Objective: To perform an admixture mapping analysis for Parkinson’s disease (PD) in the Veterans Affairs (VA) Million Veteran Program (MVP) cohort.

Background: The genetics of PD has been widely studied in populations of European origin but much less is known about genetic architecture of PD in African Americans and Latinos. Nearly 30% of Veterans identify as non-White or Hispanic/Latino and thus genetic studies of Veterans are well-suited to address this gap in knowledge. VA MVP is an initiative seeking to understand how genes, military experience, and lifestyle affect health, with over 1 million veterans enrolled to date. We analyzed the MVP Cohort using admixture mapping, a powerful method of gene mapping for diseases that show differential risk by ancestry.

Method: We selected 9,057 PD patients and 464,509 controls from the MVP cohort using ICD-9/10 codes and other characteristics extracted from the VA electronic health record. Global ancestry was estimated using unsupervised ADMIXTURE on the MVP case-control sample, 1000 Genomes Project high-coverage dataset, and Human Genome Diversity Project. We selected 400 MVP participants with more than 95% continental ancestry for Native American, African, European, and East Asian ancestries to use as a reference for local ancestry inference (LAI). LAI was performed using gnomix. Admixture mapping was performed using PLINK2.

Results: Admixture mapping identified two novel risk loci for PD driven by African ancestry on chromosomes 3p14.1 and 11p15.4, three novel risk loci on chromosomes 16p13.3-p13.13, 18q21.33-q22.1, and 20p12.3-p12.2 for Native American ancestry. Several of the genes in these regions are expressed in brain and have potential relevance to neuronal function. None of these five loci have previously been reported to overlap with significant association signals in PD genome wide association studies (GWAS).

Conclusion: Our data implicate several putative novel risk loci for PD in African Americans and Latinos, though these findings must be validated in independent populations. We are currently performing fine-mapping analyses to identify the specific variants that convey PD risk within each region.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/admixture-mapping-of-the-va-million-veteran-program-cohort-implicates-novel-genetic-risk-loci-for-pd-driven-by-african-and-native-american-ancestry/