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

Martinez-Carrasco, Alejandro, Real, Raquel, Lawton, Michael, Iwaki, Hirotaka, Tan, Manuela M. X., Wu, Lesley, Williams, Nigel M. ORCID: https://orcid.org/0000-0003-1177-6931, Carroll, Camille, Hu, Michele T. M., Grosset, Donald G., Hardy, John, Ryten, Mina, Foltynie, Tom, Ben-Shlomo, Yoav, Shoai, Maryam and Morris, Huw R. 2023. Genetic meta-analysis of levodopa induced dyskinesia in Parkinson’s disease. npj Parkinson's Disease 9 , 128. 10.1038/s41531-023-00573-2

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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.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/, Type: open-access
Publisher:	Nature Research
Date of First Compliant Deposit:	4 September 2023
Date of Acceptance:	16 August 2023
Last Modified:	08 Oct 2023 18:04
URI:	https://orca.cardiff.ac.uk/id/eprint/162197

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