Insights into Ancestral Diversity in Parkinsons Disease Risk: A Comparative Assessment of Polygenic Risk Scores

Objectives To evaluate and compare different polygenic risk score (PRS) models in predicting Parkinsons disease (PD) across diverse ancestries, focusing on identifying the most suitable approach for each population and potentially contributing to equitable advancements in precision medicine. Methods We constructed a total of 105 PRS across individual level data from seven diverse ancestries. First, a cross-ancestry conventional PRS comparison was implemented by utilizing the 90 known European risk loci with weighted effects from four independent summary statistics including European, East Asian, Latino/Admixed American, and African/Admixed. These models were adjusted by sex, age, and principal components (28 PRS) and by sex, age, and percentage of admixture (28 PRS) for comparison. Secondly, a novel and refined multi-ancestry best-fit PRS approach was then applied across the seven ancestries by leveraging multi-ancestry meta-analyzed summary statistics and using a p-value thresholding approach (49 PRS) to enhance prediction applicability in a global setting. Results European-based PRS models predicted disease status across all ancestries to differing degrees of accuracy. Ashkenazi Jewish had the highest Odds Ratio (OR): 1.96 (95% CI: 1.69-2.25, p < 0.0001) with an AUC (Area Under the Curve) of 68%. Conversely, the East Asian population, despite having fewer predictive variants (84 out of 90), had an OR of 1.37 (95% CI: 1.32-1.42) and an AUC of 62%, illustrating the cross-ancestry transferability of this model. Lower OR alongside broader confidence intervals were observed in other populations, including Africans (OR =1.38, 95% CI: 1.12-1.63, p=0.001). Adjustment by percentage of admixture did not outperform principal components. Multi-ancestry best-fit PRS models improved risk prediction in European, Ashkenazi Jewish, and African ancestries, yet didn't surpass conventional PRS in admixed populations such as Latino/American admixed and African admixed populations. Interpretation The present study represents a novel and comprehensive assessment of PRS performance across seven ancestries in PD, highlighting the inadequacy of a 'one size fits all' approach in genetic risk prediction. We demonstrated that European based PD PRS models are partially transferable to other ancestries and could be improved by a novel best-fit multi-ancestry PRS, especially in non-admixed populations. ### Competing Interest Statement MAN. and HL.s participation in this project was part of a competitive contract awarded to Data Tecnica International LLC by the National Institutes of Health to support open science research. MAN. also currently serves on the scientific advisory board for Character Bio Inc. and Neuron23 Inc. L.N.K and K.H. are employed by and hold stock or stock options in 23andMe, Inc. ### Funding Statement This work was carried out with the support and guidance of the GP2 Trainee Network which is part of the Global Parkinsons Genetics Program and funded by the Aligning Science Across Parkinsons (ASAP) initiative. Data used in the preparation of this article were obtained from Global Parkinsons Genetics Program (GP2). GP2 is funded by the Aligning Science Across Parkinsons (ASAP) initiative and implemented by The Michael J. Fox Foundation for Parkinsons Research (https://gp2.org). For a complete list of GP2 members see https://gp2.org. Additional funding was provided by The Michael J. Fox Foundation for Parkinsons Research through grant MJFF-009421/17483. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging (NIA), National Institutes of Health, Department of Health and Human Services; project number ZIAAG000534, as well as the National Institute of Neurological Disorders and Stroke. This work utilized the computational resources of the NIH HPC Biowulf cluster. (http://hpc.nih.gov) We are grateful to the Banner Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona for the provision of human biological materials. The Brain and Body Donation Program has been supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinsons Disease and Related Disorders), the National Institute on Aging (P30 AG19610 and P30AG072980, Arizona Alzheimers Disease Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimers Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901 and 1001 to the Arizona Parkinsons Disease Consortium) and the Michael J. Fox Foundation for Parkinsons Research. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Data was obtained from the Global Parkinsons Genetics Program (GP2) and can be accessed at amp-pd.org. GP2 data is accessible through a partnership with the Accelerating Medicines Partnership in Parkinsons Disease (ASAP) and can be requested via the websites application process at https://www.amp-pd.org. GWAS summary statistics from GP2s release 6 are available for all datasets(doi: 10.5281/zenodo.10472143, https://doi.org/10.5281/zenodo.10472143).23andMe summary statistics is available upon application through their website (https://research.23andme.com/dataset-access/). GenoTools (version 10; https://github.com/GP2code/GenoTools) was used for genotyping, imputation, quality control, ancestry prediction, and data processing. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data were obtained from the Global Parkinson's Genetics Program (GP2) and is accessible through a partnership with the Accelerating Medicines Partnership in Parkinson's Disease (AMP-PD) and can be requested via the website's application process (https://www.amp-pd.org/). GWAS summary statistics from GP2's release 6 are available for all datasets (doi: 10.5281/zenodo.10472143, https://doi.org/10.5281/zenodo.10472143). 23andMe summary statistics is available upon application through their website (https://research.23andme.com/dataset-access/). GenoTools (version 10; https://github.com/GP2code/GenoTools) was used for genotyping, imputation, quality control, ancestry prediction, and data processing. A secured workspace on the Terra platform was created to conduct genetic analyses using GP2 release 6 data and summary statistics (https://app.terra.bio/). Additionally, all scripts used for this study can be found in the public domain on GitHub (https://github.com/GP2code/multiancestry-PRS_PRSice; doi:10.5281/zenodo.11110944).