Abstract
Long-term treatment of Parkinson’s disease (PD) by levodopa leads to motor complication “wearing-off”. Zonisamide is a nondopaminergic antiparkinsonian drug that can improve “wearing-off” although response to the treatment varies between individuals. To clarify the genetic basis of zonisamide responsiveness, we conducted a genome-wide association study (GWAS) on 200 PD patients from a placebo-controlled clinical trial, including 67 responders whose “off” time decreased ≥1.5 h after 12 weeks of zonisamide treatment and 133 poor responders. We genotyped and evaluated the association between 611,492 single nucleotide polymorphisms (SNPs) and “off” time reduction. We also performed whole-genome imputation, gene- and pathway-based analyses of GWAS data. For promising SNPs, we examined single-tissue expression quantitative trait loci (eQTL) data in the GTEx database. SNP rs16854023 (Mouse double minute 4, MDM4) showed genome-wide significant association with reduced “off” time (PAdjusted = 4.85 × 10−9). Carriers of responsive genotype showed >7-fold decrease in mean “off” time compared to noncarriers (1.42 h vs 0.19 h; P = 2.71 × 10−7). In silico eQTL data indicated that zonisamide sensitivity is associated with higher MDM4 expression. Among the 37 pathways significantly influencing “off” time, calcium and glutamate signaling have also been associated with anti-epileptic effect of zonisamide. MDM4 encodes a negative regulator of p53. The association between improved motor fluctuation and MDM4 upregulation implies that p53 inhibition may prevent dopaminergic neuron loss and consequent motor symptoms. This is the first genome-wide pharmacogenetics study on antiparkinsonian drug. The findings provide a basis for improved management of “wearing-off” in PD by genotype-guided zonisamide treatment.
Highlights
Supplementary information The online version of this article contains supplementary material, which is available to authorized users.Parkinson’s disease (PD) is a chronic progressive movement disorder in which loss of dopaminergic neurons in the substantia nigra of the midbrain leads to motor symptoms including tremor, bradykinesia, rigidity, and postural instability [1]
single nucleotide polymorphisms (SNPs), gene, and pathway-based association analyses revealed that chromosome 1q32.1 and several pathways were significantly associated with a reduction in “off” time by zonisamide treatment in PD patients
The SNP showing the strongest association with a reduction in “off” time in the genome-wide association study (GWAS) is located between the mouse double minute 4 (MDM4) and leucine-rich repeat transmembrane neuronal 2 (LRRN2) genes
Summary
The efficacy of zonisamide in improving motor symptoms and reducing “off” time in PD patients has been evaluated in a series of doubleblind placebo-controlled clinical trials [5,6,7]. The subjects of the clinical trial have mean daily “off” time of at least 2 h for the last 7 days of the run-in period These patients have been treated with any combination drugs of levodopa and dopa decarboxylase inhibitor for at least 6 consecutive months and had responded to levodopa during the first few years of levodopa treatment. Patients who showed a decrease in UPDRS Part III total score of at least 5 points from baseline after 12 weeks of zonisamide treatment were defined as responders; and all remaining subjects were considered as poor responders. SNP genotyping and SNP-, gene-, and pathway-based association analyses were performed as described above
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