TY  - GEN
A1  - Volckmar, Anna-Lena
A1  - Han, Chung-Ting
A1  - Pütter, Carolin
A1  - Haas, Stefan
A1  - Vogel, Carla I. G.
A1  - Knoll, Nadja
A1  - Struve, Christoph
A1  - Göbel, Maria
A1  - Haas, Katharina
A1  - Herrfurth, Nikolas
A1  - Jarick, Ivonne
A1  - Grallert, Harald
A1  - Schürmann, Annette
A1  - Al- Hasani, Hadi
A1  - Hebebrand, Johannes
A1  - Sauer, Sascha
A1  - Hinney, Anke
T1  - Analysis of genes involved in body weight regulation by targeted re-sequencing
T2  - PLoS ONE
N2  - 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.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 423 
KW  - melanocortin-4 receptor gene
KW  - stimulated glucose-uptake
KW  - life-style intervention
KW  - onset extreme obesity
KW  - genome-wide analysis
KW  - mass index
KW  - FTO gene
KW  - fat mass
KW  - overweight children
KW  - diabetes-melllitus
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-410289
ER  -