Dataset Information

Polygenic risk prediction and SNCA haplotype analysis in a Latino Parkinson's disease cohort.

ABSTRACT:

Background

Large-scale Parkinson's disease (PD) genome-wide association studies (GWAS) have, until recently, only been conducted on subjects with European-ancestry. Consequently, polygenic risk scores (PRS) constructed using PD GWAS data are likely to be less predictive when applied to non-European cohorts.

Methods

Using GWAS data from the largest study to date, we constructed a PD PRS for a Latino PD cohort (1497 subjects from LARGE-PD) and tested it for association with PD status and age at onset. We validated the PRS performance by testing it in an independent Latino cohort (448 subjects) and by repeating the analysis in LARGE-PD with the addition of 440 external Peruvian controls. We also tested SNCA haplotypes for association with PD risk in LARGE-PD and a European-ancestry PD cohort.

Results

The GWAS-significant PD PRS had an area under the receiver-operator curve (AUC) of 0.668 (95% CI: 0.640-0.695) in LARGE-PD. The inclusion of external Peruvian controls mitigated this result, dropping the AUC 0.632 (95% CI: 0.607-0.657). At the SNCA locus, haplotypes differ by ancestry. Ancestry-specific SNCA haplotypes were associated with PD status in both LARGE-PD and the European-ancestry cohort (p-value < 0.05). These haplotypes both include the rs356182 G-allele, but only share 14% of their variants overall.

Conclusion

The PD PRS has potential for PD risk prediction in Latinos, but variability caused by admixture patterns and bias in a European-ancestry PD PRS data limits its utility. The inclusion of diverse subjects can help elucidate PD risk loci and improve risk prediction in non-European cohorts.

SUBMITTER: Loesch DP

PROVIDER: S-EPMC10112543 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Publications

Polygenic risk prediction and SNCA haplotype analysis in a Latino Parkinson's disease cohort.

Loesch Douglas P DP Horimoto Andrea R V R ARVR Sarihan Elif Irem EI Inca-Martinez Miguel M Mason Emily E Cornejo-Olivas Mario M Torres Luis L Mazzetti Pilar P Cosentino Carlos C Sarapura-Castro Elison E Rivera-Valdivia Andrea A Medina Angel C AC Dieguez Elena E Raggio Victor V Lescano Andres A Tumas Vitor V Borges Vanderci V Ferraz Henrique B HB Rieder Carlos R CR Schumacher-Schuh Artur A Santos-Lobato Bruno L BL Velez-Pardo Carlos C Jimenez-Del-Rio Marlene M Lopera Francisco F Moreno Sonia S Chana-Cuevas Pedro P Fernandez William W Arboleda Gonzalo G Arboleda Humberto H Arboleda-Bustos Carlos E CE Yearout Dora D Zabetian Cyrus P CP Thornton Timothy A TA Mata Ignacio F IF O'Connor Timothy D TD

Parkinsonism & related disorders 20220618

<h4>Background</h4>Large-scale Parkinson's disease (PD) genome-wide association studies (GWAS) have, until recently, only been conducted on subjects with European-ancestry. Consequently, polygenic risk scores (PRS) constructed using PD GWAS data are likely to be less predictive when applied to non-European cohorts.<h4>Methods</h4>Using GWAS data from the largest study to date, we constructed a PD PRS for a Latino PD cohort (1497 subjects from LARGE-PD) and tested it for association with PD statu ...[more]

PMID: 35917738

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Project description:Background: Various studies have reported associations between synuclein alpha (SNCA) polymorphisms and Parkinson's disease (PD) risk. However, the results are inconsistent. We conducted a comprehensive meta-analysis of the associations between SNCA single-nucleotide polymorphisms (SNPs) and PD risk in overall populations and subpopulations by ethnicity. Methods: Standard meta-analysis was conducted according to our protocol with a cutoff point of p < 0.05. To find the most relevant SNCA SNPs, we used a cutoff point of p < 1 × 10-5 in an analysis based on the allele model. In the subgroup analysis by ethnicity, we divided the overall populations into five ethnic groups. We conducted further analysis on the most relevant SNPs using dominant and recessive models to identify the contributions of heterozygotes and homozygotes regarding each SNP. Results: In our comprehensive meta-analysis, 24,075 cases and 22,877 controls from 36 articles were included. We included 16 variants in the meta-analysis and found 12 statistically significant variants with p < 0.05. After narrowing down the variants using the p < 1 × 10-5 cutoff, in overall populations, seven SNPs increased the risk of PD (rs2736990, rs356220, rs356165, rs181489, rs356219, rs11931074, and rs2737029, with odds ratios [ORs] of 1.22-1.38) and one SNP decreased the risk (rs356186, with an OR of 0.77). In the East Asian group, rs2736990 and rs11931074 increased the risk (with ORs of 1.22-1.34). In the European group, five SNPs increased the risk (rs356219, rs181489, rs2737029, rs356165, and rs11931074, with ORs of 1.26-1.37) while one SNP decreased the risk (rs356186, with an OR of 0.77). The heterozygotes and homozygotes contributed differently depending on the variant. Conclusions: In summary, we found eight SNCA SNPs associated with PD risk, which had obvious differences between ethnicities. Seven SNPs increased the risk of PD and one SNP decreased the risk in the overall populations. In the East Asian group, rs2736990 and rs11931074 increased the risk. In the European group, rs356219, rs181489, rs2737029, rs356165, and rs11931074 increased the risk while rs356186 decreased the risk. Variants with the highest ORs and allele frequencies in our analysis should be given priority when carrying out genetic screening.

Project description:ObjectiveGenome-wide association studies (GWAS) have identified over 30 susceptibility loci associated with Alzheimer's disease (AD). Using AD GWAS data from the International Genomics of Alzheimer's Project (IGAP), Polygenic Risk Score (PRS) was successfully applied to predict life time risk of AD development. A recently introduced Polygenic Hazard Score (PHS) is able to quantify individuals with age-specific genetic risk for AD. The aim of this study was to quantify the age-specific genetic risk for AD with PRS and compare the results generated by PRS with those from PHS.MethodsQuantification of individual differences in age-specific genetic risk for AD identified by the PRS, was performed with Cox Regression on 9903 (2626 cases and 7277 controls) individuals from the Genetic and Environmental Risk in Alzheimer's Disease consortium (GERAD). Polygenic Hazard Scores were generated for the same individuals. The age-specific genetic risk for AD identified by the PRS was compared with that generated by the PHS. This was repeated using varying SNPs P-value thresholds for disease association.ResultsPolygenic Risk Score significantly predicted the risk associated with age at AD onset when SNPs were preselected for association to AD at P ≤ 0.001. The strongest effect (B = 0.28, SE = 0.04, P = 2.5 × 10-12) was observed for PRS based upon genome-wide significant SNPs (P ≤ 5 × 10-8). The strength of association was weaker with less stringent SNP selection thresholds.InterpretationBoth PRS and PHS can be used to predict an age-specific risk for developing AD. The PHS approach uses SNP effect sizes derived with the Cox Proportional Hazard Regression model. When SNPs were selected based upon AD GWAS case/control P ≤ 10-3, we found no advantage of using SNP effects sizes calculated with the Cox Proportional Hazard Regression model in our study. When SNPs are selected for association with AD risk at P > 10-3, the age-specific risk prediction results are not significant for either PRS or PHS. However PHS could be more advantageous than PRS of age specific AD risk predictions when SNPs are prioritized for association with AD age at onset (i.e., powerful Cox Regression GWAS study).

Dataset Information

Polygenic risk prediction and SNCA haplotype analysis in a Latino Parkinson's disease cohort.

Background

Methods

Results

Conclusion

Publications

Polygenic risk prediction and SNCA haplotype analysis in a Latino Parkinson's disease cohort.

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