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Lookup NU author(s): Professor Camille CarrollORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2023, Springer Nature Limited. 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.
Author(s): Martinez-Carrasco A, Real R, Lawton M, Iwaki H, Tan MMX, Wu L, Williams NM, Carroll C, Hu MTM, Grosset DG, Hardy J, Ryten M, Foltynie T, Ben-Shlomo Y, Shoai M, Morris HR
Publication type: Article
Publication status: Published
Journal: npj Parkinson's Disease
Year: 2023
Volume: 9
Online publication date: 31/08/2023
Acceptance date: 16/08/2023
Date deposited: 12/02/2025
ISSN (electronic): 2373-8057
Publisher: Nature Research
URL: https://doi.org/10.1038/s41531-023-00573-2
DOI: 10.1038/s41531-023-00573-2
Data Access Statement: GWAS summary statistics are publicly available in the Zenodo ASAP data repository (https://doi.org/10.5281/zenodo.7795604). Supplementary Figures and Tables are available in the Zenodo ASAP data repository (https://zenodo.org/record/7802755#.ZC2RAnbMK38). TPD data are available upon access request from https://www.trackingparkinsons.org.uk/about-1/data/. The PDBP and PPMI data was accessed from Accelerating Medicines Partnership: Parkinson’s Disease (AMP-PD) and data are available upon registration at https://www.amp-pd.org/. OPDC data are available upon request from the Dementias Platform UK (https://portal.dementiasplatform.uk/Apply). PD-STAT is available upon request to the principal investigator (C Carroll, Plymouth University, https://penctu.psmd.plymouth.ac.uk/pdstat/#:~:text=PD%20STAT%20%2D%20Simvastatin%20as%20a,brain%20from%20injury%20or%20loss.). HapMap phase 3 data (HapMap3) is available for download at ftp://ftp.ncbi.nlm.nih.gov/hapmap/.
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