Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications

被引：35

作者：

Sterenborg, Rosalie B. T. M. ^{[2
]}

Steinbrenner, Inga ^{[3
,4
]}

Li, Yong ^{[3
,4
]}

Bujnis, Melissa N. ^{[5
]}

Naito, Tatsuhiko ^{[7
]}

Marouli, Eirini ^{[9
]}

Galesloot, Tessel E. ^{[10
]}

Babajide, Oladapo ^{[8
]}

Andreasen, Laura ^{[11
,12
]}

Astrup, Arne ^{[13
]}

Asvold, Bjorn Olav ^{[14
,15
]}

Bandinelli, Stefania ^{[16
]}

Beekman, Marian ^{[17
]}

Beilby, John P. ^{[18
]}

Bork-Jensen, Jette ^{[19
]}

Boutin, Thibaud ^{[20
]}

Brody, Jennifer A. ^{[21
]}

Brown, Suzanne J. ^{[22
]}

Brumpton, Ben ^{[14
,23
]}

Campbell, Purdey J. ^{[22
]}

Cappola, Anne R. ^{[24
]}

Ceresini, Graziano ^{[25
,26
]}

Chaker, Layal ^{[27
,28
,29
]}

Chasman, Daniel, I ^{[30
,31
]}

Concas, Maria Pina ^{[32
]}

de Almeida, Rodrigo Coutinho ^{[17
]}

Cross, Simone M. ^{[33
]}

Cucca, Francesco ^{[34
,35
]}

Deary, Ian J. ^{[36
]}

Kjaergaard, Alisa Devedzic ^{[37
]}

Tcheugui, Justin B. Echouffo ^{[38
]}

Ellervik, Christina ^{[31
,39
,40
,41
]}

Eriksson, Johan G. ^{[42
,43
]}

Ferrucci, Luigi ^{[44
]}

Freudenberg, Jan ^{[45
]}

Fuchsberger, Christian ^{[46
]}

Gieger, Christian ^{[47
]}

Giulianini, Franco ^{[30
]}

Gogele, Martin ^{[46
]}

Graham, Sarah E. ^{[48
]}

Grarup, Niels ^{[19
]}

Gunjaca, Ivana ^{[49
]}

Hansen, Torben ^{[19
]}

Harding, Barbara N. ^{[21
,50
]}

Harris, Sarah E. ^{[36
]}

Haunso, Stig ^{[11
,51
]}

Hayward, Caroline ^{[20
]}

Hui, Jennie ^{[52
,53
]}

Ittermann, Till ^{[54
,55
]}

Jukema, J. Wouter ^{[56
,57
]}

机构：

[1] Radboud Univ Nijmegen, Med Ctr, Dept Internal Med, Div Endocrinol, Nijmegen, Netherlands

[2] Erasmus MC, Acad Ctr Thyroid Dis, Dept Internal Med, Rotterdam, Netherlands

[3] Univ Freiburg, Inst Genet Epidemiol, Fac Med, Freiburg, Germany

[4] Univ Freiburg, Med Ctr, Freiburg, Germany

[5] Univ Utah, Salt Lake City, UT USA

[6] Osaka Univ, Dept Stat Genet, Grad Sch Med, Suita, Osaka, Japan

[7] RIKEN Ctr Integrat Med Sci, Lab Syst Genet, Yokohama, Kanagawa, Japan

[8] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England

[9] Queen Mary Univ London, Digital Environm Res Inst, London, England

[10] Radboud Univ Nijmegen, Dept Hlth Evidence, Med Ctr, Nijmegen, Netherlands

[11] Copenhagen Univ Hosp, Dept Cardiol, Lab Mol Cardiol, Rigshosp, Copenhagen, Denmark

[12] Univ Copenhagen, Dept Biomed Sci, Copenhagen, Denmark

[13] Novo Nordisk Fdn, Dept Obes & Nutr Sci, Hellerup, Denmark

[14] Norwegian Univ Sci & Technol, KG Jebsen Ctr Genet Epidemiol, Dept Publ Hlth & Nursing, NTNU, Trondheim, Norway

[15] Trondheim Reg & Univ Hosp, Dept Endocrinol, Clin Med, St Olavs Hosp, Trondheim, Norway

[16] Azienda Sanitaria Toscana Ctr, Geriatr Unit, Florence, Italy

[17] Leiden Univ, Med Ctr, Dept Biomed Data Sci, Sect Mol Epidemiol, Leiden, Netherlands

[18] Univ Western Australia, Sch Biomed Sci, Perth, WA 6009, Australia

[19] Univ Copenhagen, Novo Nordisk Fdn Ctr Basic Metab Res, Fac Hlth & Med Sci, Copenhagen, Denmark

[20] Univ Edinburgh, Western Gen Hosp, Inst Genet & Canc, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland

[21] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA

[22] Sir Charles Gairdner Hosp, Dept Endocrinol & Diabet, Nedlands, WA 6009, Australia

[23] Norwegian Univ Sci & Technol, Hunt Res Ctr, Dept Publ Hlth & Nursing, N-7600 Levanger, Norway

[24] Univ Penn, Div Endocrinol Diabet & Metab, Philadelphia, PA USA

[25] Univ Parma, Oncol Endocrinol, Parma, Italy

[26] Azienda Osped Univ Parma, Parma, Italy

[27] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands

[28] Univ Med Ctr, Dept Epidemiol, Erasmus MC, Rotterdam, Netherlands

[29] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA

[30] Brigham & Womens Hosp, Div Prevent Med, Boston, MA USA

[31] Harvard Med Sch, Boston, MA USA

[32] Inst Maternal & Child Hlth IRCCS Burlo Garofolo, Trieste, Italy

[33] QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia

[34] CNR, Ist Ric Genet & Biomed, I-09042 Monserrato, CA, Italy

[35] Univ Sassari, Dipartimento Sci Biomed, Vle San Pietro, I-07100 Sassari, SS, Italy

[36] Univ Edinburgh, Dept Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland

[37] Aarhus Univ Hosp, Steno Diabet Ctr Aarhus, Palle Juul Jensens Blvd 11,Entrance A, DK-8200 Aarhus, Denmark

[38] Johns Hopkins Sch Med, Div Endocrinol Diabet & Metab, Baltimore, MD 21205 USA

[39] Univ Copenhagen, Fac Med Sci, Dept Clin Med, Copenhagen, Denmark

[40] Boston Childrens Hosp, Dept Lab Med, Boston, MA USA

[41] Zealand Univ Hosp, Dept Clin Biochem, Koge, Denmark

[42] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland

[43] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Obstet & Gynecol, Singapore, Singapore

[44] NIA, Longitudinal Study Sect, Baltimore, MD USA

[45] Regeneron Pharmaceut Inc, New York, NY USA

[46] Univ Lubeck, Eurac Res, Inst Biomed, Bolzano, Italy

[47] Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Inst Epidemiol, Neuherberg, Germany

[48] Univ Michigan, Dept Internal Med, Cardiol, Ann Arbor, MI 48109 USA

[49] Univ Split, Sch Med, Dept Med Biol, Split, Croatia

[50] Barcelona Inst Global Hlth, Barcelona, Spain

来源：

NATURE COMMUNICATIONS | 2024年 / 15卷 / 01期

基金：

英国医学研究理事会; 英国生物技术与生命科学研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; SUBCLINICAL HYPOTHYROIDISM; MENDELIAN RANDOMIZATION; ATRIAL-FIBRILLATION; NORMAL RANGE; CANCER-RISK; POPULATION; HORMONE; RELAXIN; HYPERTHYROIDISM;

D O I：

10.1038/s41467-024-44701-9

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.

引用

页数：18

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