Genetic variants in genes involved in creatine biosynthesis in patients with severe obesity or anorexia nervosa

Luisa S Rajcsanyi; Anne Hoffmann; Adhideb Ghosh; Birgit Matrisch-Dinkler; Yiran Zheng; Triinu Peters; Wenfei Sun; Hua Dong; Falko Noé; Christian Wolfrum; Beate Herpertz-Dahlmann; Jochen Seitz; Martina de Zwaan; Wolfgang Herzog; Stefan Ehrlich; Stephan Zipfel; Katrin Giel; Karin Egberts; Roland Burghardt; Manuel Föcker; Linus T Tsai; Timo D Müller; Matthias Blüher; Johannes Hebebrand; Raphael Hirtz; Anke Hinney

doi:10.3389/fgene.2023.1128133

Genetic variants in genes involved in creatine biosynthesis in patients with severe obesity or anorexia nervosa

Front Genet. 2023 Apr 10:14:1128133. doi: 10.3389/fgene.2023.1128133. eCollection 2023.

Authors

Luisa S Rajcsanyi^{1

2}, Anne Hoffmann³, Adhideb Ghosh⁴, Birgit Matrisch-Dinkler¹, Yiran Zheng^{1

2}, Triinu Peters^{1

2}, Wenfei Sun⁴, Hua Dong⁴, Falko Noé⁴, Christian Wolfrum⁴, Beate Herpertz-Dahlmann⁵, Jochen Seitz⁵, Martina de Zwaan⁶, Wolfgang Herzog⁷, Stefan Ehrlich^{8

9}, Stephan Zipfel^{10

11}, Katrin Giel^{10

11}, Karin Egberts¹², Roland Burghardt¹³, Manuel Föcker¹⁴, Linus T Tsai¹⁵, Timo D Müller^{16

17}, Matthias Blüher³, Johannes Hebebrand^{1

2}, Raphael Hirtz^{1

18

19}, Anke Hinney^{1

2}

Affiliations

¹ Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
² Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, Essen, Germany.
³ 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.
⁴ Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland.
⁵ Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital of the RWTH Aachen, Aachen, Germany.
⁶ Department of Psychosomatic Medicine and Psychotherapy, Hannover Medical School, Hannover, Germany.
⁷ Department of Internal Medicine II, General Internal and Psychosomatic Medicine, University of Heidelberg, Heidelberg, Germany.
⁸ Translational Developmental Neuroscience Section, Division of Psychological and Social Medicine and Developmental Neurosciences, Faculty of Medicine, TU Dresden, Dresden, Germany.
⁹ Eating Disorders Research and Treatment Center, Department of Child and Adolescent Psychiatry, Faculty of Medicine, TU Dresden, Dresden, Germany.
¹⁰ Department of Psychosomatic Medicine and Psychotherapy, Medical University Hospital Tübingen, Tübingen, Germany.
¹¹ Center of Excellence in Eating Disorders KOMET, Tübingen, Germany.
¹² 12 Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Würzburg, Würzburg, Germany.
¹³ 13 Child and Adolescent Psychiatry Clinic, Oberberg Fachklinik Fasanenkiez Berlin, Berlin, Germany.
¹⁴ 14 Department of Child and Adolescent Psychiatry, University Hospital Münster, Münster, Germany.
¹⁵ 15 Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States.
¹⁶ 16 Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, München, Germany.
¹⁷ 17 German Center for Diabetes Research (DZD), Neuherberg, Germany.
¹⁸ 18 Department of Pediatrics, Division of Rare Diseases, and CeSER, Ruhr-University Bochum, Bochum, Germany.
¹⁹ 19 Department of Pediatric Endocrinology and Diabetology, Clinic for Pediatrics II, University Hospital Essen, Essen, Germany.

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.

Keywords: BAT; GWAS; TDT; creatine metabolism; in silico.

Copyright © 2023 Rajcsanyi, Hoffmann, Ghosh, Matrisch-Dinkler, Zheng, Peters, Sun, Dong, Noé, Wolfrum, Herpertz-Dahlmann, Seitz, de Zwaan, Herzog, Ehrlich, Zipfel, Giel, Egberts, Burghardt, Föcker, Tsai, Müller, Blüher, Hebebrand, Hirtz and Hinney.

Abstract

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