Noyce, A;
(2019)
Genomewide association study of Parkinson's disease clinical biomarkers in 12 longitudinal patients' cohorts.
Movement Disorders
10.1002/mds.27845.
(In press).
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Abstract
Background: Several reports have identified different patterns of Parkinson’s disease progression in individuals carrying missense variants in GBA or LRRK2 genes. The overall contribution of genetic factors to the severity and progression of Parkinson’s disease, however, has not been well studied. // Objectives: To test the association between genetic variants and the clinical features and progression of Parkinson’s disease on a genome-wide scale. // Methods: We accumulated individual data from 12 longitudinal cohorts in a total of 4,093 patients with 22,307 observations over a median of 3.81 years. Genome-wide associations were evaluated for 25 cross-sectional and longitudinal phenotypes. Specific variants of interest, including 90 recently-identified disease risk variants, were also investigated post-hoc for candidate associations with these phenotypes. Results: Two variants were genome-wide significant. Rs382940(T>A), within the intron of SLC44A1, was associated with reaching Hoehn and Yahr stage 3 or higher faster (HR 2.04 [1.58, 2.62], P-value = 3.46E-8). Rs61863020(G>A), an intergenic variant and eQTL for ADRA2A, was associated with a lower prevalence of insomnia at baseline (OR 0.63 [0,52, 0.75], P-value = 4.74E-8). In the targeted analysis, we found nine associations between known Parkinson’s risk variants and more severe motor/cognitive symptoms. Also, we replicated previous reports of GBA coding variants (rs2230288: p.E365K, rs75548401:p.T408M) being associated with greater motor and cognitive decline over time, and APOE E4 tagging variant (rs429358) being associated with greater cognitive deficits in patients. // Conclusions: We identified novel genetic factors associated with heterogeneity of Parkinson’s disease. The results can be used for validation or hypothesis tests regarding Parkinson’s disease.
| Type: | Article |
|---|---|
| Title: | Genomewide association study of Parkinson's disease clinical biomarkers in 12 longitudinal patients' cohorts |
| DOI: | 10.1002/mds.27845 |
| Publisher version: | https://doi.org/10.1002/mds.27845 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10078933 |
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