Assessment of common genetic variation in Alzheimer’s and Parkinson’s diseases reveals global distinction in population attributable risk

Emerging evidence suggests that the genetic architecture of Alzheimer’s (AD) and Parkinson’s diseases (PD) risk varies across ancestries. This study seeks to explore distinct and universal genetic targets across individuals of Latino, African/African Admixed, East Asian, and European populations by implementing Population Attributable Risk (PAR) comparisons on summary statistics from genome-wide association studies (GWAS). PAR was calculated for the most significant disease variants using summary statistics derived from select multi-ancestry GWAS meta-analyses, followed by fine-mapping analysis to validate genetic contribution of disease variants to European, African/African Admixed, East Asian, and Latino individuals. For both AD, APOE4 PAR estimates were universally high across all ancestries, with TSPAN14 and PICALM emerging as other common targets. Attributable risk varied across PD-related major risk loci including variation nearby GBA1 and LRRK2. In contrast, SNCA, MCCC1, VPS13C, and MAPT loci demonstrated comparable attributable risk across ancestries. This cross-ancestry evaluation of PAR reinforces the genetic heterogeneity of AD and PD. In consideration of the complex etiology of these diseases, these findings may inform the strategic prioritization of therapeutic targets and improve global health outcomes. Competing Interest Statement L.J., H.I, M.B.M, and M.A.N.'s participation in this project was part of a competitive contract awarded to DataTecnica LLC by the National Institutes of Health to support open science research. M.A.N. also owns stock in Clover Therapeutics and Neuron23 Inc. Funding Statement 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 (IFM received R01NS132437-01A1). C.C.C is funded by a Canadian Institutes of Health Research Vanier Scholarship. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the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 Footnotes

revised to include additional analyses; Title, along with the rest of the manuscript, contains minor re-wording; Figure 1 and Figure 2 include re-worded headers; Supplemental files updated; Author list updated. Data Availability Data (DOI 10.5281/zenodo.13755496, release 8) used in the preparation of this article were obtained from Global Parkinson's Genetics Program (GP2). GP2 is funded by the Aligning Science Across Parkinson's (ASAP) initiative and implemented by The Michael J. Fox Foundation for Parkinson's Research (https://gp2.org). For a complete list of GP2 members see https://gp2.org. Information about data access and all scripts for analyses are publicly available on GitHub (DOI 10.5281/zenodo.13774455; https://github.com/GP2code/PAR-ADPD/).