The best validated susceptibility variants for Parkinson's disease are located in the α-synuclein (SNCA) and microtubule-associated protein tau (MAPT) genes. Recently, a protective p.N551K-R1398H-K1423K haplotype in the leucine-rich repeat kinase 2 (LRRK2) gene was identified, with p.R1398H appearing to be the most likely functional variant. To date, the consistency of the protective effect of LRRK2 p.R1398H across MAPT and SNCA variant genotypes has not been assessed. To address this, we examined 4 SNCA variants (rs181489, rs356219, rs11931074, and rs2583988), the MAPT H1-haplotype-defining variant rs1052553, and LRRK2 p.R1398H (rs7133914) in Caucasian (n = 10,322) and Asian (n = 2289) series. There was no evidence of an interaction of LRRK2 p.R1398H with MAPT or SNCA variants (all p ≥ 0.10); the protective effect of p.R1398H was observed at similar magnitude across MAPT and SNCA genotypes, and the risk effects of MAPT and SNCA variants were observed consistently for LRRK2 p.R1398H genotypes. Our results indicate that the association of LRRK2 p.R1398H with Parkinson's disease is independent of SNCA and MAPT variants, and vice versa, in Caucasian and Asian populations.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3829604 | PMC |
| http://dx.doi.org/10.1016/j.neurobiolaging.2013.07.013 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Elucidating the genetic contributions to Parkinson's disease (PD) etiology across diverse ancestries is a critical priority for the development of targeted therapies in a global context. We conducted the largest sequencing characterization of potentially disease-causing, protein-altering and splicing mutations in 710 cases and 11,827 controls from genetically predicted African or African admixed ancestries. We explored copy number variants (CNVs) and runs of homozygosity (ROHs) in prioritized early onset and familial cases.
View Article and Find Full Text PDFA network-based systems genetics framework identifies pathobiology and drug repurposing in Parkinson's disease.
NPJ Parkinsons Dis
January 2025
Cleveland Clinic Genome Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA.
Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder. However, current treatments only manage symptoms and lack the ability to slow or prevent disease progression. We utilized a systems genetics approach to identify potential risk genes and repurposable drugs for PD.
View Article and Find Full Text PDFUnraveling Hormonal Influence of Menstrual Cycle in a Young Patient with LRRK2-Parkinson's Disease.
Mov Disord Clin Pract
January 2025
Department of Neurology, Unidade Local de Saúde de São João, EPE, Porto, Portugal.
NERINE reveals rare variant associations in gene networks across multiple phenotypes and implicates an subnetwork in Parkinson's disease.
bioRxiv
January 2025
Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
Gene networks encapsulate biological knowledge, often linked to polygenic diseases. While model system experiments generate many plausible gene networks, validating their role in human phenotypes requires evidence from human genetics. Rare variants provide the most straightforward path for such validation.
View Article and Find Full Text PDFA STING-CASM-GABARAP pathway activates LRRK2 at lysosomes.
J Cell Biol
February 2025
Department of Cell Biology, Yale University School of Medicine, New Haven, CT, USA.
Mutations that increase LRRK2 kinase activity have been linked to Parkinson's disease and Crohn's disease. LRRK2 is also activated by lysosome damage. However, the endogenous cellular mechanisms that control LRRK2 kinase activity are not well understood.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!