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Genetic meta-analysis of levodopa induced dyskinesia in Parkinson’s disease

Authors: Alejandro Martinez-Carrasco; Raquel Real; Michael Lawton; Hirotaka Iwaki; Manuela M. X. Tan; Lesley Wu; Nigel M. Williams; +9 Authors

Genetic meta-analysis of levodopa induced dyskinesia in Parkinson’s disease

Abstract

Abstract The genetic basis of levodopa-induced-dyskinesia (LiD) is poorly understood, and there have been few well-powered genome-wide studies. We performed a genome-wide survival meta-analyses to study the effect of genetic variation on the development of LiD in five separate longitudinal cohorts, and meta-analysed the results. We included 2784 PD patients, of whom 14.6% developed LiD. We found female sex (HR = 1.35, SE = 0.11, P = 0.007) and younger age at onset (HR = 1.8, SE = 0.14, P = 2 × 10 −5 ) increased the probability of developing LiD. We identified three genetic loci significantly associated with time-to-LiD onset. rs72673189 on chromosome 1 (HR = 2.77, SE = 0.18, P = 1.53 × 10 −8 ) located at the LRP8 locus, rs189093213 on chromosome 4 (HR = 3.06, SE = 0.19, P = 2.81 × 10 −9 ) in the non-coding RNA LINC02353 locus, and rs180924818 on chromosome 16 (HR = 3.13, SE = 0.20, P = 6.27 × 10 −9 ) in the XYLT1 locus. Based on a functional annotation analysis on chromosome 1, we determined that changes in DNAJB4 gene expression, close to LRP8, are an additional potential cause of increased susceptibility to LiD. Baseline anxiety status was significantly associated with LiD (OR = 1.14, SE = 0.03, P = 7.4 × 10 −5 ). Finally, we performed a candidate variant analysis of previously reported loci, and found that genetic variability in ANKK1 ( rs1800497 , HR = 1.27, SE = 0.09, P = 8.89 × 10 −3 ) and BDNF ( rs6265 , HR = 1.21, SE = 0.10, P = 4.95 × 10 −2 ) loci were significantly associated with time to LiD in our large meta-analysis.

Keywords

Risk factors, 610, Neurology. Diseases of the nervous system, RC346-429, Genome-wide association studies, Neurological disorders, Article

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selected citations
These citations are derived from selected sources.
This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
10
Top 10%
Average
Top 10%
Green
gold