Dataset Information

Fine Mapping of a GWAS-Derived Obesity Candidate Region on Chromosome 16p11.2.

ABSTRACT:

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.

SUBMITTER: Volckmar AL

PROVIDER: S-EPMC4425372 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Publications

Fine Mapping of a GWAS-Derived Obesity Candidate Region on Chromosome 16p11.2.

Volckmar Anna-Lena AL Song Jie-Yun JY Jarick Ivonne I Pütter Carolin C Göbel Maria M Horn Lucie L Struve Christoph C Haas Katharina K Knoll Nadja N Grallert Harald H Illig Thomas T Reinehr Thomas T Wang Hai-Jun HJ Hebebrand Johannes J Hinney Anke A

PloS one 20150508 5

<h4>Introduction</h4>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 l ...[more]

PMID: 25955518

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Project description:BACKGROUND: Porcine chromosome X harbors four QTL strongly affecting backfat thickness (BFT), ham weight (HW), intramuscular fat content (IMF) and loin eye area (LEA). The confidence intervals (CI) of these QTL overlap and span more than 30 cM, or approximately 80 Mb. This study therefore attempts to fine map these QTL by joint analysis of two large-scale F? populations (Large White × Meishan and White Duroc × Erhualian constructed by INRA and JXAU respectively) and furthermore, to determine whether these QTL are caused by mutations in three positional candidate genes (ACSL4, SERPINA7 and IRS4) involved in lipid biosynthesis. RESULTS: A female-specific linkage map with an average distance of 2 cM between markers in the initial QTL interval (SW2456-SW1943) was created and used here. The CI of QTL for BFT, HW and LEA were narrowed down to 6-7 cM, resulting from the joint analysis. For IMF, two linked QTL were revealed in the INRA population but not in the JXAU population, causing a wider CI (13 cM) for IMF QTL. Linkage analyses using two subsets of INRA F? dam families demonstrate that the BFT and HW QTL were segregating in the Meishan pigs. Moreover, haplotype comparisons between these dams suggest that within the refined QTL region, the recombination coldspot (~34 Mb) flanked by markers MCSE3F14 and UMNP1218 is unlikely to contain QTL genes. Two SNPs in the ACSL4 gene were identified and showed significant association with BFT and HW, but they and the known polymorphisms in the other two genes are unlikely to be causal mutations. CONCLUSION: The candidate QTL regions have been greatly reduced and the QTL are most likely located downstream of the recombination coldspot. The segregation of SSCX QTL for BFT and HW within Meishan breed provides an opportunity for us to make effective use of Meishan chromosome X in crossbreeding. Further studies should attempt to identify the impact of additional DNA sequence (e.g. CNV) and expression variation in the three genes or their surrounding genes on these traits.

Dataset Information

Fine Mapping of a GWAS-Derived Obesity Candidate Region on Chromosome 16p11.2.

Introduction

Methods

Results

Conclusion

Publications

Fine Mapping of a GWAS-Derived Obesity Candidate Region on Chromosome 16p11.2.

Similar Datasets

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