Genome-wide association studies (GWAS) have revealed association of a locus approximately 25b downstream of the TMEM18 gene with body mass and obesity. We utilized targeted re-sequencing of the body mass associated locus in proximity of TMEM18 in a case-control population of severely obese children and adolescents from the Stockholm area. We expanded our study to include the TMEM18 gene itself, with the aim of identifying body mass associated genetic variants. Sequencing was performed on the SOLiD platform, on long-range PCR fragments generated through targeted amplification of the regions of interest. Candidate single nucleotide polymorphisms (SNPs) were validated by TaqMan genotyping. We were able to observe 131 SNPs across the re-sequenced regions. Chi squared tests comparing the allele frequencies between cases and controls revealed 57 SNPs as candidates for association with obesity. Validation and replication genotyping revealed robust associations for SNPs within the haplotype block region located downstream from the TMEM18 gene. This study provides a high resolution map of the genetic variation pattern in the TMEM18 gene, as well as the associated haplotype block, and further strengthens the association of variants within the proximal haplotype block with obesity and body mass.

中文翻译：

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在小儿肥胖病例对照队列中，通过超深度靶向再测序确定与TMEM18相关的肥胖相关基因变异。

全基因组关联研究（GWAS）显示，TMEM18基因下游约25b的基因座与体重和肥胖症相关。在斯德哥尔摩地区一个严重肥胖的儿童和青少年的病例对照人群中，我们在TMEM18附近使用了与体重相关的基因座的靶向重测序。我们扩大了研究范围，将TMEM18基因本身包括在内，目的是鉴定与体重相关的遗传变异。在SOLiD平台上，对通过目标区域的靶向扩增产生的长距离PCR片段进行测序。候选单核苷酸多态性（SNPs）已通过TaqMan基因分型验证。我们能够在重新排序的区域中观察到131个SNP。卡方检验比较了病例与对照之间的等位基因频率，发现有57个SNPs与肥胖相关。验证和复制基因分型显示了位于TMEM18基因下游的单倍型区域内SNP的强相关性。这项研究提供了TMEM18基因以及相关单体型模块的遗传变异模式的高分辨率图，并进一步加强了近端单体型模块内的变体与肥胖症和体重的联系。