Hypothesis-independent pathway analysis implicates GABA and Acetyl-CoA metabolism in primary open-angle glaucoma and normal-pressure glaucoma

Abstract

Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. Using genome-wide association single-nucleotide polymorphism data from the Glaucoma Genes and Environment study and National Eye Institute Glaucoma Human Genetics Collaboration comprising 3,108 cases and 3,430 controls, we assessed biologic pathways as annotated in the KEGG database for association with risk of POAG. After correction for genic overlap among pathways, we found 4 pathways, butanoate metabolism (hsa00650), hematopoietic cell lineage (hsa04640), lysine degradation (hsa00310) and basal transcription factors (hsa03022) related to POAG with permuted p < 0.001. In addition, the human leukocyte antigen (HLA) gene family was significantly associated with POAG (p < 0.001). In the POAG subset with normal-pressure glaucoma (NPG), the butanoate metabolism pathway was also significantly associated (p < 0.001) as well as the MAPK and Hedgehog signaling pathways (hsa04010 and hsa04340), glycosaminoglycan biosynthesis-heparan sulfate pathway (hsa00534) and the phenylalanine, tyrosine and tryptophan biosynthesis pathway (hsa0400). The butanoate metabolism pathway overall, and specifically the aspects of the pathway that contribute to GABA and acetyl-CoA metabolism, was the only pathway significantly associated with both POAG and NPG. Collectively these results implicate GABA and acetyl-CoA metabolism in glaucoma pathogenesis, and suggest new potential therapeutic targets.

Genomic loci modulating retinal ganglion cell death following elevated IOP in the mouse

“…The intronic variant rs62391530 showed the strongest relation to POAG with a nominal p-value of 0.02 and an effect size of −0.16. Even though ALDH7A1 variants did not reach the genome-wide significance threshold of 5 × 10 −8 , this gene is part of the KEGG “butanoate metabolic pathway”, which was previously identified to be associated with both POAG and NTG (Bailey et al, 2014). …”

“…While GWAS have identified many genes associated with glaucoma risk, a recent analysis (Bailey et al, 2014) used a randomized analysis to take the single gene data and assign associated molecular pathways. One pathway involved butanoate metabolism (KEGG pathway hsa00650; see Fig.…”

“…One pathway involved butanoate metabolism (KEGG pathway hsa00650; see Fig. 3 in (Bailey et al, 2014)). This pathway is associated with both POAG (8 genes with nominal association) and NTG (8 genes with nominal associations) Of the 5 enzymes (ALDH1B1, ALDH2, ALDH3A2, ALDH7A1 and ALDH9A1) associated with the conversion of Acetaldehyde to Acetyl-CoA, three (ALDH1B1, ALDH2 and ALDH3A2) have a nominal association with either POAG or NTG.…”

Pathway analysis by randomization incorporating structure—PARIS: an update

“…We executed PARIS on GWAS results from 480 k SNPs evaluated by the NEIGHBOR consortium (Bailey et al, 2014;Wiggs et al, 2012). Comparing results from a prior version of PARIS (1.1.3) to this new version (2.4), results are highly correlated (Fig.…”

“…1B and C) for the 199 overlapping KEGG pathways, using gene boundary thresholds of 0 and 50 kb. To provide a comprehensive and unbiased comparison, we utilized the database and pathway definition files that were previously utilized with version 1.1.3 of PARIS (Bailey et al, 2014). Pathway P-values were highly correlated, as indicated in Figure 1B and C. Further, we evaluated the number of pathways attaining P < 0.05 ( Table 1) and found that with both the 0 and 50 kb gene boundary extension options, the same pathways achieved this significance threshold, except in one case, where a pathway was P < 0.05 in the prior version of PARIS and P 0.05 in the updated version due to difference in random number generation between the two versions.…”