Department of Child and Adolescent Psychiatry, University of Duisburg-Essen, Essen, Germany.
PLoS One. 2013;8(2):e55884. doi: 10.1371/journal.pone.0055884. Epub 2013 Feb 8.
There are hints of an altered mitochondrial function in obesity. Nuclear-encoded genes are relevant for mitochondrial function (3 gene sets of known relevant pathways: (1) 16 nuclear regulators of mitochondrial genes, (2) 91 genes for oxidative phosphorylation and (3) 966 nuclear-encoded mitochondrial genes). Gene set enrichment analysis (GSEA) showed no association with type 2 diabetes mellitus in these gene sets. Here we performed a GSEA for the same gene sets for obesity. Genome wide association study (GWAS) data from a case-control approach on 453 extremely obese children and adolescents and 435 lean adult controls were used for GSEA. For independent confirmation, we analyzed 705 obesity GWAS trios (extremely obese child and both biological parents) and a population-based GWAS sample (KORA F4, n = 1,743). A meta-analysis was performed on all three samples. In each sample, the distribution of significance levels between the respective gene set and those of all genes was compared using the leading-edge-fraction-comparison test (cut-offs between the 50(th) and 95(th) percentile of the set of all gene-wise corrected p-values) as implemented in the MAGENTA software. In the case-control sample, significant enrichment of associations with obesity was observed above the 50(th) percentile for the set of the 16 nuclear regulators of mitochondrial genes (p(GSEA,50) = 0.0103). This finding was not confirmed in the trios (p(GSEA,50) = 0.5991), but in KORA (p(GSEA,50) = 0.0398). The meta-analysis again indicated a trend for enrichment (p(MAGENTA,50) = 0.1052, p(MAGENTA,75) = 0.0251). The GSEA revealed that weak association signals for obesity might be enriched in the gene set of 16 nuclear regulators of mitochondrial genes.
肥胖与线粒体功能改变有关。核编码基因与线粒体功能相关（已知相关途径的 3 个基因集：（1）16 个线粒体基因的核调节因子，（2）91 个氧化磷酸化基因和（3）966 个核编码线粒体基因）。基因集富集分析（GSEA）显示这些基因集中与 2 型糖尿病无关。在这里，我们针对肥胖进行了相同基因集的 GSEA。使用病例对照方法对 453 名极度肥胖的儿童和青少年和 435 名瘦的成年对照组进行了全基因组关联研究（GWAS）数据，进行 GSEA。为了进行独立验证，我们分析了 705 个肥胖 GWAS 三胞胎（极度肥胖的儿童及其两位生物学父母）和一个基于人群的 GWAS 样本（KORA F4，n=1743）。对所有三个样本进行了荟萃分析。在每个样本中，使用 MAGENTA 软件中实现的领先边缘分数比较测试（在所有基因校正 p 值的集合的第 50（th）和第 95（th）百分位数之间的截止值）比较各自基因集与所有基因之间的显著性水平分布，以比较各自基因集与所有基因之间的显著性水平分布。在病例对照样本中，在第 16 个核线粒体基因调节因子集的第 50（th）百分位以上观察到与肥胖相关的显著富集（p（GSEA，50）=0.0103）。这一发现未在三胞胎中得到证实（p（GSEA，50）=0.5991），但在 KORA 中得到证实（p（GSEA，50）=0.0398）。荟萃分析再次表明富集趋势（p（MAGENTA，50）=0.1052，p（MAGENTA，75）=0.0251）。GSEA 显示，肥胖的弱关联信号可能在 16 个核线粒体基因调节因子基因集中富集。
