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Genet."],"abstract":"<jats:p>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 (<jats:italic>CKB<\/jats:italic>, <jats:italic>CKMT1B<\/jats:italic>, and <jats:italic>GATM<\/jats:italic>) revealed one sex-dimorphic BMI-associated SNP in <jats:italic>CKB<\/jats:italic> (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, <jats:italic>CKB<\/jats:italic> and <jats:italic>GATM<\/jats:italic>, and nine variants in the coding sequence of <jats:italic>CKMT1B<\/jats:italic>. Non-synonymous variants identified in <jats:italic>CKB<\/jats:italic> and <jats:italic>CKMT1B<\/jats:italic> 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). <jats:italic>In silico<\/jats:italic> 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 <jats:italic>CKMT1B<\/jats:italic>. Subsequent correlation analyses in 1,479 individuals of the Leipzig Obesity BioBank revealed distinct correlations of <jats:italic>CKB<\/jats:italic> 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 <jats:italic>in vitro<\/jats:italic> analyses are needed to assess the functional implications of these findings.<\/jats:p>","DOI":"10.3389\/fgene.2023.1128133","type":"journal-article","created":{"date-parts":[[2023,4,10]],"date-time":"2023-04-10T04:28:46Z","timestamp":1681100926000},"update-policy":"http:\/\/dx.doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Genetic variants in genes involved in creatine biosynthesis in patients with severe obesity or anorexia nervosa"],"prefix":"10.3389","volume":"14","author":[{"given":"Luisa S.","family":"Rajcsanyi","sequence":"first","affiliation":[]},{"given":"Anne","family":"Hoffmann","sequence":"additional","affiliation":[]},{"given":"Adhideb","family":"Ghosh","sequence":"additional","affiliation":[]},{"given":"Birgit","family":"Matrisch-Dinkler","sequence":"additional","affiliation":[]},{"given":"Yiran","family":"Zheng","sequence":"additional","affiliation":[]},{"given":"Triinu","family":"Peters","sequence":"additional","affiliation":[]},{"given":"Wenfei","family":"Sun","sequence":"additional","affiliation":[]},{"given":"Hua","family":"Dong","sequence":"additional","affiliation":[]},{"given":"Falko","family":"No\u00e9","sequence":"additional","affiliation":[]},{"given":"Christian","family":"Wolfrum","sequence":"additional","affiliation":[]},{"given":"Beate","family":"Herpertz-Dahlmann","sequence":"additional","affiliation":[]},{"given":"Jochen","family":"Seitz","sequence":"additional","affiliation":[]},{"given":"Martina","family":"de Zwaan","sequence":"additional","affiliation":[]},{"given":"Wolfgang","family":"Herzog","sequence":"additional","affiliation":[]},{"given":"Stefan","family":"Ehrlich","sequence":"additional","affiliation":[]},{"given":"Stephan","family":"Zipfel","sequence":"additional","affiliation":[]},{"given":"Katrin","family":"Giel","sequence":"additional","affiliation":[]},{"given":"Karin","family":"Egberts","sequence":"additional","affiliation":[]},{"given":"Roland","family":"Burghardt","sequence":"additional","affiliation":[]},{"given":"Manuel","family":"F\u00f6cker","sequence":"additional","affiliation":[]},{"given":"Linus T.","family":"Tsai","sequence":"additional","affiliation":[]},{"given":"Timo D.","family":"M\u00fcller","sequence":"additional","affiliation":[]},{"given":"Matthias","family":"Bl\u00fcher","sequence":"additional","affiliation":[]},{"given":"Johannes","family":"Hebebrand","sequence":"additional","affiliation":[]},{"given":"Raphael","family":"Hirtz","sequence":"additional","affiliation":[]},{"given":"Anke","family":"Hinney","sequence":"additional","affiliation":[]}],"member":"1965","published-online":{"date-parts":[[2023,4,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"724","DOI":"10.1001\/archgenpsychiatry.2011.74","article-title":"Mortality rates in patients with anorexia nervosa and other eating disorders. 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