Frontiers in Genetics (Apr 2023)
Genetic variants in genes involved in creatine biosynthesis in patients with severe obesity or anorexia nervosa
- Luisa S. Rajcsanyi,
- Luisa S. Rajcsanyi,
- Anne Hoffmann,
- Adhideb Ghosh,
- Birgit Matrisch-Dinkler,
- Yiran Zheng,
- Yiran Zheng,
- Triinu Peters,
- Triinu Peters,
- Wenfei Sun,
- Hua Dong,
- Falko Noé,
- Christian Wolfrum,
- Beate Herpertz-Dahlmann,
- Jochen Seitz,
- Martina de Zwaan,
- Wolfgang Herzog,
- Stefan Ehrlich,
- Stefan Ehrlich,
- Stephan Zipfel,
- Stephan Zipfel,
- Katrin Giel,
- Katrin Giel,
- Karin Egberts,
- Roland Burghardt,
- Manuel Föcker,
- Linus T. Tsai,
- Timo D. Müller,
- Timo D. Müller,
- Matthias Blüher,
- Johannes Hebebrand,
- Johannes Hebebrand,
- Raphael Hirtz,
- Raphael Hirtz,
- Raphael Hirtz,
- Anke Hinney,
- Anke Hinney
Affiliations
- Luisa S. Rajcsanyi
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- Luisa S. Rajcsanyi
- Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, Essen, Germany
- Anne Hoffmann
- Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Leipzig, Germany
- Adhideb Ghosh
- Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland
- Birgit Matrisch-Dinkler
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- Yiran Zheng
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- Yiran Zheng
- Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, Essen, Germany
- Triinu Peters
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- Triinu Peters
- Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, Essen, Germany
- Wenfei Sun
- Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland
- Hua Dong
- Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland
- Falko Noé
- Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland
- Christian Wolfrum
- Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland
- Beate Herpertz-Dahlmann
- Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital of the RWTH Aachen, Aachen, Germany
- Jochen Seitz
- Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital of the RWTH Aachen, Aachen, Germany
- Martina de Zwaan
- Department of Psychosomatic Medicine and Psychotherapy, Hannover Medical School, Hannover, Germany
- Wolfgang Herzog
- Department of Internal Medicine II, General Internal and Psychosomatic Medicine, University of Heidelberg, Heidelberg, Germany
- Stefan Ehrlich
- Translational Developmental Neuroscience Section, Division of Psychological and Social Medicine and Developmental Neurosciences, Faculty of Medicine, TU Dresden, Dresden, Germany
- Stefan Ehrlich
- Eating Disorders Research and Treatment Center, Department of Child and Adolescent Psychiatry, Faculty of Medicine, TU Dresden, Dresden, Germany
- Stephan Zipfel
- 0Department of Psychosomatic Medicine and Psychotherapy, Medical University Hospital Tübingen, Tübingen, Germany
- Stephan Zipfel
- 1Center of Excellence in Eating Disorders KOMET, Tübingen, Germany
- Katrin Giel
- 0Department of Psychosomatic Medicine and Psychotherapy, Medical University Hospital Tübingen, Tübingen, Germany
- Katrin Giel
- 1Center of Excellence in Eating Disorders KOMET, Tübingen, Germany
- Karin Egberts
- 2Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Würzburg, Würzburg, Germany
- Roland Burghardt
- 3Child and Adolescent Psychiatry Clinic, Oberberg Fachklinik Fasanenkiez Berlin, Berlin, Germany
- Manuel Föcker
- 4Department of Child and Adolescent Psychiatry, University Hospital Münster, Münster, Germany
- Linus T. Tsai
- 5Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
- Timo D. Müller
- 6Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, München, Germany
- Timo D. Müller
- 7German Center for Diabetes Research (DZD), Neuherberg, Germany
- Matthias Blüher
- Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Leipzig, Germany
- Johannes Hebebrand
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- Johannes Hebebrand
- Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, Essen, Germany
- Raphael Hirtz
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- Raphael Hirtz
- 8Department of Pediatrics, Division of Rare Diseases, and CeSER, Ruhr-University Bochum, Bochum, Germany
- Raphael Hirtz
- 9Department of Pediatric Endocrinology and Diabetology, Clinic for Pediatrics II, University Hospital Essen, Essen, Germany
- Anke Hinney
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- Anke Hinney
- Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, Essen, Germany
- DOI
- https://doi.org/10.3389/fgene.2023.1128133
- Journal volume & issue
-
Vol. 14
Abstract
Increased thermogenesis in brown adipose tissue might have an obesity-reducing effect in humans. In transgenic mice, depletion of genes involved in creatine metabolism results in disrupted thermogenic capacity and altered effects of high-fat feeding on body weight. Data analyses of a sex-stratified genome-wide association study (GWAS) for body mass index (BMI) within the genomic regions of genes of this pathway (CKB, CKMT1B, and GATM) revealed one sex-dimorphic BMI-associated SNP in CKB (rs1136165). The effect size was larger in females than in males. A mutation screen of the coding regions of these three candidate genes in a screening group (192 children and adolescents with severe obesity, 192 female patients with anorexia nervosa, and 192 healthy-lean controls) identified five variants in each, CKB and GATM, and nine variants in the coding sequence of CKMT1B. Non-synonymous variants identified in CKB and CKMT1B were genotyped in an independent confirmation study group (781 families with severe obesity (trios), 320 children and adolescents with severe obesity, and 253 healthy-lean controls). In silico tools predicted mainly benign yet protein-destabilizing potentials. A transmission disequilibrium test in trios with severe obesity indicated an obesity-protective effect of the infrequent allele at rs149544188 located in CKMT1B. Subsequent correlation analyses in 1,479 individuals of the Leipzig Obesity BioBank revealed distinct correlations of CKB with the other two genes in omental visceral adipose tissue (VAT) and abdominal subcutaneous adipose tissue (SAT). Furthermore, between-subject comparisons of gene expression levels showed generally higher expressions of all three genes of interest in VAT than in SAT. Future in vitro analyses are needed to assess the functional implications of these findings.
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