Search

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.

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's disease (PD) and Alzheimer's disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1 *04 subtypes best accounted for the association, strongest with HLA-DRB1 *04:04 and HLA-DRB1 *04:07, and intermediary with HLA-DRB1 *04:01 and HLA-DRB1 *04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1 *04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1 *04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.