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Volckmar, A.L.* ; Song, J.Y.* ; Jarick, I.* ; Pütter, C.* ; Göbel, M.* ; Horn, L.C.* ; Struve, C.* ; Haas, K.* ; Knoll, N.* ; Grallert, H. ; Illig, T. ; Reinehr, T.* ; Wang, H.J.* ; Hebebrand, J.* ; Hinney, A.*

Fine mapping of a GWAS-derived obesity candidate region on chromosome 16p11.2.

PLoS ONE 10:e0125660 (2015)
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INTRODUCTION: Large-scale genome-wide association studies (GWASs) have identified 97 chromosomal loci associated with increased body mass index in population-based studies on adults. One of these SNPs, rs7359397, tags a large region (approx. 1MB) with high linkage disequilibrium (r²>0.7), which comprises five genes (SH2B1, APOBR, sulfotransferases: SULT1A1 and SULT1A2, TUFM). We had previously described a rare mutation in SH2B1 solely identified in extremely obese individuals but not in lean controls. METHODS: The coding regions of the genes APOBR, SULT1A1, SULT1A2, and TUFM were screened for mutations (dHPLC, SSCP, Sanger re-sequencing) in 95 extremely obese children and adolescents. Detected non-synonymous variants were genotyped (TaqMan SNP Genotyping, MALDI TOF, PCR-RFLP) in independent large study groups (up to 3,210 extremely obese/overweight cases, 485 lean controls and 615 obesity trios). In silico tools were used for the prediction of potential functional effects of detected variants. RESULTS: Except for TUFM we detected non-synonymous variants in all screened genes. Two polymorphisms rs180743 (APOBR p.Pro428Ala) and rs3833080 (APOBR p.Gly369_Asp370del9) showed nominal association to (extreme) obesity (uncorrected p = 0.003 and p = 0.002, respectively). In silico analyses predicted a functional implication for rs180743 (APOBR p.Pro428Ala). Both APOBR variants are located in the repetitive region with unknown function. CONCLUSION: Variants in APOBR contributed as strongly as variants in SH2B1 to the association with extreme obesity in the chromosomal region chr16p11.2. In silico analyses implied no functional effect of several of the detected variants. Further in vitro or in vivo analyses on the functional implications of the obesity associated variants are warranted.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Genome-wide Association; Body-mass Index; Performance Liquid-chromatography; Macrophage Apo-b-48 Receptor; Exonic Splicing Enhancers; Onset Extreme Obesity; Apolipoprotein B48; Mutation Detection; Adult Obesity; Human Sh2b1
ISSN (print) / ISBN 1932-6203
Journal PLoS ONE
Quellenangaben Volume: 10, Issue: 5, Pages: , Article Number: e0125660 Supplement: ,
Publisher Public Library of Science (PLoS)
Publishing Place Lawrence, Kan.
Reviewing status Peer reviewed