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

Alejandro Martinez-Carrasco; Raquel Real; Michael Lawton; Hirotaka Iwaki; Manuela M X Tan; Lesley Wu; Nigel M Williams; Camille Carroll; Michele T M Hu; Donald G Grosset; John Hardy; Mina Ryten; Tom Foltynie; Yoav Ben-Shlomo; Maryam Shoai; Huw R Morris

doi:10.1038/s41531-023-00573-2

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

NPJ Parkinsons Dis. 2023 Aug 31;9(1):128. doi: 10.1038/s41531-023-00573-2.

Authors

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.

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.