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4 results on '"Hansen, Torben [0000-0001-8748-3831]"'

1. Discovery of drug-omics associations in type 2 diabetes with generative deep-learning models

Author

Allesøe, Rosa Lundbye, Lundgaard, Agnete Troen, Hernández Medina, Ricardo, Aguayo-Orozco, Alejandro, Johansen, Joachim, Nissen, Jakob Nybo, Brorsson, Caroline, Mazzoni, Gianluca, Niu, Lili, Biel, Jorge Hernansanz, Leal Rodríguez, Cristina, Brasas, Valentas, Webel, Henry, Benros, Michael Eriksen, Pedersen, Anders Gorm, Chmura, Piotr Jaroslaw, Jacobsen, Ulrik Plesner, Mari, Andrea, Koivula, Robert, Mahajan, Anubha, Vinuela, Ana, Tajes, Juan Fernandez, Sharma, Sapna, Haid, Mark, Hong, Mun-Gwan, Musholt, Petra B, De Masi, Federico, Vogt, Josef, Pedersen, Helle Krogh, Gudmundsdottir, Valborg, Jones, Angus, Kennedy, Gwen, Bell, Jimmy, Thomas, E Louise, Frost, Gary, Thomsen, Henrik, Hansen, Elizaveta, Hansen, Tue Haldor, Vestergaard, Henrik, Muilwijk, Mirthe, Blom, Marieke T, 't Hart, Leen M, Pattou, Francois, Raverdy, Violeta, Brage, Soren, Kokkola, Tarja, Heggie, Alison, McEvoy, Donna, Mourby, Miranda, Kaye, Jane, Hattersley, Andrew, McDonald, Timothy, Ridderstråle, Martin, Walker, Mark, Forgie, Ian, Giordano, Giuseppe N, Pavo, Imre, Ruetten, Hartmut, Pedersen, Oluf, Hansen, Torben, Dermitzakis, Emmanouil, Franks, Paul W, Schwenk, Jochen M, Adamski, Jerzy, McCarthy, Mark I, Pearson, Ewan, Banasik, Karina, Rasmussen, Simon, Brunak, Søren, IMI DIRECT Consortium, Lundgaard, Agnete Troen [0000-0001-7447-6560], Hernández Medina, Ricardo [0000-0001-6373-2362], Johansen, Joachim [0000-0001-7052-1870], Niu, Lili [0000-0003-4571-4368], Biel, Jorge Hernansanz [0000-0002-3125-2951], Leal Rodríguez, Cristina [0000-0002-3133-0630], Benros, Michael Eriksen [0000-0003-4939-9465], Pedersen, Anders Gorm [0000-0001-9650-8965], Jacobsen, Ulrik Plesner [0000-0001-9181-6854], Koivula, Robert [0000-0002-1646-4163], Vinuela, Ana [0000-0003-3771-8537], Haid, Mark [0000-0001-6118-1333], Hong, Mun-Gwan [0000-0001-8603-8293], Kennedy, Gwen [0000-0002-9856-3236], Thomas, E Louise [0000-0003-4235-4694], Frost, Gary [0000-0003-0529-6325], Hansen, Tue Haldor [0000-0001-5948-8993], Kaye, Jane [0000-0002-7311-4725], Hattersley, Andrew [0000-0001-5620-473X], Ridderstråle, Martin [0000-0002-3270-9167], Pedersen, Oluf [0000-0002-3321-3972], Hansen, Torben [0000-0001-8748-3831], Schwenk, Jochen M [0000-0001-8141-8449], Rasmussen, Simon [0000-0001-6323-9041], Brunak, Søren [0000-0003-0316-5866], and Apollo - University of Cambridge Repository

Subjects
Deep Learning, Diabetes Mellitus, Type 2, Humans, Algorithms
Abstract

The application of multiple omics technologies in biomedical cohorts has the potential to reveal patient-level disease characteristics and individualized response to treatment. However, the scale and heterogeneous nature of multi-modal data makes integration and inference a non-trivial task. We developed a deep-learning-based framework, multi-omics variational autoencoders (MOVE), to integrate such data and applied it to a cohort of 789 people with newly diagnosed type 2 diabetes with deep multi-omics phenotyping from the DIRECT consortium. Using in silico perturbations, we identified drug-omics associations across the multi-modal datasets for the 20 most prevalent drugs given to people with type 2 diabetes with substantially higher sensitivity than univariate statistical tests. From these, we among others, identified novel associations between metformin and the gut microbiota as well as opposite molecular responses for the two statins, simvastatin and atorvastatin. We used the associations to quantify drug-drug similarities, assess the degree of polypharmacy and conclude that drug effects are distributed across the multi-omics modalities.

Published
2023

2. Genome-wide association analyses of physical activity and sedentary behavior provide insights into underlying mechanisms and roles in disease prevention

Author

Wang, Zhe, Emmerich, Andrew, Pillon, Nicolas J., Moore, Tim, Hemerich, Daiane, Cornelis, Marilyn C., Mazzaferro, Eugenia, Broos, Siacia, Ahluwalia, Tarunveer S., Bartz, Traci M., Bentley, Amy R., Bielak, Lawrence F., Chong, Mike, Chu, Audrey Y., Berry, Diane, Dorajoo, Rajkumar, Dueker, Nicole D., Kasbohm, Elisa, Feenstra, Bjarke, Feitosa, Mary F., Gieger, Christian, Graff, Mariaelisa, Hall, Leanne M., Haller, Toomas, Hartwig, Fernando P., Hillis, David A., Huikari, Ville, Heard-Costa, Nancy, Holzapfel, Christina, Jackson, Anne U., Johansson, Åsa, Jørgensen, Anja Moltke, Kaakinen, Marika A., Karlsson, Robert, Kerr, Kathleen F., Kim, Boram, Koolhaas, Chantal M., Kutalik, Zoltan, Lagou, Vasiliki, Lind, Penelope A., Lorentzon, Mattias, Lyytikäinen, Leo-Pekka, Mangino, Massimo, Metzendorf, Christoph, Monroe, Kristine R., Pacolet, Alexander, Pérusse, Louis, Pool, Rene, Richmond, Rebecca C., Rivera, Natalia V., Robiou-du-Pont, Sebastien, Schraut, Katharina E., Schulz, Christina-Alexandra, Stringham, Heather M., Tanaka, Toshiko, Teumer, Alexander, Turman, Constance, van der Most, Peter J., Vanmunster, Mathias, van Rooij, Frank J. A., van Vliet-Ostaptchouk, Jana V., Zhang, Xiaoshuai, Zhao, Jing-Hua, Zhao, Wei, Balkhiyarova, Zhanna, Balslev-Harder, Marie N., Baumeister, Sebastian E., Beilby, John, Blangero, John, Boomsma, Dorret I., Brage, Søren Karl, Braund, Peter S., Brody, Jennifer A., Bruinenberg, Marcel, Ekelund, Ulf, Liu, Ching-Ti, Cole, John W., Collins, Francis S., Cupples, L. Adrienne, Esko, Tõnu, Enroth, Stefan, Faul, Jessica D., Fernandez-Rhodes, Lindsay, Fohner, Alison E., Franco, Oscar H., Galesloot, Tessel E., Gordon, Scott D., Grarup, Niels, Hartman, Catharina A., Heiss, Gerardo, Hui, Jennie, Illig, Thomas, Jago, Russell, James, Alan, Joshi, Peter K., Jung, Taeyeong, Kähönen, Mika, Kilpeläinen, Tuomas O., Koh, Woon-Puay, Kolcic, Ivana, Kraft, Peter P., Kuusisto, Johanna, Launer, Lenore J., Li, Aihua, Linneberg, Allan, Luan, Jian’an, Vidal, Pedro Marques, Medland, Sarah E., Milaneschi, Yuri, Moscati, Arden, Musk, Bill, Nelson, Christopher P., Nolte, Ilja M., Pedersen, Nancy L., Peters, Annette, Peyser, Patricia A., Power, Christine, Raitakari, Olli T., Reedik, Mägi, Reiner, Alex P., Ridker, Paul M., Rudan, Igor, Ryan, Kathy, Sarzynski, Mark A., Scott, Laura J., Scott, Robert A., Sidney, Stephen, Siggeirsdottir, Kristin, Smith, Albert V., Smith, Jennifer A., Sonestedt, Emily, Strøm, Marin, Tai, E. Shyong, Teo, Koon K., Thorand, Barbara, Tönjes, Anke, Tremblay, Angelo, Uitterlinden, Andre G., Vangipurapu, Jagadish, van Schoor, Natasja, Völker, Uwe, Willemsen, Gonneke, Williams, Kayleen, Wong, Quenna, Xu, Huichun, Young, Kristin L., Yuan, Jian Min, Zillikens, M. Carola, Zonderman, Alan B., Ameur, Adam, Bandinelli, Stefania, Bis, Joshua C., Boehnke, Michael, Bouchard, Claude, Chasman, Daniel I., Smith, George Davey, de Geus, Eco J. C., Deldicque, Louise, Dörr, Marcus, Evans, Michele K., Ferrucci, Luigi, Fornage, Myriam, Fox, Caroline, Garland, Theodore, Gudnason, Vilmundur, Gyllensten, Ulf, Hansen, Torben, Hayward, Caroline, Horta, Bernardo L., Hyppönen, Elina, Jarvelin, Marjo-Riitta, Johnson, W. Craig, Kardia, Sharon L. R., Kiemeney, Lambertus A., Laakso, Markku, Langenberg, Claudia, Lehtimäki, Terho, Marchand, Loic Le, Alizadeh, Behrooz Z., Boezen, H. Marike, Franke, Lude, Swertz, Morris, Wijmenga, Tjitske Nienke, van der Harst, Pim, Navis, Gerjan, Rots, Marianne, Wolffenbuttel, Bruce H. R., Magnusson, Patrik K. E., Martin, Nicholas G., Melbye, Mads, Metspalu, Andres, Meyre, David, North, Kari E., Ohlsson, Claes, Oldehinkel, Albertine J., Orho-Melander, Marju, Pare, Guillaume, Park, Taesung, Pedersen, Oluf, Penninx, Brenda W. J. H., Pers, Tune H., Polasek, Ozren, Prokopenko, Inga, Rotimi, Charles N., Samani, Nilesh J., Sim, Xueling, Snieder, Harold, Sørensen, Thorkild I. A., Spector, Tim D., Timpson, Nicholas J., van Dam, Rob M., van der Velde, Nathalie, van Duijn, Cornelia M., Vollenweider, Peter, Völzke, Henry, Voortman, Trudy, Waeber, Gérard, Wareham, Nicholas J., Weir, David R., Wichmann, Heinz-Erich, Wilson, James F., Hevener, Andrea L., Krook, Anna, Zierath, Juleen R., Thomis, Martine A. I., Loos, Ruth J. F., Hoed, Marcel den, Epidemiology, Internal Medicine, Tampere University, Department of Clinical Chemistry, Clinical Medicine, Department of Clinical Physiology and Nuclear Medicine, Wang, Zhe, Emmerich, Andrew, Pillon, Nicolas J, Moore, Tim, Hyppönen, Elina, den Hoed, Marcel, Lifelines Cohort Study, Alizadeh, B.Z., Boezen, H.M., Franke, L., Swertz, M., Wijmenga, C., van der Harst, P., Navis, G., Rots, M., Wolffenbuttel, BHR, Wang, Zhe [0000-0002-8046-4969], Emmerich, Andrew [0000-0002-0908-9924], Pillon, Nicolas J [0000-0003-1107-9490], Moore, Tim [0000-0003-4250-3370], Ameur, Adam [0000-0001-6085-6749], Bis, Joshua C [0000-0002-3409-1110], Boehnke, Michael [0000-0002-6442-7754], Bouchard, Claude [0000-0002-0048-491X], Chasman, Daniel I [0000-0003-3357-0862], Smith, George Davey [0000-0002-1407-8314], de Geus, Eco JC [0000-0001-6022-2666], Dörr, Marcus [0000-0001-7471-475X], Ferrucci, Luigi [0000-0002-6273-1613], Fornage, Myriam [0000-0003-0677-8158], Garland, Theodore [0000-0002-7916-3552], Gyllensten, Ulf [0000-0002-6316-3355], Hansen, Torben [0000-0001-8748-3831], Horta, Bernardo L [0000-0001-9843-412X], Hyppönen, Elina [0000-0003-3670-9399], Johnson, W Craig [0000-0002-3161-3753], Kiemeney, Lambertus A [0000-0002-2368-1326], Laakso, Markku [0000-0002-3394-7749], Langenberg, Claudia [0000-0002-5017-7344], Lehtimäki, Terho [0000-0002-2555-4427], Magnusson, Patrik KE [0000-0002-7315-7899], Martin, Nicholas G [0000-0003-4069-8020], Melbye, Mads [0000-0001-8264-6785], Metspalu, Andres [0000-0002-3718-796X], Meyre, David [0000-0003-4850-7444], North, Kari E [0000-0002-8903-0366], Ohlsson, Claes [0000-0002-9633-2805], Oldehinkel, Albertine J [0000-0003-3925-3913], Orho-Melander, Marju [0000-0002-3578-2503], Pare, Guillaume [0000-0002-6795-4760], Park, Taesung [0000-0002-8294-590X], Pedersen, Oluf [0000-0002-3321-3972], Pers, Tune H [0000-0003-0207-4831], Polasek, Ozren [0000-0002-5765-1862], Prokopenko, Inga [0000-0003-1624-7457], Rotimi, Charles N [0000-0001-5759-053X], Sim, Xueling [0000-0002-1233-7642], Snieder, Harold [0000-0003-1949-2298], Sørensen, Thorkild IA [0000-0003-4821-430X], Spector, Tim D [0000-0002-9795-0365], Timpson, Nicholas J [0000-0002-7141-9189], Voortman, Trudy [0000-0003-2830-6813], Waeber, Gérard [0000-0003-4193-788X], Wareham, Nicholas J [0000-0003-1422-2993], Weir, David R [0000-0002-1661-2402], Wilson, James F [0000-0001-5751-9178], Krook, Anna [0000-0002-0891-0258], Zierath, Juleen R [0000-0001-6891-7497], Thomis, Martine AI [0000-0001-9093-2191], Loos, Ruth JF [0000-0002-8532-5087], Hoed, Marcel den [0000-0001-8081-428X], Apollo - University of Cambridge Repository, Center for Liver, Digestive and Metabolic Diseases (CLDM), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Geriatrics, AMS - Ageing & Vitality, APH - Aging & Later Life, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, APH - Mental Health, APH - Methodology, and AMS - Sports

Subjects
Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], 631/208/205/2138, 610 Medicine & health, heritability, Actinin/genetics, Cross-Sectional Studies, Exercise/physiology, Genome-Wide Association Study, Humans, Leisure Activities, Sedentary Behavior, apolipoprotein-e genotype, Lifelines Cohort Study, 360 Social problems & social services, 692/308/575, Genetics, Actinin, Exercise, Medicinsk genetik, exercise, APOLIPOPROTEIN-E GENOTYPE, LD SCORE REGRESSION, GENE-EXPRESSION, EXERCISE, COMPLEX, PERFORMANCE, GWAS, HERITABILITY, MORTALITY, FITNESS, 360 Soziale Probleme, Sozialdienste, 692/308/2056, article, gwas, gene-expression, mortality, 3142 Public health care science, environmental and occupational health, fitness, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], LD score regression, 3111 Biomedicine, 610 Medizin und Gesundheit, Medical Genetics, complex, performance
Abstract

Funder: Kjell och Märta Beijers Stiftelse (Kjell and Marta Beijer Foundation); doi: https://doi.org/10.13039/501100006353, Although physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Combining data for up to 703,901 individuals from 51 studies in a multi-ancestry meta-analysis of genome-wide association studies yields 99 loci that associate with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), leisure screen time (LST) and/or sedentary behavior at work. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. A missense variant in ACTN3 makes the alpha-actinin-3 filaments more flexible, resulting in lower maximal force in isolated type IIA muscle fibers, and possibly protection from exercise-induced muscle damage. Finally, Mendelian randomization analyses show that beneficial effects of lower LST and higher MVPA on several risk factors and diseases are mediated or confounded by body mass index (BMI). Our results provide insights into physical activity mechanisms and its role in disease prevention.

Published
2022
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3. Re-analysis of public genetic data reveals a rare X-chromosomal variant associated with type 2 diabetes

Author

Claire Morgan, Antonio Zorzano, Jason Flannick, Claudia Langenberg, David Torrents, Torben Hansen, Juan R. González, Tune H. Pers, Jorge Ferrer, Ehm A. Andersson, Jian'an Luan, Jose C. Florez, Ivan Brandslund, Aaron Leong, Marit E. Jørgensen, Ignasi Moran, Pascal Timshel, Robert A. Scott, Cramer Christensen, Emil V. R. Appel, Niels Grarup, Paula Cortes-Sánchez, Jonathan Marti, Varindepal Kaur, Oluf Pedersen, Santi González, Elias Rodriguez-Fos, Nicholas J. Wareham, Miriam S. Udler, Josep M. Mercader, Torben Jørgensen, Montserrat Puiggròs, Sílvia Bonàs-Guarch, Irene Miguel-Escalada, Carlos Díaz, David Sebastián, Rosa M. Badia, Daniel R. Witte, Allan Linneberg, Friman Sánchez, Mercè Planas-Fèlix, Marta Guindo-Martínez, Goutham Atla, Ministerio de Economía y Competitividad (España), European Foundation for the Study of Diabetes, Instituto de Salud Carlos III, Generalitat de Catalunya, Wellcome Trust, European Commission, Fundación 'la Caixa', National Institute for Health Research (UK), Novo Nordisk Foundation, Badia, Rosa M. [0000-0003-2941-5499], Bonàs-Guarch, Sílvia [0000-0002-2085-7488], Guindo-Martínez, Marta [0000-0002-8099-9170], Miguel-Escalada, Irene [0000-0003-3461-6404], Grarup, Niels [0000-0001-5526-1070], Rodriguez-Fos, Elias [0000-0002-2555-0178], Planas-Fèlix, Mercè [0000-0002-8267-576X], González, Santi [0000-0001-5685-4580], Morgan, Claire C [0000-0002-8191-3738], Moran, Ignasi [0000-0002-3307-7106], Puiggros, Montserrat [0000-0001-5034-7924], Linneberg, Allan [0000-0002-0994-0184], Jørgensen, Marit E [0000-0001-8356-5565], Hansen, Torben [0000-0001-8748-3831], Ferrer, Jorge [0000-0002-5959-5729], Mercader, Josep Maria [0000-0001-8494-3660], Torrents, David [0000-0002-6086-9037], Apollo - University of Cambridge Repository, Barcelona Supercomputing Center, Medical Research Council (MRC), Universitat de Barcelona, and Badia, Rosa M.

Subjects
Male, 0301 basic medicine, Insulin Resistance/genetics, General Physics and Astronomy, GLUCOSE, Technical support, 0302 clinical medicine, Human genetics, Risk Factors, Gene Regulatory Networks, lcsh:Science, media_common, Independent research, RISK, INSULIN-RESISTANCE, Diabetis, Genètica humana, Genome, Multidisciplinary, Genetic Predisposition to Disease/genetics, Diabetes, Biobank, 3. Good health, Multidisciplinary Sciences, Research centre, Science & Technology - Other Topics, LOW-FREQUENCY, DIET-INDUCED OBESITY, Genetic data, SUSCEPTIBILITY LOCI, Genotype, Science, Library science, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Chromosomes, Human, X/genetics, Diabetis--Diagnòstic, Political science, MD Multidisciplinary, Journal Article, Humans, media_common.cataloged_instance, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, European union, METAANALYSIS, Alleles, Chromosomes, Human, X, Science & Technology, Models, Genetic, Diabetes--Diagnosis, Extramural, PANCREATIC-ISLETS, General Chemistry, 030104 developmental biology, CELLS, Susceptibility locus, lcsh:Q, Insulin Resistance, 030217 neurology & neurosurgery, Gene Regulatory Networks/genetics, Genome-Wide Association Study, Ciències de la salut [Àrees temàtiques de la UPC]
Abstract

The reanalysis of existing GWAS data represents a powerful and cost-effective opportunity to gain insights into the genetics of complex diseases. By reanalyzing publicly available type 2 diabetes (T2D) genome-wide association studies (GWAS) data for 70,127 subjects, we identify seven novel associated regions, five driven by common variants (LYPLAL1, NEUROG3, CAMKK2, ABO, and GIP genes), one by a low-frequency (EHMT2), and one driven by a rare variant in chromosome Xq23, rs146662057, associated with a twofold increased risk for T2D in males. rs146662057 is located within an active enhancer associated with the expression of Angiotensin II Receptor type 2 gene (AGTR2), a modulator of insulin sensitivity, and exhibits allelic specific activity in muscle cells. Beyond providing insights into the genetics and pathophysiology of T2D, these results also underscore the value of reanalyzing publicly available data using novel genetic resources and analytical approaches., This work has been sponsored by the grant SEV-2011-00067 of Severo Ochoa Program, awarded by the Spanish Government. This work was supported by an EFSD/Lilly research fellowship. Josep M. Mercader was supported by Sara Borrell Fellowship from the Instituto Carlos III and Beatriu de Pinós fellowship from the Agency for Management of University and Research Grants (AGAUR). Sílvia Bonàs was FI-DGR Fellowship from FI-DGR 2013 from Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR, Generalitat de Catalunya). This study makes use of data generated by the WTCCC. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113. This study also makes use of data generated by the UK10K Consortium, derived from samples from UK10K COHORT IMPUTATION (EGAS00001000713). A full list of the investigators who contributed to the generation of the data is available in www.UK10K.org. Funding for UK10K was provided by the Wellcome Trust under award WT091310. We acknowledge PRACE for awarding us to access MareNostrum supercomputer, based in Spain at Barcelona. The technical support group, particularly Pablo Ródenas and Jorge Rodríguez, from the Barcelona Supercomputing Center is gratefully acknowledged. This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 667191. Mercè Planas-Fèlix is funded by the Obra Social Fundación la Caixa fellowship under the Severo Ochoa 2013 program. Work from Irene Miguel-Escalada, Ignasi Moran, Goutham Atla, and Jorge Ferrer was supported by the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre, the Wellcome Trust (WT101033), Ministerio de Economía y Competitividad (BFU2014-54284-R) and Horizon 2020 (667191). Irene Miguel-Escalada has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska–Curie grant agreement No 658145. We acknowledge Prof. Giulio Cossu (Institute of Inflammation and Repair, University of Manchester) for providing the muscle myoblast cell line. We also acknowledge the InterAct and SIGMA Type 2 Diabetes Consortia for access to the data to replicate the rs146662075 variant. A full list of the investigators of the SIGMA Type 2 Diabetes and the InterAct consortia is provided in Supplementary Notes 3 and 4. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent research center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (www.metabol.ku.dk). This research has been conducted using the UK Biobank Resource (application number 16803). We also acknowledge Bianca C. Porneala, MS for his technical assistance in the collection and curation of the genotype and phenotype data from Partners Biobank. We also thank Marcin von Grotthuss for their support for uploading the summary statistics data to the Type 2 Diabetes Genetic Portal (AMP-T2D portal). Finally, we thank all the Computational Genomics group at the BSC for their helpful discussions and valuable comments on the manuscript.

Published
2018
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4. Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation

Author

Yolande F. M. Ramos, Tom Fiers, Jari Lahti, Tarunveer S. Ahluwalia, Elisa Kasbohm, Silvia Naitza, Hou-Feng Zheng, Charlotte Cerqueira, Ingrid Meulenbelt, Betina H. Thuesen, Ernst Rietzschel, Anne R. Cappola, John P. Walsh, Alessandro De Grandi, Johan G. Eriksson, Suzanne J. Brown, Jiaojiao Jing, Deborah Mascalzoni, Nicole Soranzo, Daniel Taliun, Margreet Kloppenburg, Purdey J Campbell, Kai-Uwe Eckardt, Yong Li, Mauro Pala, Marco Medici, Florian Kronenberg, Caterina Barbieri, Francesco Cucca, Allan Linneberg, Anna Köttgen, Bruce M. Psaty, Eric Boerwinkle, Ian J. Deary, Jennie Hui, Joris Deelen, Matthijs Moed, Astrid Petersmann, Graziano Ceresini, Michela Marina, Iris Postmus, Alice M. Arnold, Michiaki Kubo, J. Brent Richards, Marc De Buyzere, Henriette E. Meyer zu Schwabedissen, Eleonora Porcu, Christian Fuchsberger, Celia Di Munno, Dan E. Arking, David J. Stott, Toshiko Tanaka, Sofie Bekaert, Andrew A. Hicks, W. Edward Visser, Wouter den Hollander, Martin Gögele, Cinzia Sala, Peter P. Pramstaller, Georg Homuth, Yukinori Okada, Arne Astrup, Arif B. Ekici, Ulla T. Schultheiss, Richard A. Jensen, Christa Meisinger, Romana T. Netea-Maier, Rafael T. Mikolajczyk, Theo J. Visser, Marian Beekman, Michela Traglia, David C. Liewald, Koichi Matsuda, Thorkild I. A. Sørensen, Ilja M. Nolte, André G. Uitterlinden, David Schlessinger, Luigi Ferrrucci, Shuo Li, Alexander Teumer, Daniel Tiller, Sarah E. Harris, J. Wouter Jukema, Rajesh Rawal, Tim De Meyer, Kadri Haljas, Greet Roef, Yoichiro Kamatani, Karin Halina Greiser, Jean-Marc Kaufman, Serena Sanna, Bruce H. R. Wolffenbuttel, Scott Wilson, Daniela Toniolo, Ee Mun Lim, Stefan Groeneweg, Caroline S. Fox, Torben Hansen, Masato Akiyama, Christian Gieger, Layal Chaker, Tim D. Spector, Ian Ford, Martin den Heijer, P. Eline Slagboom, Elizabeth Selvin, Lambertus A. Kiemeney, Emil V. R. Appel, Niels Grarup, Diana van Heemst, Youri Taes, Robin P. Peeters, Henry Völzke, Cristian Pattaro, Daniel Medenwald, John M. Starr, Qiong Yang, Jerome I. Rotter, M. Arfan Ikram, Edoardo Fiorillo, Till Ittermann, Oluf Pedersen, Eero Kajantie, John Beilby, Tessel E. Galesloot, Fernando Rivadeneira, Paul Redmond, Bruno Lapauw, Lifelines Cohort Study, Alizadeh, B.Z., Boezen, H.M., Franke, L., van der Harst, P., Navis, G., Rots, M., Snieder, H., Swertz, M.A., Wijmenga, C., Life Course Epidemiology (LCE), Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Clinicum, University of Helsinki, Department of Psychology and Logopedics, Doctoral Programme in Cognition, Learning, Instruction and Communication, Medicum, Lastentautien yksikkö, Children's Hospital, HUS Children and Adolescents, Developmental Psychology Research Group, Internal medicine, AGEM - Endocrinology, metabolism and nutrition, Amsterdam Movement Sciences - Rehabilitation & Development, Amsterdam Movement Sciences - Restoration and Development, APH - Aging & Later Life, Epidemiology, Internal Medicine, Teumer, Alexander [0000-0002-8309-094X], Ahluwalia, Tarunveer S [0000-0002-7464-3354], Appel, Emil Vincent R [0000-0001-7704-6611], Astrup, Arne [0000-0001-8968-8996], Beekman, Marian [0000-0003-0585-6206], Beilby, John P [0000-0002-4915-2254], Ekici, Arif B [0000-0001-6099-7066], Grarup, Niels [0000-0001-5526-1070], Hansen, Torben [0000-0001-8748-3831], Hicks, Andrew A [0000-0001-6320-0411], Ikram, M Arfan [0000-0003-0372-8585], Jukema, J Wouter [0000-0002-3246-8359], Kamatani, Yoichiro [0000-0001-8748-5597], Kronenberg, Florian [0000-0003-2229-1120], Lahti, Jari [0000-0002-4310-5297], Li, Shuo [0000-0003-2331-2448], Liewald, David CM [0000-0002-0544-7368], Linneberg, Allan [0000-0002-0994-0184], Mascalzoni, Deborah [0000-0003-4156-1464], Meulenbelt, Ingrid [0000-0001-7786-7081], Netea-Maier, Romana T [0000-0002-9603-0460], Nolte, Ilja M [0000-0001-5047-4077], Okada, Yukinori [0000-0002-0311-8472], Ramos, Yolande FM [0000-0003-1459-413X], Richards, J Brent [0000-0002-3746-9086], Soranzo, Nicole [0000-0003-1095-3852], Yang, Qiong [0000-0002-3658-1375], Köttgen, Anna [0000-0002-4671-3714], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Genetic variants, endocrine system diseases, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], Thyroid Gland, Thyrotropin, Metabolyzing hormone (AADAT), General Physics and Astronomy, EFFICIENT, Genome-wide association study, Thyroid hormone transporter (SLC17A4), Disease, VARIANTS, Bioinformatics, Hyperthyroidism, DISEASE, 0302 clinical medicine, SUBCLINICAL HYPOTHYROIDISM, Risk Factors, Genome-wide analysis, Chlorocebus aethiops, Faculty of Science, Medicine, lcsh:Science, POPULATION, RISK, education.field_of_study, Multidisciplinary, HERITABILITY, Thyroid disease, Thyroid, Thyroid dysfunction, ASSOCIATION, 3. Good health, medicine.anatomical_structure, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], COS Cells, Thyroid function, Sodium-Phosphate Cotransporter Proteins, Type I, Thyroid Hormones, endocrine system, PARTICIPANT DATA-ANALYSIS, Science, Population, 030209 endocrinology & metabolism, Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9], Polymorphism, Single Nucleotide, White People, Article, General Biochemistry, Genetics and Molecular Biology, MONOCARBOXYLATE TRANSPORTER-8, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Hypothyroidism, Animals, Humans, ddc:610, education, METAANALYSIS, Genetic association, 2-Aminoadipate Transaminase, IDENTIFICATION, business.industry, Biology and Life Sciences, Biological Transport, General Chemistry, REFERENCE RANGE, medicine.disease, R1, 2-Aminoadipate Transaminase/genetics, 2-Aminoadipate Transaminase/metabolism, Cercopithecus aethiops, European Continental Ancestry Group, Gene Expression Regulation/genetics, Genome-Wide Association Study, Hyperthyroidism/genetics, Hyperthyroidism/physiopathology, Hypothyroidism/genetics, Hypothyroidism/physiopathology, Sodium-Phosphate Cotransporter Proteins, Type I/genetics, Sodium-Phosphate Cotransporter Proteins, Type I/metabolism, Thyroid Gland/metabolism, Thyroid Gland/physiopathology, Thyroid Hormones/genetics, Thyroid Hormones/metabolism, Thyrotropin/metabolism, 030104 developmental biology, Gene Expression Regulation, ATRIAL-FIBRILLATION, lcsh:Q, 3111 Biomedicine, business, Thyroid hormone regulation, Hormone
Abstract

Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves’ disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets., Thyroid dysfunction is a common public health problem and associated with cardiovascular co-morbidities. Here, the authors carry out genome-wide meta-analysis for thyroid hormone (TH) levels, hyper- and hypothyroidism and identify SLC17A4 as a TH transporter and AADAT as a TH metabolizing enzyme.

Published
2018
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