Genome-Wide Analysis of Copy Number Variation in Latin American Parkinson's Disease Patients

Abstract

Background: Parkinson's disease is the second most common neurodegenerative disorder and affects people from all ethnic backgrounds, yet little is known about the genetics of Parkinson's disease in non-European populations. In addition, the overall identification of copy number variants at a genome-wide level has been understudied in Parkinson's patients. The objective of this study was to understand the genome-wide burden of copy number variants in Latinos and its association with Parkinson's disease.

Methods: We used genome-wide genotyping data from 747 Parkinson's disease patients and 632 controls from the Latin American Research Consortium on the Genetics of Parkinson's disease.

Results: Genome-wide copy number burden analysis showed that patients were significantly enriched for copy number variants overlapping known Parkinson's disease genes compared with controls (odds ratio, 3.97; 95%CI, 1.69-10.5; P = 0.018). PRKN showed the strongest copy number burden, with 20 copy number variant carriers. These patients presented an earlier age of disease onset compared with patients with other copy number variants (median age at onset, 31 vs 57 years, respectively; P = 7.46 × 10^-7 ).

Conclusions: We found that although overall genome-wide copy number variant burden was not significantly different, Parkinson's disease patients were significantly enriched with copy number variants affecting known Parkinson's disease genes. We also identified that of 250 patients with early-onset disease, 5.6% carried a copy number variant on PRKN in our cohort. Our study is the first to analyze genome-wide copy number variant association in Latino Parkinson's disease patients and provides insights about this complex disease in this understudied population. © 2020 International Parkinson and Movement Disorder Society.

Keywords: Latin America; Parkinson's disease; copy number variants; genetics.

FIG. 1.

(A) Forest plot showing the CNV burden for PD patients compared with controls. Odds ratios (ORs) and P values were calculated using logistic regression for CNVs corrected for age, sex, and first 5 components of PCA. P values were adjusted with FDR for multiple testing. OR > 1 indicates an increased risk for PD per unit of CNV burden. (B) Table showing number of CNV carriers in any of the 19 known PD genes. (C) Visualization of CNVs in PRKN.

FIG. 2.

Kaplan–Meier estimates of individuals (PD patients and controls) carrying a CNV in a PD gene and individuals with other or no CNVs. Controls are censored observations because it is only known that they did not develop PD up to the age of their last visit. Probability is the probability of not having symptoms associated with PD. Age at visit or age at onset is time to onset of PD symptoms for cases and time to the last visit for controls. Highlight around the curves shows 95% confidence intervals.