Integrative Approaches Identify Genetic Determinants of Levodopa Induced Dyskinesia

Levodopa induced dyskinesia (LID) is a serious side effect of levodopa treatment in Parkinson's disease (PD), with limited interventions. Understanding the genetic impact on LID would help inform future intervention studies. We performed integrative genomic analysis approaches to identify the genetic determinants of LID in a Chinese multi-center prospective, observational PD cohort. In this cohort, 46 of 315 PD patients developed LID during 2.5 years of follow-up. First, we performed a genome-wide association study (GWAS) in this cohort, followed by a meta-analysis integrating our GWAS summary data with additional data of European ancestry. Both GWAS analyses identified the Bromodomain Containing 3 (BRD3) as a LID susceptibility gene (P < 5 × 10^-8); however, the genetic variants within the BRD3 gene differed between the analyses. Then, we conducted a multi-tissue transcriptome-wide association study (TWAS) through integrating our GWAS summary data with six gene expression quantitative trait loci (eQTLs) datasets from tissues involved in the levodopa transport-to-function pathway, including stomach, blood, caudate, putamen, nucleus accumbens, and frontal cortex. We found that the expression levels of the TRAPPC12 Antisense RNA 1 (TRAPPC12-AS1) and Williams Beuren Syndrome Chromosome Region 27 (WBSCR27) in all tissues were associated with LID occurrence. Finally, we executed the summary data-based mendelian randomization (SMR) and identified that LID was causally associated with the two genes' expression in all tissues. In conclusion, our findings support new candidate genes for LID susceptibility, providing novel potential targets for future intervention studies.