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Cell. 2014 Jan 16;156(1-2):343-58. doi: 10.1016/j.cell.2013.10.058.

Leveraging cross-species transcription factor binding site patterns: from diabetes risk loci to disease mechanisms.

Collaborators (158)

Voight BF, Scott LJ, Steinthorsdottir V, Morris AP, Dina C, Welch RP, Zeggini E, Huth C, Aulchenko YS, Thorleifsson G, McCulloch LJ, Ferreira T, Grallert H, Amin N, Wu G, Willer CJ, Raychaudhuri S, McCarroll SA, Langenberg C, Hofmann OM, Dupuis J, Qi L, Segrè AV, van Hoek M, Navarro P, Ardlie K, Balkau B, Benediktsson R, Bennett AJ, Blagieva R, Boerwinkle E, Bonnycastle LL, Boström KB, Bravenboer B, Bumpstead S, Burtt NP, Charpentier G, Chines PS, Cornelis M, Couper DJ, Crawford G, Doney AS, Elliott KS, Elliott AL, Erdos MR, Fox CS, Franklin CS, Ganser M, Gieger C, Grarup N, Green T, Griffin S, Groves CJ, Guiducci C, Hadjadj S, Hassanali N, Herder C, Isomaa B, Jackson AU, Johnson PR, Jørgensen T, Kao WH, Klopp N, Kong A, Kraft P, Kuusisto J, Lauritzen T, Li M, Lieverse A, Lindgren CM, Lyssenko V, Marre M, Meitinger T, Midthjell K, Morken MA, Narisu N, Nilsson P, Owen KR, Payne F, Perry JR, Petersen AK, Platou C, Proença C, Prokopenko I, Rathmann W, Rayner NW, Robertson NR, Rocheleau G, Roden M, Sampson MJ, Saxena R, Shields BM, Shrader P, Sigurdsson G, Sparsø T, Strassburger K, Stringham HM, Sun Q, Swift AJ, Thorand B, Tichet J, Tuomi T, van Dam RM, van Haeften TW, van Herpt T, van Vliet-Ostaptchouk JV, Walters GB, Weedon MN, Wijmenga C, Witteman J, Bergman RN, Cauchi S, Collins FS, Gloyn AL, Gyllensten U, Hansen T, Hide WA, Hitman GA, Hofman A, Hunter DJ, Hveem K, Laakso M, Mohlke KL, Morris AD, Palmer CN, Pramstaller PP, Rudan I, Sijbrands E, Stein LD, Tuomilehto J, Uitterlinden A, Walker M, Wareham NJ, Watanabe RM, Abecasis GR, Boehm BO, Campbell H, Daly MJ, Hattersley AT, Hu FB, Meigs JB, Pankow JS, Pedersen O, Wichmann HE, Barroso I, Florez JC, Frayling TM, Groop L, Sladek R, Thorsteinsdottir U, Wilson JF, Illig T, Froguel P, van Duijn CM, Stefansson K, Altshuler D, Boehnke M, McCarthy MI.

Author information

1
Chair of Nutritional Medicine, Technische Universität München, Else Kröner-Fresenius-Center for Nutritional Medicine, 85350 Freising-Weihenstephan, Germany; Nutritional Medicine Unit, ZIEL-Research Center for Nutrition and Food Sciences, Technische Universität München, 85350 Freising-Weihenstephan, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Clinical Cooperation Group Nutrigenomics and Type 2 Diabetes, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany and Technische Universität München, 85350 Freising-Weihenstephan, Germany; Hebrew SeniorLife Institute for Aging Research, Harvard Medical School, Boston, MA 02131, USA. Electronic address: melinaclaussnitzer@hsl.harvard.edu.
2
Department of Clinical Science, University of Bergen, 5021 Bergen, Norway; K.G. Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, N-5021 Bergen, Norway; Hormone Laboratory, Haukeland University Hospital, 5021 Bergen, Norway.
3
Genomatix Software GmbH, 80335 Munich, Germany.
4
German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
5
Chair of Nutritional Medicine, Technische Universität München, Else Kröner-Fresenius-Center for Nutritional Medicine, 85350 Freising-Weihenstephan, Germany; Nutritional Medicine Unit, ZIEL-Research Center for Nutrition and Food Sciences, Technische Universität München, 85350 Freising-Weihenstephan, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Clinical Cooperation Group Nutrigenomics and Type 2 Diabetes, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany and Technische Universität München, 85350 Freising-Weihenstephan, Germany.
6
Institut für Humangenetik, Universitätsklinikum Essen, Universität-Duisburg-Essen, 45147 Essen, Germany.
7
Diabetes and Endocrinology Research Unit, Department of Clinical Sciences, Lund University, Malmö 20502, Sweden.
8
Nutritional Medicine Unit, ZIEL-Research Center for Nutrition and Food Sciences, Technische Universität München, 85350 Freising-Weihenstephan, Germany; Chair of Molecular Nutritional Medicine, Technische Universität München, Else Kröner-Fresenius-Center for Nutritional Medicine, 85350 Freising-Weihenstephan, Germany.
9
Department of Internal Medicine II-Cardiology, University of Ulm Medical Center, 89081 Ulm, Germany; Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, 85764 Neuherberg, Germany.
10
Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, 85764 Neuherberg, Germany; Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-Universität, 81377 Munich, Germany; Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, 81377 Munich, Germany.
11
Research Unit Stem Cell Dynamics, Helmholtz Center Munich-German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany; Department of Biosystems Science and Engineering (D-BSSE), ETH Zurich, 4058 Basel, Switzerland.
12
Chair of Nutritional Medicine, Technische Universität München, Else Kröner-Fresenius-Center for Nutritional Medicine, 85350 Freising-Weihenstephan, Germany; Nutritional Medicine Unit, ZIEL-Research Center for Nutrition and Food Sciences, Technische Universität München, 85350 Freising-Weihenstephan, Germany; Else Kröner-Fresenius-Center for Nutritional Medicine, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
13
Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, German Research Center for Environmental Health, Germany; Department of Neurology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
14
Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA.
15
Department of Medicine, Karolinska Institutet, Center for Endocrinology and Metabolism, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden.
16
German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Research Unit Protein Science, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
17
Department of Medicine, University of Leipzig, 04103 Leipzig, Germany.
18
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Hanover Unified Biobank, Hanover Medical School, 30625 Hanover, Germany.
19
Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany; Department of Physiology and Biophysics, Weill Cornell Medical College in Qatar, Education City, Qatar Foundation, PO Box 24144, Doha, Qatar.
20
Hebrew SeniorLife Institute for Aging Research, Harvard Medical School, Boston, MA 02131, USA; Molecular and Integrative Physiological Sciences, Harvard School of Public Health, Boston, MA 02115, USA.
21
Chair of Nutritional Medicine, Technische Universität München, Else Kröner-Fresenius-Center for Nutritional Medicine, 85350 Freising-Weihenstephan, Germany; Nutritional Medicine Unit, ZIEL-Research Center for Nutrition and Food Sciences, Technische Universität München, 85350 Freising-Weihenstephan, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Clinical Cooperation Group Nutrigenomics and Type 2 Diabetes, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany and Technische Universität München, 85350 Freising-Weihenstephan, Germany; Else Kröner-Fresenius-Center for Nutritional Medicine, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
22
Chair of Nutritional Medicine, Technische Universität München, Else Kröner-Fresenius-Center for Nutritional Medicine, 85350 Freising-Weihenstephan, Germany; Nutritional Medicine Unit, ZIEL-Research Center for Nutrition and Food Sciences, Technische Universität München, 85350 Freising-Weihenstephan, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Clinical Cooperation Group Nutrigenomics and Type 2 Diabetes, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany and Technische Universität München, 85350 Freising-Weihenstephan, Germany; Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg 85764, Germany. Electronic address: helmut.laumen@tum.de.

Abstract

Genome-wide association studies have revealed numerous risk loci associated with diverse diseases. However, identification of disease-causing variants within association loci remains a major challenge. Divergence in gene expression due to cis-regulatory variants in noncoding regions is central to disease susceptibility. We show that integrative computational analysis of phylogenetic conservation with a complexity assessment of co-occurring transcription factor binding sites (TFBS) can identify cis-regulatory variants and elucidate their mechanistic role in disease. Analysis of established type 2 diabetes risk loci revealed a striking clustering of distinct homeobox TFBS. We identified the PRRX1 homeobox factor as a repressor of PPARG2 expression in adipose cells and demonstrate its adverse effect on lipid metabolism and systemic insulin sensitivity, dependent on the rs4684847 risk allele that triggers PRRX1 binding. Thus, cross-species conservation analysis at the level of co-occurring TFBS provides a valuable contribution to the translation of genetic association signals to disease-related molecular mechanisms.

PMID:
24439387
DOI:
10.1016/j.cell.2013.10.058
[Indexed for MEDLINE]
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