Exome-wide association study of levodopa-induced dyskinesia in Parkinson\u2019s disease

Eva König,Alessandra Nicoletti,Teresa Esposito,Cristian Pattaro,Nicola Modugno,Anne Picard,Andrew A Hicks,Francisco S Domingues,Mario Zappia,Peter P Pramstaller,Christine Schwienbacher,Alessandro Gialluisi,Hagen Blankenburg,Irene Pichler,Roberto Melotti,Grazia Annesi,Marina Ciullo

doi:10.1038/s41598-021-99393-8

Eva König, Alessandra Nicoletti + Show 15 more

Open Access

PDF Available

https://doi.org/10.1038/s41598-021-99393-8

Copy DOI

Export

Save

Cite

Abstract
Highlights/Summary
Full-Text PDF
Similar Papers

Abstract

Listen

Levodopa is the standard long-term dopamine replacement therapy to treat Parkinson’s disease (PD) symptoms. With time, levodopa may induce debilitating dyskinesias (LID), the treatment of which represents a large clinically unmet need. However, time-to-LID onset varies between patients, reflecting a possible genetic component. We performed an hypothesis-free whole-exome sequencing (WES)-based screening of time-to-LID onset and attempted replication of previously published candidate gene studies. A WES association analysis was carried out in 134 PD patients in a meta-analytical framework. Replication was attempted in an independent study of 97 PD patients. Variants from previously reported candidate genes (OPRM1, COMT, BDNF) were also specifically examined. We significantly replicated, for the first time, an association of variant rs1799971 in the OPRM1 gene with time-to-LID onset. Furthermore, we identified two novel potentially functional variants, in the MAD2L2 (rs2233019) and MAP7 (rs35350783) genes, which were significantly associated at the discovery stage. In the replication study, the two variants showed direction-consistent effects but did not achieve the replication significance threshold. Our study provides the first WES results for time-to-LID onset, where we replicate association at OPRM1, and suggest new variants in MAD2L2 and MAP7 genes that are significant in discovery, but require larger datasets for replication. The results are being made publicly available to allow for independent external validation.

Highlights

Levodopa is the standard long-term dopamine replacement therapy to treat Parkinson’s disease (PD) symptoms
When testing three variants identified in previous candidate gene studies, we replicated the association of rs1799971 in OPRM1 (Fig. 2A, hazard ratio (HR) = 1.38, 95%CI: 1.03, + ∞, p-value = 0.038)
Two novel variants were associated with time-to-levodopa may induce debilitating dyskinesias (LID) onset in our data (Fig. 2B,C; Supplementary Figure S1; Supplementary Table S1): the splice donor variant rs2233019 in the mitotic arrest deficient 2 like 2 (MAD2L2) gene (p-value = 2.3 × 1 0–6), and the missense variant rs35350783 in the microtubule associated protein 7 (MAP7) gene (p-value = 2.4 × 1 0–6)

Summary

Introduction

Levodopa is the standard long-term dopamine replacement therapy to treat Parkinson’s disease (PD) symptoms. We performed an hypothesis-free whole-exome sequencing (WES)-based screening of time-to-LID onset and attempted replication of previously published candidate gene studies. Our study provides the first WES results for time-toLID onset, where we replicate association at OPRM1, and suggest new variants in MAD2L2 and MAP7 genes that are significant in discovery, but require larger datasets for replication. Long recognized since the introduction of levodopa (L-dopa) for the management of Parkinson’s disease (PD), levodopa-induced dyskinesias (LID) are the most clinically challenging factors in the long-term management of PD patients. Several studies have reported associations of specific genetic variants with LID susceptibility based on candidate gene approaches with a focus on dopamine receptors and metabolism. No hypothesisfree approach for wide disclosure of LID-associated genes has been reported To address this gap, we conducted an exome-wide association study of time-to-LID onset on 231 PD patients (Fig. 1)

Methods

Results

Conclusion