A pH-eQTL Interaction at the RIT2–SYT4 Parkinson’s Disease Risk Locus in the Substantia Nigra

Abstract

Parkinson’s disease causes severe motor and cognitive disabilities that result from the progressive loss of dopamine neurons in the substantia nigra. The rs12456492 variant in the RIT2 gene has been repeatedly associated with increased risk for Parkinson’s disease. From a transcriptomic perspective, a meta-analysis found that RIT2 gene expression is correlated with pH in the human brain. To assess these pH associations in relation to Parkinson’s disease risk, we examined the two datasets that assayed rs12456492, gene expression, and pH in the postmortem human brain. Using the BrainEAC dataset, we replicate the positive correlation between RIT2 gene expression and pH in the human brain (n = 100). Furthermore, we found that the relationship between expression and pH is influenced by rs12456492. When tested across ten brain regions, this interaction is specifically found in the substantia nigra. A similar association was found for the co-localized SYT4 gene. In addition, SYT4 associations are stronger in a combined model with both genes, and the SYT4 interaction appears to be specific to males. In the Genotype-Tissue Expression (GTEx) dataset, the pH associations involving rs12456492 and expression of either SYT4 and RIT2 were not seen. This null finding may be due to the short postmortem intervals of the GTEx tissue samples. In the BrainEAC data, we tested the effect of postmortem interval and only observed the interactions in samples with the longer intervals. These previously unknown associations suggest novel roles for rs12456492, RIT2, and SYT4 in the regulation and response to pH in the substantia nigra.