Leveraging cross-species transcription factor binding site patterns: from diabetes risk loci to disease mechanisms.
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.
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.
Melina
M
Claussnitzer
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.
Simon N
SN
Dankel
Genomatix Software GmbH, 80335 Munich, Germany.
Bernward
B
Klocke
German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Harald
H
Grallert
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.
Viktoria
V
Glunk
Institut für Humangenetik, Universitätsklinikum Essen, Universität-Duisburg-Essen, 45147 Essen, Germany.
Tea
T
Berulava
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.
Heekyoung
H
Lee
Diabetes and Endocrinology Research Unit, Department of Clinical Sciences, Lund University, Malmö 20502, Sweden.
Nikolay
N
Oskolkov
Diabetes and Endocrinology Research Unit, Department of Clinical Sciences, Lund University, Malmö 20502, Sweden.
Joao
J
Fadista
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.
Kerstin
K
Ehlers
German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Simone
S
Wahl
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.
Christoph
C
Hoffmann
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.
Kun
K
Qian
Diabetes and Endocrinology Research Unit, Department of Clinical Sciences, Lund University, Malmö 20502, Sweden.
Tina
T
Rönn
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.
Helene
H
Riess
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.
Martina
M
Müller-Nurasyid
Genomatix Software GmbH, 80335 Munich, Germany.
Nancy
N
Bretschneider
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.
Timm
T
Schroeder
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.
Thomas
T
Skurk
Institut für Humangenetik, Universitätsklinikum Essen, Universität-Duisburg-Essen, 45147 Essen, Germany.
Bernhard
B
Horsthemke
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.
Derek
D
Spieler
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.
Martin
M
Klingenspor
Genomatix Software GmbH, 80335 Munich, Germany.
Martin
M
Seifert
Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA.
Michael J
MJ
Kern
Department of Medicine, Karolinska Institutet, Center for Endocrinology and Metabolism, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden.
Niklas
N
Mejhert
Department of Medicine, Karolinska Institutet, Center for Endocrinology and Metabolism, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden.
Ingrid
I
Dahlman
Diabetes and Endocrinology Research Unit, Department of Clinical Sciences, Lund University, Malmö 20502, Sweden.
Ola
O
Hansson
German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Research Unit Protein Science, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Stefanie M
SM
Hauck
Department of Medicine, University of Leipzig, 04103 Leipzig, Germany.
Matthias
M
Blüher
Department of Medicine, Karolinska Institutet, Center for Endocrinology and Metabolism, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden.
Peter
P
Arner
Diabetes and Endocrinology Research Unit, Department of Clinical Sciences, Lund University, Malmö 20502, Sweden.
Leif
L
Groop
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Hanover Unified Biobank, Hanover Medical School, 30625 Hanover, Germany.
Thomas
T
Illig
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.
Karsten
K
Suhre
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.
Yi-Hsiang
YH
Hsu
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.
Gunnar
G
Mellgren
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.
Hans
H
Hauner
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.
Helmut
H
Laumen
D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D017124:Conserved Sequence; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance; D047495:PPAR gamma / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012045:Regulatory Sequences, Nucleic Acid; D014157:Transcription Factors / Q000378:metabolism
D018398:Homeodomain Proteins; D047495:PPAR gamma; C082157:PRRX1 protein, human; D014157:Transcription Factors