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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.

Original publication




Journal article



Publication Date





343 - 358


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:


DIAGRAM+Consortium, Cells, Cultured, Cell Line, Animals, Humans, Diabetes Mellitus, Type 2, Insulin Resistance, Homeodomain Proteins, PPAR gamma, Transcription Factors, Gene Expression Regulation, Regulatory Sequences, Nucleic Acid, Conserved Sequence, Polymorphism, Single Nucleotide, Genome-Wide Association Study