Open Access Research article

Mutation screen in the GWAS derived obesity gene SH2B1 including functional analyses of detected variants

Anna-Lena Volckmar1, Florian Bolze2, Ivonne Jarick3, Nadja Knoll1, André Scherag4, Thomas Reinehr5, Thomas Illig67, Harald Grallert6, Heinz-Erich Wichmann6, Susanna Wiegand8, Heike Biebermann8, Heiko Krude8, Pamela Fischer-Posovszky9, Winfried Rief10, Martin Wabitsch9, Martin Klingenspor2, Johannes Hebebrand1 and Anke Hinney1*

Author Affiliations

1 Department of Child and Adolescent Psychiatry, University Duisburg-Essen, Virchowstr. 171, D 45147, Essen, Germany

2 Molecular Nutritional Medicine, Else Kröner-Fresenius Center and Research Center for Nutrition and Food Science, Technical University Munich, München, Germany

3 Institute of Medical Biometry and Epidemiology, University of Marburg, Marburg, Germany

4 Institute of Medical Informatics, Biometry and Epidemiology, University of Duisburg-Essen, Essen, Germany

5 Vestische Children's Hospital Datteln, University of Witten/Herdecke, North Rhine-Westphalia, Germany

6 Institute of Epidemiology, Helmholtz-Zentrum, Munich, Germany

7 Hannover Unified Biobank, Hannover Medical School, Hannover, Germany

8 Institute of Experimental Pediatric Endocrinology, Charité, Berlin, Germany

9 Division of Pediatric Endocrinology and Diabetes, Department of Children and Adolescent Medicine, University of Ulm University Medical Center, Ulm, Germany

10 Division of Clinical Psychology, University of Marburg, Marburg, Germany

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BMC Medical Genomics 2012, 5:65  doi:10.1186/1755-8794-5-65

Published: 27 December 2012



The SH2B1 gene (Src-homology 2B adaptor protein 1 gene) is a solid candidate gene for obesity. Large scale GWAS studies depicted markers in the vicinity of the gene; animal models suggest a potential relevance for human body weight regulation.


We performed a mutation screen for variants in the SH2B1 coding sequence in 95 extremely obese children and adolescents. Detected variants were genotyped in independent childhood and adult study groups (up to 11,406 obese or overweight individuals and 4,568 controls). Functional implications on STAT3 mediated leptin signalling of the detected variants were analyzed in vitro.


We identified two new rare mutations and five known SNPs (rs147094247, rs7498665, rs60604881, rs62037368 and rs62037369) in SH2B1. Mutation g.9483C/T leads to a non-synonymous, non-conservative exchange in the beta (βThr656Ile) and gamma (γPro674Ser) splice variants of SH2B1. It was additionally detected in two of 11,206 (extremely) obese or overweight children, adolescents and adults, but not in 4,506 population-based normal-weight or lean controls. The non-coding mutation g.10182C/A at the 3’ end of SH2B1 was only detected in three obese individuals. For the non-synonymous SNP rs7498665 (Thr484Ala) we observed nominal over-transmission of the previously described risk allele in 705 obesity trios (nominal p = 0.009, OR = 1.23) and an increased frequency of the same allele in 359 cases compared to 429 controls (nominal p = 0.042, OR = 1.23). The obesity risk-alleles at Thr484Ala and βThr656Ile/γPro674Ser had no effect on STAT3 mediated leptin receptor signalling in splice variants β and γ.


The rare coding mutation βThr656Ile/γPro674Ser (g.9483C/T) in SH2B1 was exclusively detected in overweight or obese individuals. Functional analyzes did not reveal impairments in leptin signalling for the mutated SH2B1.

SH2B1; Obesity; BMI; rs7498665; Mutation screen