research Institute: Herston, QLD, AU.
³³ deCODE genetics/Amgen, Inc., Reykjavik, Iceland.
³⁴ Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
³⁵ Center for Health Data Science, Section for Health Data Science and Artificial Intelligence, Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
³⁶ Moffitt Cancer Center.
³⁷ Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
³⁸ University of Kentucky Markey Cancer Center.
³⁹ University of Kentucky-Department of Pathology and Laboratory Medicine, University of Kentucky-Chandler Medical Center, Lexington, KY, USA.
⁴⁰ University of Utah Huntsman Cancer Institute.
⁴¹ Department of Otolaryngology-Head and Neck Surgery, School of Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
⁴² Rutgers Cancer Institute of New Jersey Department of Medicine, Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
⁴³ Norris Comprehensive Cancer Center and Keck School of Medicine of University of Southern California.
⁴⁴ Department of Translational Genomics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
⁴⁵ Muthra Cancer Center.
⁴⁶ Murtha Cancer Center, Uniformed Services University/Walter Reed National Military Medical Center, Bethesda, MD, USA.
⁴⁷ University of Oklahoma Stephenson Cancer Center.
⁴⁸ Medical Oncology/Head and Neck Oncology, Stephenson Cancer Center, University of Oklahoma, Oklahoma City, Oklahoma, USA.
⁴⁹ Indiana University School of Medicine, Indianapolis, Indiana.
⁵⁰ Roswell Park Comprehensive Cancer Center.
⁵¹ Departments of Surgical Oncology and Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
⁵² University of Virginia Cancer Center.
⁵³ Department of Internal Medicine, Division of Hematology & Oncology, University of Virginia Health, Charlottesville, VA, USA.
⁵⁴ Aster Insights, Hudson, FL, USA.
⁵⁵ The Ohio State University Comprehensive Cancer Center and the Ohio State University College of Medicine, Columbus, OH, USA.
⁵⁶ University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
⁵⁷ Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China.
⁵⁸ Peking University Center for Public Health and Epidemic Preparedness and Response, Beijing, China.
⁵⁹ Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, Beijing 100191, China.
⁶⁰ Laboratory of Genome Technology, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
⁶¹ Laboratory of Clinical Genome Sequencing, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
⁶² Research Service, Rocky Mountain Regional VA Medical Center, Aurora, CO, USA.
⁶³ Transdivisional Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, MD, USA.
⁶⁴ Analytical and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁶⁵ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁶⁶ Stanley Center for Psychiatric Research and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁶⁷ Department of Medicine, Harvard Medical School, Boston, MA, USA.
⁶⁸ Human Medical Genetics and Genomics Program, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

PMID: 40463558
PMCID: PMC12132132
DOI: 10.1101/2025.05.15.25327513

Abstract

Thyroid diseases are common and highly heritable. Under the Global Biobank Meta-analysis Initiative, we performed a meta-analysis of genome-wide association studies from 19 biobanks for five thyroid diseases: thyroid cancer, benign nodular goiter, Graves' disease, lymphocytic thyroiditis, and primary hypothyroidism. We analyzed genetic association data from ~2.9 million genomes and identified 235 known and 501 novel independent variants significantly linked to thyroid diseases. We discovered genetic correlations between thyroid cancer, benign nodular goiter, and autoimmune thyroid diseases (r ² =0.21-0.97). Telomere maintenance genes contribute to benign and malignant thyroid nodular disease risk, whereas cell cycle, DNA repair, and DNA damage response genes are predominantly associated with thyroid cancer. We proposed a paradigm explaining genetic predisposition to benign and malignant thyroid nodules. We evaluated thyroid cancer polygenic risk scores (PRS) for clinical applications in thyroid cancer diagnosis. We found PRS associations with thyroid cancer risk features: multifocality, lymph node metastases, and extranodal extension.

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Figures

**Extended Data Figure 1.. Virtual Thyroid Biopsy Consortium.**
The Consortium aggregated data from 19 biobanks, 10 countries, four continents and ~2.9 million participants.

**Extended Data Figure 2.**
Thyroid disease meta-analysis case counts and prevalence across biobanks.

**Extended Data Figure 3.. Genetic correlation analysis for thyroid diseases in EUR-like GWAS meta-analysis.**
Genetic correlations were estimated using covariate-adjusted LD score regression. The asterisks denote Benjamini-Hochberg false discovery rate (FDR) <0.05.

**Extended Data Figure 4.. mRNA expression of thyroid cancer-associated genes in normal thyroid tissue and thyroid cancer.**
Genes were identified from ANNOVAR annotations of genome-wide significant variants in thyroid cancer GWAS meta-analysis and FUSION TWAS *cis*-eQTL analysis. Dark blue color shows genes with high expression in normal thyroid tissue (thyroid is among the top three highest expressing tissues in pan-tissue transcriptome analysis from NCBI Gene database https://www.ncbi.nlm.nih.gov/gene). Significant associations (at Bonferroni-corrected p-value ≤ 9.1e-05, red = positive; light blue = negative) of mRNA expression with high-risk thyroid cancer features such as presence of somatic *BRAF* V600E mutation, higher ERK score and lower thyroid differentiation score.

**Extended Data Figure 5.. Scatterplot of effect sizes of the variants in *PTCSC2* locus significantly (p-value < 5e-8) associated with thyroid cancer and benign nodular goiter.**
ThC – thyroid cancer. BNG – benign nodular goiter. ρ - Spearman correlation.

**Extended Data Figure 6.. Thyroid cancer polygenic risk score (PRS_{ThC vs. BNG}) performance by ancestry.**
Area under the receiver operating characteristic curve (AUC) and 95% confidence interval are shown for PRS_{ThC vs. BNG} developed from the leave-CCPM biobank-out thyroid cancer meta-analysis and tested on CCPM biobank participants of various ancestries. Case and control counts are shown within bars. * - p-value ≤ 0.05; ** - p ≤ 0.01.

**Extended Data Figure 7.. Whole genome sequencing data pipeline for the All of Us Research Program data.**
Variants (SNPs and indels) from participating biobanks’ GWAS summary data and PGS Catalog were extracted from the Hail variant dataset v7 object.

**Extended Data Figure 8.. Variant overlap between GWAS from participating Biobanks.**
Data is shown as a fraction of variants that are identical by chromosome, position, reference and alternate allele in harmonized GWAS summary data from two biobanks. The All of Us Research Program GWAS (top row) was performed on whole genome sequencing data and was designed to maximize variant overlap with other biobanks.

**Extended Data Figure 9.. Post-GWAS quality control workflow diagram.**
AF – allele frequency. AC – allele count, cov-LDSC – covariate-adjusted LD score regression. QQ plot – quantile-quantile plot.

Extended Data Figure 10.. Correlation of major continental ancestry fractions estimated by Summix2 (y-axis) and published by the Million Veteran Program, Colorado Center for Personalized Medicine and All of Us Research Program Biobanks (x-axis).
Multi-ancestry GWAS summary data was used for this analysis.

**Figure 1.. The study design.**
I. The Virtual Thyroid Biopsy Consortium was formed under the Global Biobank Meta-analysis Initiative. Participating biobanks performed genome-wide association studies (GWAS) for five thyroid diseases and GWAS of thyroid cancer vs. benign nodule goiters (ThC vs. BNG). **II.** Inverse variance-weighted meta-analysis was done after quality-control procedures. Previously known and novel independent genetic associations were identified. Functional inference studies included: **III**. Genetic correlation analysis with covariate-adjusted LD score regression. **IV. T**ranscriptome-wide association studies (FUSION and S-PrediXcan), V. Pathway (KEGG and Reactome), and gene-expression (The Cancer Genome Atlas and ORIEN Avatar) analyses. **VI.** Polygenic risk scores were developed for thyroid cancer, benign thyroid diseases, and to distinguish malignant and benign thyroid nodules. **VII.** Polygenic risk scores were tested for association with thyroid diseases and aggressive thyroid cancer features extracted from clinical charts and surgical histopathology reports.

**Figure 2.. Pleiotropic and phenotype-specific loci associated with thyroid diseases in multi-ancestry GWAS meta-analysis.**
The heatmap illustrates the genetic correlation (r²) between thyroid phenotypes, which was estimated using covariate-adjusted LD score regression. The asterisks denote Benjamini-Hochberg false discovery rate (FDR) <0.05. Circular plots highlight loci significantly associated with thyroid cancer and benign nodular goiter (right), and autoimmune thyroid diseases (left). Pleiotropic loci are marked by large purple dots. In the circular plot on the right small dots show loci predominantly associated with thyroid cancer or benign nodular goiter (red or blue respectively). In the circular plot on the left the small red dots depict loci which are significantly associated with Graves’ disease, but not lymphocytic thyroiditis or primary hypothyroidism. For clarity, only loci significantly associated with Graves’ disease are shown on the autoimmune thyroid diseases circular plot. The *PTCSC2* (right, yellow) is the only locus inversely associated with thyroid cancer and benign nodular goiter.

**Figure 3.. Thyroid cancer polygenic risk scores.**
Two thyroid cancer polygenic risk scores (PRS) were developed: PRS_{ThC vs. All} to identify individuals at risk in a population and PRS_{ThC vs. BNG} for clinically relevant task of discriminating malignant and benign thyroid nodules. PRS were tested in the Colorado Center for Personalized Medicine Biobank (CCPM) population (n = 94,651) and CCPM data was not used for PRS development. PRS_{ThC vs. All} was derived using PRS-CS method. PRS_{ThC vs. BNG} was calculated using independent significant associations with thyroid cancer and benign nodular goiter. A. Receiver operating characteristic curves. B. Thyroid cancer risk by PRS decile. C. PRS association with features of aggressive thyroid cancer. * - p-value ≤ 0.05. ** - p-value ≤ 1.7e-3 (Bonferroni-corrected significance threshold).

**Figure 4.. Germline genetic susceptibility to thyroid cancer and benign nodular goiter.**
We hypothesize that two biological processes with distinct genetic architecture cause thyroid nodules: 1) hyperplasia, a polyclonal follicular cell proliferation with no malignant potential, and 2) neoplasia, a clonal growth driven by somatic genetic alterations. Neoplastic nodules can be benign or malignant, and the mismatch between biological mechanisms (hyperplasia vs. neoplasia) and GWAS phenotype definitions (benign and malignant thyroid nodules) caused apparent genetic pleiotropy. Pathway and genes associated with benign nodular goiter but not thyroid cancer in GWAS meta-analysis (e.g., insulin-like growth factor 1 [IGF1] and fibroblast growth factor [FGF] signaling pathways) predispose to benign nodules that have no malignant potential (green). Pathways and genes associated with both benign nodular goiter and thyroid cancer (e.g., telomere maintenance) predispose to neoplastic thyroid nodules, benign or malignant (orange). In the absence of other genetic risk factors, patients are more likely to develop benign adenomas or low risk thyroid cancers (blue). Alternatively, genetic alterations in cell cycle and DNA damage response genes (purple, associated predominantly with thyroid cancer but nor benign nodular goiter in GWAS meta-analysis) predispose to high-risk thyroid cancer.

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This is a preprint.

Global multi-ancestry genetic study elucidates genes and biological pathways associated with thyroid cancer and benign thyroid diseases

Affiliations

Global multi-ancestry genetic study elucidates genes and biological pathways associated with thyroid cancer and benign thyroid diseases

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Abstract

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This is a preprint.

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