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Analysis of genes involved in body weight regulation by targeted re-sequencing

  • Introduction Genes involved in body weight regulation that were previously investigated in genome-wide association studies (GWAS) and in animal models were target-enriched followed by massive parallel next generation sequencing. Methods We enriched and re-sequenced continuous genomic regions comprising FTO, MC4R, TMEM18, SDCCAG8, TKNS, MSRA and TBC1D1 in a screening sample of 196 extremely obese children and adolescents with age and sex specific body mass index (BMI) >= 99th percentile and 176 lean adults (BMI <= 15th percentile). 22 variants were confirmed by Sanger sequencing. Genotyping was performed in up to 705 independent obesity trios (extremely obese child and both parents), 243 extremely obese cases and 261 lean adults. Results and Conclusion We detected 20 different non-synonymous variants, one frame shift and one nonsense mutation in the 7 continuous genomic regions in study groups of different weight extremes. For SNP Arg695Cys (rs58983546) in TBC1D1 we detected nominal association with obesity (p(TDT) =Introduction Genes involved in body weight regulation that were previously investigated in genome-wide association studies (GWAS) and in animal models were target-enriched followed by massive parallel next generation sequencing. Methods We enriched and re-sequenced continuous genomic regions comprising FTO, MC4R, TMEM18, SDCCAG8, TKNS, MSRA and TBC1D1 in a screening sample of 196 extremely obese children and adolescents with age and sex specific body mass index (BMI) >= 99th percentile and 176 lean adults (BMI <= 15th percentile). 22 variants were confirmed by Sanger sequencing. Genotyping was performed in up to 705 independent obesity trios (extremely obese child and both parents), 243 extremely obese cases and 261 lean adults. Results and Conclusion We detected 20 different non-synonymous variants, one frame shift and one nonsense mutation in the 7 continuous genomic regions in study groups of different weight extremes. For SNP Arg695Cys (rs58983546) in TBC1D1 we detected nominal association with obesity (p(TDT) = 0.03 in 705 trios). Eleven of the variants were rare, thus were only detected heterozygously in up to ten individual(s) of the complete screening sample of 372 individuals. Two of them (in FTO and MSRA) were found in lean individuals, nine in extremely obese. In silico analyses of the 11 variants did not reveal functional implications for the mutations. Concordant with our hypothesis we detected a rare variant that potentially leads to loss of FTO function in a lean individual. For TBC1D1, in contrary to our hypothesis, the loss of function variant (Arg443Stop) was found in an obese individual. Functional in vitro studies are warranted.show moreshow less

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Metadaten
Author:Anna-Lena Volckmar, Chung-Ting HanORCiD, Carolin Pütter, Stefan Haas, Carla I. G. Vogel, Nadja Knoll, Christoph Struve, Maria Göbel, Katharina Haas, Nikolas Herrfurth, Ivonne Jarick, Harald Grallert, Annette SchürmannORCiDGND, Hadi Al- Hasani, Johannes Hebebrand, Sascha Sauer, Anke Hinney
URN:urn:nbn:de:kobv:517-opus4-410289
Parent Title (English):PLoS ONE
Series (Serial Number):Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe (423)
Document Type:Postprint
Language:English
Date of first Publication:2018/05/18
Year of Completion:2016
Publishing Institution:Universität Potsdam
Release Date:2018/05/18
Tag:FTO gene; diabetes-melllitus; fat mass; genome-wide analysis; life-style intervention; mass index; melanocortin-4 receptor gene; onset extreme obesity; overweight children; stimulated glucose-uptake
Pagenumber:16
Source:PLoS ONE 11 (2016) Nr. 2, S. 1–16 DOI: 10.1371/journal.pone.0147904
Organizational units:Mathematisch-Naturwissenschaftliche Fakultät
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 50 Naturwissenschaften / 500 Naturwissenschaften und Mathematik
6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Peer Review:Referiert
Publication Way:Open Access
Grantor:Public Library of Science (PLOS)
Licence (German):License LogoCreative Commons - Namensnennung, 4.0 International