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Volckmar, A.L.* ; Han, C.T.* ; Pütter, C.* ; Haas, S.* ; Vogel, C.I.* ; Knoll, N.* ; Struve, C.* ; Göbel, M.* ; Haas, K.* ; Herrfurth, N.* ; Jarick, I.* ; Grallert, H. ; Schürmann, A.* ; Al-Hasani, H.* ; Hebebrand, J.* ; Sauer, S.* ; Hinney, A.*

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

PLoS ONE 11:e0147904 (2016)
Verlagsversion DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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 (pTDT = 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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Melanocortin-4 Receptor Gene; Stimulated Glucose-uptake; Life-style Intervention; Onset Extreme Obesity; Genome-wide Analysis; Mass Index; Fto Gene; Fat Mass; Overweight Children; Diabetes-mellitus
ISSN (print) / ISBN 1932-6203
Zeitschrift PLoS ONE
Quellenangaben Band: 11, Heft: 2, Seiten: , Artikelnummer: e0147904 Supplement: ,
Verlag Public Library of Science (PLoS)
Verlagsort Lawrence, Kan.
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Epidemiology II (EPI2)