Genetics of Parkinson's disease heterogeneity: A genome-wide association study of clinical subtypes.

Autor: Dulski J; Department of Neurology, Mayo Clinic, Jacksonville, FL, USA; Division of Neurological and Psychiatric Nursing, Faculty of Health Sciences, Medical University of Gdansk, Gdansk, Poland; Neurology Department, St Adalbert Hospital, Copernicus PL Ltd., Gdansk, Poland; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. Electronic address: Dulski.Jaroslaw@mayo.edu., Uitti RJ; Department of Neurology, Mayo Clinic, Jacksonville, FL, USA., Beasley A; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Hernandez D; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA., Ramanan VK; Department of Neurology, Mayo Clinic, Rochester, MN, USA., Cahn EJ; Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MN, USA., Ren Y; Division of Clinical Trials and Biostatistics, Mayo Clinic, Jacksonville, FL, USA., Johnson PW; Division of Clinical Trials and Biostatistics, Mayo Clinic, Jacksonville, FL, USA., Quicksall ZS; Division of Clinical Trials and Biostatistics, Mayo Clinic, Jacksonville, FL, USA., Wszolek ZK; Department of Neurology, Mayo Clinic, Jacksonville, FL, USA., Ross OA; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA; Department of Clinical Genomics, Mayo Clinic, Jacksonville, FL, USA., Heckman MG; Division of Clinical Trials and Biostatistics, Mayo Clinic, Jacksonville, FL, USA. Electronic address: heckman.michael@mayo.edu.
Jazyk: angličtina
Zdroj: Parkinsonism & related disorders [Parkinsonism Relat Disord] 2024 Feb; Vol. 119, pp. 105935. Date of Electronic Publication: 2023 Nov 26.
DOI: 10.1016/j.parkreldis.2023.105935
Abstrakt: Introduction: Substantial heterogeneity between individual patients in the clinical presentation of Parkinson's disease (PD) has led to the classification of distinct PD subtypes. However, genetic susceptibility factors for specific PD subtypes are not well understood. Therefore, the present study aimed to investigate the genetics of PD heterogeneity by performing a genome-wide association study (GWAS) of PD subtypes.
Methods: A total of 799 PD patients were included and classified into tremor-dominant (TD) (N = 345), akinetic-rigid (AR) (N = 227), gait-difficulty (GD) (N = 82), and mixed (MX) (N = 145) phenotypic subtypes. After array genotyping and subsequent imputation, a total of 7,918,344 variants were assessed for association with each PD subtype using logistic regression models that were adjusted for age, sex, and the top five principal components of GWAS data.
Results: We identified one genome-wide significant association (P < 5 × 10 -8 ), which was between the MIR3976HG rs7504760 variant and the AR subtype (Odds ratio [OR] = 6.12, P = 2.57 × 10 -8 ). Suggestive associations (P < 1 × 10 -6 ) were observed regarding TD for RP11-497G19.3/RP11-497G19.1 rs7304254 (OR = 3.33, P = 3.89 × 10 -7 ), regarding GD for HES2 rs111473931 (OR = 3.18, P = 6.85 × 10 -7 ), RP11-400D2.3/CTD-2012I17.1 rs149082205 (OR = 8.96, P = 9.08 × 10 -7 ), and RN7SL408P/SGK1 rs56161738 (OR = 2.97, P = 6.19 × 10 -7 ), and regarding MX for MMRN2 rs112991171 (OR = 4.98, P = 1.02 × 10 -7 ).
Conclusion: Our findings indicate that genetic variation may account for part of the clinical heterogeneity of PD. In particular, we found a novel genome-wide significant association between MIR3976HG variation and the AR PD subtype. Replication of these findings will be important in order to better define the genetic architecture of clinical variability in PD disease presentation.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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