Objective: To assess the predictive ability of European-derived PD PRS model of 90 risk SNPs identified from the largest PD GWAS[1]in Egyptians and study its association with clinical outcomes, given the ethnicity-variable penetrance of genetic risk factors, directionality and magnitude of effects

Background: Genetic factors are well known contributors to PD susceptibility and clinical heterogeneity. Similar to rare pathogenic mutations, the cumulative effect of common SNPs identified from European PD GWAS are used for identification of high risk patients, prediction of clinical & treatment outcomes. Assessing such high powered PRS models in independent populations & testing clinical associations are required to address health disparities due to lack of ancestry-specific PRS

Method: A total of 293cases and 358controls were recruited from 16centres in Egypt through ENN&IPDGC Africa[2]. Genotyping was conducted using the Neurobooster platform in collaboration with GP2[3,4]. PRS was calculated using 86 genotyped/imputed SNPs. The relationship between PRS, disease risk and clinical variables; age at onset, UPDRS score and MMSE&MoCA scores was tested using generalized linear models.

Results: PRS significantly predicted PD status with higher PRS in cases compared to controls [T1,F1,2]. A possible contributor to the higher AUC in our dataset compared to original test dataset(HBS) is the higher frequency of carriers of large effect variants such as LRRK2 G2019S (2.78% vs 0.5%). Odds Ratio (OR=1.566,95%CI=1.261-1.968) is higher than recently reported in a different African population[5], illustrating the cross-ancestry transferability of this model in Egyptians

The previously reported association between AAO and PRS was not observed; the AAO for top PRS quartile, of OR=2.16,1.23-3.85[F3], was widely spread and a group of low PRS quartile had early AAO(<40 years)[F4] which maybe attributed to rare not common risk SNPs represented in this PRS

Total UPDRS scores adjusted for age and disease duration showed significant association with PRS highlighting its potential to identify high risk cases predicted to develop severe age-dependent clinical outcomes.

No significant association between PRS and cognitive impairment was observed possibly due to limited sample size.

Conclusion: European-based PD PRS is transferable to Egyptians with comparable performance

figure1 PD PRS distribution in cases and controls

figure2 PD PRS boxplot by PD status

figure3 OR of developing PD for each PRS quartile

table1 Association between PRS & different traits

figure4 Age at onset for high vs low PRS quartiles

References: 1. Nalls MA, Blauwendraat C, Vallerga CL, Heilbron K, Bandres-Ciga S, Chang D, Tan M, Kia DA, Noyce AJ, Xue A, Bras J. Identification of novel risk loci, causal insights, and heritable risk for Parkinson’s disease: a meta-analysis of genome-wide association studies. The Lancet Neurology. 2019 Dec 1;18(12):1091-102.
2. Rizig M, Okubadejo N, Salama M, Thomas O, Akpalu A, Gouider R. The international Parkinson disease genomics consortium Africa. The Lancet Neurology. 2021 May 1;20(5):335.
3. KRÜGER R. GP2: The Global Parkinson’s Genetics Program. Movement Disorders. 2021;36(4).
4. Bandres‐Ciga S, Faghri F, Majounie E, Koretsky MJ, Kim J, Levine KS, Leonard H, Makarious MB, Iwaki H, Crea PW, Hernandez DG. Neurobooster array: a genome‐wide genotyping platform to study neurological disorders across diverse populations. Movement Disorders. 2024 Nov;39(11):2039-48.
5. Awad PS, Makarious MB, Elsayed I, Sanyaolu A, Crea PW, Schuh AF, Levine KS, Vitale D, Korestky MJ, Kim J, Leal TP. Insights into Ancestral Diversity in Parkinsons Disease Risk: A Comparative Assessment of Polygenic Risk Scores. MedRxiv. 2024 May 9:2023-11.

« Back to 2025 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/european-derived-parkinsons-disease-polygenic-risk-score-model-is-associated-with-pd-status-updrs-score-but-not-age-at-onset-or-cognitive-impairment-in-an-egyptian-pd-dataset/