Fine-mapping of the non-coding variation driving the Caucasian LRRK2 GWAS signal in Parkinson's disease.

Autor: Heckman MG; Division of Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, FL, USA. Electronic address: heckman.michael@mayo.edu., Labbé C; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Kolicheski AL; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Soto-Beasley AI; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Walton RL; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Valentino RR; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Brennan ER; Division of Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, FL, USA., Johnson PW; Division of Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, FL, USA., Baheti S; Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA., Sarangi V; Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA., Ren Y; Division of Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, FL, USA., Uitti RJ; Department of Neurology, 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. Electronic address: ross.owen@mayo.edu.
Jazyk: angličtina
Zdroj: Parkinsonism & related disorders [Parkinsonism Relat Disord] 2021 Feb; Vol. 83, pp. 22-30. Date of Electronic Publication: 2021 Jan 11.
DOI: 10.1016/j.parkreldis.2020.12.016
Abstrakt: Introduction: Genome-wide association studies (GWAS) have confirmed the leucine-rich repeat kinase 2 (LRRK2) gene as a susceptibility locus for idiopathic Parkinson's disease (PD) in Caucasians. Though the rs1491942 and rs76904798 variants have shown the strongest associations, the causal variant(s) remains unresolved. Therefore, the aim of this study was to identify variants that may be driving the LRRK2 GWAS signal by sequencing the entire LRRK2 gene in Caucasian PD patients and controls.
Methods: A discovery series (287 PD patients, 294 controls) and replication series (362 PD patients, 168 controls) were included. The entire LRRK2 gene as well as 10 Kb upstream/downstream was sequenced. Candidate potential causal variants were considered to be those that (a) were in at least weak linkage disequilibrium with the two GWAS-nominated variants (rs1491942 and rs76904798), and (b) displayed an association odds ratio (OR) that is stronger than the two GWAS variants.
Results: Thirty-four candidate variants (all intronic/intergenic) that may drive the LRRK2 PD GWAS signal were identified in the discovery series. However, examination of the replication series for these variants did not reveal any with a consistently stronger OR than both PD GWAS variants. Evaluation of public databases to determine which candidate variants are most likely to have a direct functional effect on LRRK2 expression was inconclusive.
Conclusion: Though our findings provide novel insights into the LRRK2 GWAS association, a clear causal variant was not identified. The identified candidate variants can form the basis for future experiments and functional studies that can more definitively assess causal LRRK2 variants.
(Copyright © 2021 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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