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

Alejandro Martinez-Carrasco^{1

2

3}, Raquel Real^{4

5

6}, Michael Lawton⁷, Hirotaka Iwaki^{8

9}, Manuela M X Tan¹⁰, Lesley Wu^{4

5

6}, Nigel M Williams¹¹, Camille Carroll^{12

13}, Michele T M Hu^{14

15}, Donald G Grosset¹⁶, John Hardy^{6

17

18

19

20

21}, Mina Ryten^{6

22

23}, Tom Foltynie⁴, Yoav Ben-Shlomo⁷, Maryam Shoai^{6

17

18}, Huw R Morris^{24

25

26}

Affiliations

¹ Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, UK. alejandro.carrasco.20@ucl.ac.uk.
² UCL Movement Disorders Centre, University College London, London, UK. alejandro.carrasco.20@ucl.ac.uk.
³ Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815, USA. alejandro.carrasco.20@ucl.ac.uk.
⁴ Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, UK.
⁵ UCL Movement Disorders Centre, University College London, London, UK.
⁶ Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815, USA.
⁷ Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
⁸ Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
⁹ Data Tecnica International, Glen Echo, MD, USA.
¹⁰ Department of Neurology, Oslo University Hospital, Oslo, Norway.
¹¹ Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
¹² Faculty of Health, University of Plymouth, Plymouth, UK.
¹³ Translational and Clinical Research Institute, Newcastle University, Newcastle, UK.
¹⁴ Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, University of Oxford, Oxford, UK.
¹⁵ Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK.
¹⁶ School of Neuroscience and Psychology, University of Glasgow, Glasgow, UK.
¹⁷ Department of Neurodegenerative Diseases, UCL Queen Square Institute of Neurology, University College London, London, UK.
¹⁸ UK Dementia Research Institute, University College London, London, UK.
¹⁹ Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, London, UK.
²⁰ National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre, London, UK.
²¹ Institute for Advanced Study, The Hong Kong University of Science and Technology, Hong Kong SAR, China.
²² Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, University College London, London, UK.
²³ NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, London, UK.
²⁴ Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, UK. h.morris@ucl.ac.uk.
²⁵ UCL Movement Disorders Centre, University College London, London, UK. h.morris@ucl.ac.uk.
²⁶ Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815, USA. h.morris@ucl.ac.uk.

PMID: 37652906
PMCID: PMC10471743
DOI: 10.1038/s41531-023-00573-2

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

Alejandro Martinez-Carrasco et al. NPJ Parkinsons Dis. 2023.

. 2023 Aug 31;9(1):128.

doi: 10.1038/s41531-023-00573-2.

Authors

Affiliations

¹ Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, UK. alejandro.carrasco.20@ucl.ac.uk.
² UCL Movement Disorders Centre, University College London, London, UK. alejandro.carrasco.20@ucl.ac.uk.
³ Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815, USA. alejandro.carrasco.20@ucl.ac.uk.
⁴ Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, UK.
⁵ UCL Movement Disorders Centre, University College London, London, UK.
⁶ Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815, USA.
⁷ Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
⁸ Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
⁹ Data Tecnica International, Glen Echo, MD, USA.
¹⁰ Department of Neurology, Oslo University Hospital, Oslo, Norway.
¹¹ Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
¹² Faculty of Health, University of Plymouth, Plymouth, UK.
¹³ Translational and Clinical Research Institute, Newcastle University, Newcastle, UK.
¹⁴ Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, University of Oxford, Oxford, UK.
¹⁵ Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK.
¹⁶ School of Neuroscience and Psychology, University of Glasgow, Glasgow, UK.
¹⁷ Department of Neurodegenerative Diseases, UCL Queen Square Institute of Neurology, University College London, London, UK.
¹⁸ UK Dementia Research Institute, University College London, London, UK.
¹⁹ Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, London, UK.
²⁰ National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre, London, UK.
²¹ Institute for Advanced Study, The Hong Kong University of Science and Technology, Hong Kong SAR, China.
²² Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, University College London, London, UK.
²³ NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, London, UK.
²⁴ Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, UK. h.morris@ucl.ac.uk.
²⁵ UCL Movement Disorders Centre, University College London, London, UK. h.morris@ucl.ac.uk.
²⁶ Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815, USA. h.morris@ucl.ac.uk.

PMID: 37652906
PMCID: PMC10471743
DOI: 10.1038/s41531-023-00573-2

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.

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Conflict of interest statement

H.R.M. reports paid consultancy from Roche. Research Grants from Parkinson’s UK, Cure Parkinson’s Trust, PSP Association, CBD Solutions, Drake Foundation, Medical Research Council (MRC), Michael J. Fox Foundation. Dr Morris is a co-applicant on a patent application related to C9ORF72 - Method for diagnosing a neurodegenerative disease (PCT/GB2012/052140). D.G.G. has received grants from Michael’s Movers, the Neurosciences Foundation, and Parkinson’s UK, and honoraria from AbbVie, BIAL Pharma, Britannia Pharmaceuticals, GE Healthcare, and consultancy fees from Acorda Therapeutics and the Glasgow Memory Clinic. M.T.M.H. received funding/grant support from Parkinson’s UK, Oxford NIHR BRC, University of Oxford, CPT, Lab10X, NIHR, Michael J. Fox Foundation, H2020 European Union, GE Healthcare and the PSP Association. She also received payment for Advisory Board attendance/consultancy for Biogen, Roche, Sanofi, CuraSen Therapeutics, Evidera, Manus Neurodynamica, Lundbeck. Y.B.-S. has received grant funding from the MRC, NIHR, Parkinson’s UK, NIH, and ESRC. C.C receives salary from University Hospitals Plymouth NHS Trust and National Institute of Health and Care Research. She has received advisory, consulting or lecture fees from AbbVie, Bial, Scient, Orkyn, Abidetex, UCB, Pfizer, EverPharma, Lundbeck, Global Kinetics, Kyowa Kirin, Britannia and Medscape, and research funding from Parkinson’s UK, Edmond J Safra Foundation, National Institute of Health and Care Research and Cure Parkinson’s. J.H. is supported by the UK Dementia Research Institute, which receives its funding from DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society, and Alzheimer’s Research UK. He is also supported by the MRC, Wellcome Trust, Dolby Family Fund, National Institute for Health Research University, College London Hospitals Biomedical Research Centre. All other authors report no competing interests. M.A.L. received fees for advising on a secondary analysis of an RCT sponsored by North Bristol NHS trust that studied off-state Dyskinesia.

Figures

**Fig. 1. LiD GWSS meta-analysis Manhattan plot.**
The GWSS was conducted using a Cox proportional hazards model in each cohort separately, and results were meta-analysed. Red dots indicate the variant with the lowest P value at each genome-wide significant genetic *locus*. Genome-wide significance was set at 5 × 10⁻⁸ and is indicated by the red dashed line.

**Fig. 2. Forest plots of lead genetic associated variants.**
a *LRP8* rs72673189 variant (I² = 0 ; Q: χ² = 0.24, df = 3, P = 1.53e-08). b *LINC02353* rs189093213 variant (I² = 21.4 ;Q: χ² = 5.09, df = 4, P = 1.67e-09). c XYLT1 rs180924818 variant (I² = 0; χ² = 0.77, df = 2, P = 6.27e–09). I² = I² Index of heterogeneity HR Hazard ratio, P P value, Q Cochran’s Cochran’s Q test of heterogeneity, df degrees of freedom.

**Fig. 3. Survival curves of candidate SNPs.**
a Kaplan-Meier curve for Survival probability (LiD free probability) based on rs72673189 carrier status in PD patients. b Kaplan-Meier curve for Survival probability (LiD free probability) based on rs189093213 carrier status in PD patients. c Kaplan-Meier curve for Survival probability (LiD free probability) based on rs180924818 carrier status in PD patients. The blue curve represents genetic variant carriers, whereas the yellow curve represents non-carriers. p = p value. Number at risk represents the number of PD patients remaining on the study at the different time points (0, 5, 10, 15 years). The colour expansion on each curve represents the confidence interval (CI).

**Fig. 4. LRP8 locus fine-mapping and brain cell type specific regulatory marks.**
From top to bottom, locus plot, transcript plot, the fine-mapping nominated variants across fine-mapping tools, brain cell type specific regulatory element marks. In the locus plot, the SNPs are coloured in red as LD (given by R2) increases, and blue as the LD decreases. In the fine-mapping track, we highlight the SNPs with the highest posterior probabilities for each fine-mapping tool (ABF, FINEMAP, SUSIE, POLYFUN_SUSIE). In addition, we highlight in yellow the Consensus SNP with the highest mean Posterior Probability (mean). In the cell type specific regulatory element marks, the first four rows are the density marks (y-axis) from ATAC-seq assay (in pink), and CHIP-seq assays (H3K27ac in blue, and H3K4me3 in cyan), in astrocytes, microglia, neurons, and oligodendrocytes. The next four rows are the distal anchored chromatin loops (black curves). We see how, only in neurons, there is a chromatin loop forming from the *LRP8* GWS and the fine-mapped consensus variant towards the LRP8 promoter (purple).

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Update of

Genetic meta-analysis of levodopa induced dyskinesia in Parkinson's disease.
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. Martinez-Carrasco A, et al. medRxiv [Preprint]. 2023 May 30:2023.05.24.23290362. doi: 10.1101/2023.05.24.23290362. medRxiv. 2023. Update in: NPJ Parkinsons Dis. 2023 Aug 31;9(1):128. doi: 10.1038/s41531-023-00573-2. PMID: 37425912 Free PMC article. Updated. Preprint.

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Update of

References

Grants and funding

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