Secondary Analysis of Publicly Available Data Reveals Superoxide and Oxygen Radical Pathways are Enriched for Associations Between Type 2 Diabetes and Low-Frequency Variants

Authors

  • Mojgan Yazdanpanah,

    Corresponding author
    1. Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada
    2. Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
    • British Columbia Clinical Genomics Network, University of British Columbia, Vancouver, British Columbia, Canada
    Search for more papers by this author
  • Chuhua Chen,

    1. Statistics and Actuarial Science, Simon Fraser University, Burnaby, British Columbia, Canada
    Search for more papers by this author
  • Jinko Graham

    1. Statistics and Actuarial Science, Simon Fraser University, Burnaby, British Columbia, Canada
    Search for more papers by this author

Corresponding author: Mojgan Yazdanpanah, British Columbia Clinical Genomics Network, Department of Medical Genetics, University of British Columbia, Vancouver, Canada, Box 153, Children's and Women's Hospital, 4480 Oak Street, Vancouver, British Columbia, 6H 3V4, Canada. Tel: 1 604 875 2000 ext. 4636; Fax: 778-782-4368; E-mail: mojganyazdanpanah@yahoo.com

Summary

Genome-wide association studies explain at most 5%-10% of the heritable components of type 2 diabetes. Some of the “missing type 2 diabetes heritability” could be explained by low-frequency variants. We examined the associations between low-frequency variants and type 2 diabetes, using data from 2538 diabetic and 2977 nondiabetic subjects in the publicly available database of Genotypes and Phenotypes. We applied two approaches. First, we combined information from all low-frequency (1%-5%) variants at a locus in a gene-centric analysis of associations with diabetes. Next, we searched for gene ontology (GO) biological processes that were enriched for gene-centric associations, after correcting for multiple testing to control the false discovery rate (FDR). We found three GO biological processes that were significantly enriched for associations to diabetes: “response to superoxide” (FDR-adjusted p = 2.7 × 10−3), “response to oxygen radical” (FDR-adjusted p = 2.7 × 10−3), and “heart contraction” (FDR-adjusted p = 2.6 × 10−2). There were three genes that contributed to “response to superoxide” and “oxygen radical” pathways, including the SOD1 gene. Gene-centric tests of association with low-frequency variants, followed by analysis to evaluate which biological pathways are enriched for these associations has the potential to recover, at least some proportion of, the “missing heritability” of type 2 diabetes.

Ancillary