Secondary analysis of publicly available data reveals superoxide and oxygen radical pathways are enriched for associations between type 2 diabetes and low-frequency variants.
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.
British Columbia Clinical Genomics Network, University of British Columbia, Vancouver, British Columbia, Canada; Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada; Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
Mojgan
M
Yazdanpanah
Chuhua
C
Chen
Jinko
J
Graham
D030541:Databases, Genetic; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D053858:Metabolic Networks and Pathways; D020641:Polymorphism, Single Nucleotide; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism*
D017382:Reactive Oxygen Species; D013481:Superoxides
Rare variants; SOD1; collapsing method; pathway analysis; superoxide and oxygen radical pathways; type 2 diabetes