ArticleCell2014
Leveraging cross-species transcription factor binding site patterns: from diabetes risk loci to disease mechanisms.
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In one paragraph
Article in Cell, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 77 papers, 2 of them syntheses that pooled it.
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77citing papers in PubMed, 2 pooled it
9.4field-weighted citation impact, top 1% of its field
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Who cites it
77 citing papers in PubMed, 2 syntheses or guidelines pooled it, 128 citations in OpenAlex.
- Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes.Nature genetics · 2018Pooled it
- Trans-ethnic Meta-analysis and Functional Annotation Illuminates the Genetic Architecture of Fasting Glucose and Insulin.American journal of human genetics · 2016Pooled it
- Human Genetics of Adipose Dysfunction: Genomic Mechanisms and Therapeutic Opportunities in Cardiometabolic Disease.Arteriosclerosis, thrombosis, and vascular biology · 2026Review
- Scalable context-dependent single-cell eQTL mapping reveals disease-relevant regulatory variation beyond static models.medRxiv : the preprint server for health sciences · 2026Article
- Bridging the variant-to-function gap in type 2 diabetes: advances and challenges.Diabetologia · 2026Review
- Tissue-Specific Multi-Omics Integration Demonstrates Molecular Signatures Connecting Obesity to Immune Vulnerability.Metabolites · 2026Article
- Navigating the Strengths and Constraints of Mouse Models in Obesity Research.Endocrinology · 2025Review
- Genome-wide identification and analysis of recurring patterns of epigenetic variation across individuals.Communications biology · 2025Article
- Variant-to-function approaches for adipose tissue: Insights into cardiometabolic disorders.Cell genomics · 2025Review
- Distinct Roles of Common Genetic Variants and Their Contributions to Diabetes: MODY and Uncontrolled T2DM.Biomolecules · 2025Review
- Computational Assessment of the Expression-modulating Potential for Non-coding Variants.Genomics, proteomics & bioinformatics · 2023Article
- A non-coding variant linked to metabolic obesity with normal weight affects actin remodelling in subcutaneous adipocytes.Nature metabolism · 2023Article
- Physiological and pathological roles of lipogenesis.Nature metabolism · 2023Review
- Paired related homeobox 1 attenuates autophagy via acetyl-CoA carboxylase 1-regulated fatty acid metabolism in salivary adenoid cystic carcinoma.FEBS open bio · 2022Article
- A leukemia-protective germline variant mediates chromatin module formation via transcription factor nucleation.Nature communications · 2022Article
- Long-read isoform sequencing reveals tissue-specific isoform expression between active and hibernating brown bears (Ursus arctos).G3 (Bethesda, Md.) · 2022Article
- Gaining insight into metabolic diseases from human genetic discoveries.Trends in genetics : TIG · 2021Review
- REVA as A Well-curated Database for Human Expression-modulating Variants.Genomics, proteomics & bioinformatics · 2021Article
- Linking theScience advances · 2021Article
- Extensive pleiotropism and allelic heterogeneity mediate metabolic effects ofScience (New York, N.Y.) · 2021Article
17 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
38 authors at 12 institutions in 6 countries.
Melina ClaussnitzerChair 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.
Simon N DankelDepartment 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.
Bernward KlockeGenomatix Software GmbH, 80335 Munich, Germany.
Harald GrallertGerman Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Viktoria GlunkChair 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.
Tea BerulavaInstitut für Humangenetik, Universitätsklinikum Essen, Universität-Duisburg-Essen, 45147 Essen, Germany.
Heekyoung LeeChair 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.
Nikolay OskolkovDiabetes and Endocrinology Research Unit, Department of Clinical Sciences, Lund University, Malmö 20502, Sweden.
Joao FadistaDiabetes and Endocrinology Research Unit, Department of Clinical Sciences, Lund University, Malmö 20502, Sweden.
Kerstin EhlersChair 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.
Simone WahlGerman Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Christoph HoffmannNutritional 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.
Kun QianChair 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.
Tina RönnDiabetes and Endocrinology Research Unit, Department of Clinical Sciences, Lund University, Malmö 20502, Sweden.
Helene RiessDepartment 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.
Martina Müller-NurasyidInstitute 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.
Nancy BretschneiderGenomatix Software GmbH, 80335 Munich, Germany.
Timm SchroederResearch 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.
Thomas SkurkChair 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.
Bernhard HorsthemkeInstitut für Humangenetik, Universitätsklinikum Essen, Universität-Duisburg-Essen, 45147 Essen, Germany.
DIAGRAM+Consortium
Derek SpielerInstitute 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.
Martin KlingensporNutritional 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 SeifertGenomatix Software GmbH, 80335 Munich, Germany.
Michael J KernDepartment of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA.
Niklas MejhertDepartment of Medicine, Karolinska Institutet, Center for Endocrinology and Metabolism, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden.
Ingrid DahlmanDepartment of Medicine, Karolinska Institutet, Center for Endocrinology and Metabolism, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden.
Ola HanssonDiabetes and Endocrinology Research Unit, Department of Clinical Sciences, Lund University, Malmö 20502, Sweden.
Stefanie M HauckGerman Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Research Unit Protein Science, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Matthias BlüherDepartment of Medicine, University of Leipzig, 04103 Leipzig, Germany.
Peter ArnerDepartment of Medicine, Karolinska Institutet, Center for Endocrinology and Metabolism, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden.
Leif GroopDiabetes and Endocrinology Research Unit, Department of Clinical Sciences, Lund University, Malmö 20502, Sweden.
Thomas IlligResearch Unit of Molecular Epidemiology, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Hanover Unified Biobank, Hanover Medical School, 30625 Hanover, Germany.
Karsten SuhreInstitute 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.
Yi-Hsiang HsuHebrew 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.
Gunnar MellgrenDepartment 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.
Hans HaunerChair 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.
Helmut LaumenChair 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.
Helmholtz Zentrum München · DEKarolinska University Hospital · SELund University · SEMedical University of South Carolina · USHaukeland University Hospital · NOSoftware (Germany) · DETUM Klinikum · DEEssen University Hospital · DEHarvard University · USWeihenstephan-Triesdorf University of Applied Sciences · DELeipzig University · DEUniversität Ulm · DE
Funding
Medical Research Council MC_U106179471Medical Research Council MC_U106179474Medical Research Council MC_UU_12015/1Medical Research Council MC_UU_12015/4Wellcome Trust 086596Wellcome Trust 090532
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.
Indexed as
Polymorphism, Single NucleotideAnimalsCell LineCells, CulturedConserved SequenceDiabetes Mellitus, Type 2Gene Expression RegulationGenome-Wide Association StudyHomeodomain ProteinsHumansInsulin ResistancePPAR gammaRegulatory Sequences, Nucleic AcidTranscription FactorsHomeodomain ProteinsPPAR gammaPRRX1 protein, humanTranscription Factors
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