AI Article Synopsis

  • The study explores how copy number variations (CNVs) affect the development of Parkinson's disease (PD), aiming to identify new genetic mechanisms linked to sporadic cases of the disease.
  • Utilizing data from over 11,000 PD patients and nearly 9,000 controls, the researchers discovered 14 significant CNV loci associated with PD, including various gene duplications and deletions.
  • The research highlights a higher prevalence of CNVs in specific PD-related genes among patients and suggests that certain CNVs, especially those involving the gene, may lead to earlier onset of the disease in early-onset PD cases.

Article Abstract

Objective: Our study investigates the impact of copy number variations (CNVs) on Parkinson's disease (PD) pathogenesis using genome-wide data, aiming to uncover novel genetic mechanisms and improve the understanding of the role of CNVs in sporadic PD.

Methods: We applied a sliding window approach to perform CNV-GWAS and conducted genome-wide burden analyses on CNV data from 11,035 PD patients (including 2,731 early-onset PD (EOPD)) and 8,901 controls from the COURAGE-PD consortium.

Results: We identified 14 genome-wide significant CNV loci associated with PD, including one deletion and 13 duplications. Among these, duplications in 7q22.1, 11q12.3 and 7q33 displayed the highest effect. Two significant duplications overlapped with PD-related genes and , but none overlapped with recent significant SNP-based GWAS findings. Five duplications included genes associated with neurological disease, and four overlapping genes were dosage-sensitive and intolerant to loss-of-function variants. Enriched pathways included neurodegeneration, steroid hormone biosynthesis, and lipid metabolism. In early-onset cases, four loci were significantly associated with EOPD, including three known duplications and one novel deletion in . CNV burden analysis showed a higher prevalence of CNVs in PD-related genes in patients compared to controls (OR=1.56 [1.18-2.09], p=0.0013), with showing the highest burden (OR=1.47 [1.10-1.98], p=0.026). Patients with CNVs in had an earlier disease onset. Burden analysis with controls and EOPD patients showed similar results.

Interpretation: This is the largest CNV-based GWAS in PD identifying novel CNV regions and confirming the significant CNV burden in EOPD, primarily driven by the gene, warranting further investigation.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11370542PMC
http://dx.doi.org/10.1101/2024.08.21.24311915DOI Listing

Publication Analysis

Top Keywords

copy number
8
number variations
8
parkinson's disease
8
loci associated
8
pd-related genes
8
cnv burden
8
burden analysis
8
burden
5
cnv
5
duplications
5

Similar Publications

Want 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!