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Gene Set of Nuclear-Encoded Mitochondrial Regulators Is Enriched for Common Inherited Variation in Obesity

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Listed:
  • Nadja Knoll
  • Ivonne Jarick
  • Anna-Lena Volckmar
  • Martin Klingenspor
  • Thomas Illig
  • Harald Grallert
  • Christian Gieger
  • Heinz-Erich Wichmann
  • Annette Peters
  • Johannes Hebebrand
  • André Scherag
  • Anke Hinney

Abstract

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 50th and 95th 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 50th percentile for the set of the 16 nuclear regulators of mitochondrial genes (pGSEA,50 = 0.0103). This finding was not confirmed in the trios (pGSEA,50 = 0.5991), but in KORA (pGSEA,50 = 0.0398). The meta-analysis again indicated a trend for enrichment (pMAGENTA,50 = 0.1052, pMAGENTA,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.

Suggested Citation

  • Nadja Knoll & Ivonne Jarick & Anna-Lena Volckmar & Martin Klingenspor & Thomas Illig & Harald Grallert & Christian Gieger & Heinz-Erich Wichmann & Annette Peters & Johannes Hebebrand & André Scherag &, 2013. "Gene Set of Nuclear-Encoded Mitochondrial Regulators Is Enriched for Common Inherited Variation in Obesity," PLOS ONE, Public Library of Science, vol. 8(2), pages 1-10, February.
    • Handle: RePEc:plo:pone00:0055884
    DOI: 10.1371/journal.pone.0055884
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    References listed on IDEAS

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    1. Ayellet V Segrè & DIAGRAM Consortium & MAGIC investigators & Leif Groop & Vamsi K Mootha & Mark J Daly & David Altshuler, 2010. "Common Inherited Variation in Mitochondrial Genes Is Not Enriched for Associations with Type 2 Diabetes or Related Glycemic Traits," PLOS Genetics, Public Library of Science, vol. 6(8), pages 1-19, August.
    2. Marina Evangelou & Augusto Rendon & Willem H Ouwehand & Lorenz Wernisch & Frank Dudbridge, 2012. "Comparison of Methods for Competitive Tests of Pathway Analysis," PLOS ONE, Public Library of Science, vol. 7(7), pages 1-10, July.
    3. André Scherag & Christian Dina & Anke Hinney & Vincent Vatin & Susann Scherag & Carla I G Vogel & Timo D Müller & Harald Grallert & H-Erich Wichmann & Beverley Balkau & Barbara Heude & Marjo-Riitta Ja, 2010. "Two New Loci for Body-Weight Regulation Identified in a Joint Analysis of Genome-Wide Association Studies for Early-Onset Extreme Obesity in French and German Study Groups," PLOS Genetics, Public Library of Science, vol. 6(4), pages 1-10, April.
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