Institute for Medical Informatics, Biometry and Epidemiology, University of Duisburg-Essen, Essen, Germany.
PLoS Genet. 2010 Apr 22;6(4):e1000916. doi: 10.1371/journal.pgen.1000916.
Meta-analyses of population-based genome-wide association studies (GWAS) in adults have recently led to the detection of new genetic loci for obesity. Here we aimed to discover additional obesity loci in extremely obese children and adolescents. We also investigated if these results generalize by estimating the effects of these obesity loci in adults and in population-based samples including both children and adults. We jointly analysed two GWAS of 2,258 individuals and followed-up the best, according to lowest p-values, 44 single nucleotide polymorphisms (SNP) from 21 genomic regions in 3,141 individuals. After this DISCOVERY step, we explored if the findings derived from the extremely obese children and adolescents (10 SNPs from 5 genomic regions) generalized to (i) the population level and (ii) to adults by genotyping another 31,182 individuals (GENERALIZATION step). Apart from previously identified FTO, MC4R, and TMEM18, we detected two new loci for obesity: one in SDCCAG8 (serologically defined colon cancer antigen 8 gene; p = 1.85x10(-8) in the DISCOVERY step) and one between TNKS (tankyrase, TRF1-interacting ankyrin-related ADP-ribose polymerase gene) and MSRA (methionine sulfoxide reductase A gene; p = 4.84x10(-7)), the latter finding being limited to children and adolescents as demonstrated in the GENERALIZATION step. The odds ratios for early-onset obesity were estimated at approximately 1.10 per risk allele for both loci. Interestingly, the TNKS/MSRA locus has recently been found to be associated with adult waist circumference. In summary, we have completed a meta-analysis of two GWAS which both focus on extremely obese children and adolescents and replicated our findings in a large followed-up data set. We observed that genetic variants in or near FTO, MC4R, TMEM18, SDCCAG8, and TNKS/MSRA were robustly associated with early-onset obesity. We conclude that the currently known major common variants related to obesity overlap to a substantial degree between children and adults.
最近,基于人群的全基因组关联研究(GWAS)的荟萃分析导致了新的肥胖遗传位点的发现。在这里,我们旨在发现极度肥胖的儿童和青少年中额外的肥胖位点。我们还通过估计这些肥胖位点在成人和包括儿童和成人在内的基于人群的样本中的效应来研究这些结果是否具有普遍性。我们联合分析了 2258 个人的两项 GWAS,并根据最低 p 值,在 3141 个人中对 21 个基因组区域的 44 个单核苷酸多态性(SNP)进行了后续分析。在这个发现阶段之后,我们探索了从极度肥胖的儿童和青少年(来自 5 个基因组区域的 10 个 SNP)中获得的发现是否可以推广到(i)人群水平和(ii)通过对另外 31182 个人进行基因分型来推广到成人(推广阶段)。除了先前鉴定的 FTO、MC4R 和 TMEM18 之外,我们还检测到肥胖的两个新位点:一个位于 SDCCAG8(血清定义的结肠癌抗原 8 基因;在发现阶段的 p = 1.85x10(-8))和一个位于 TNKS(端粒酶,TRF1 相互作用的膜相关 ADP-核糖基化酶基因)和 MSRA(甲硫氨酸亚砜还原酶 A 基因;在推广阶段,p = 4.84x10(-7))之间,后者的发现仅限于儿童和青少年。对于两个位点,早发性肥胖的优势比估计为每个风险等位基因约 1.10。有趣的是,最近发现 TNKS/MSRA 位点与成人腰围有关。总之,我们完成了对两项都集中在极度肥胖的儿童和青少年的 GWAS 的荟萃分析,并在一个大型随访数据集上验证了我们的发现。我们观察到 FTO、MC4R、TMEM18、SDCCAG8 和 TNKS/MSRA 中的遗传变异与早发性肥胖密切相关。我们得出结论,目前已知的与肥胖相关的主要常见变异在儿童和成人之间有很大程度的重叠。