Results from one of the largest and diverse genetic studies of Parkinson’s disease to date reveal that genetics may play a much greater role in the condition than previously recognized, especially in some ancestries that have historically been underrepresented in clinical studies. Published in The Lancet Neurology, the findings highlight the importance of representative genetic data for the development of targeted treatments that are effective across diverse populations.
Parkinson’s disease is a progressive neurodegenerative condition that affects more than 10 million people worldwide. While decades of research have uncovered key genetic drivers, most cases arise from a complex combination of genetic and environmental factors that can vary widely across populations and individuals.
“The genetic architecture of Parkinson’s disease varies considerably across ancestries, yet most previous genetic studies have focused on individuals of European ancestry,” write the authors of the study, led by Christine Klein, MD, professor of neurogenetics at the University of Lübeck. “This large-scale, multi-ancestry genetic study offers crucial insights into the population-specific genetic architecture of Parkinson’s disease.”
Klein’s team analyzed genome and exome sequencing data from nearly 100,000 individuals across 11 ancestries, using retrospective data from the Global Parkinson’s Genetic Program (GP2). In particular, the study focused on 18 genes with a well-established link to Parkinson’s disease, including both causal and risk variants.
While some genetic contributors were shared across ancestries, the analysis revealed that certain ancestry-specific differences are larger than previously thought. For instance, risk variants of GBA1, the most common across all ancestries, were present in just about 4% of individuals with east Asian ancestry, compared to nearly 53% of those with African ancestry.
The study also identified the first carriers of causal variants in the LRRK2 gene of African ancestries, highlighting the need to include underrepresented populations in large-scale genetic studies. Overall, 2% of Parkinson’s patients were found to carry a single causal genetic variant across 16 genes, ranging from 0.4% among individuals from African ancestry to 10.7% for those with Ashkenazi jew ancestry.
These findings have important implications for ongoing clinical trials evaluating targeted therapies aimed at Parkinson’s patients carrying GBA1 and LRRK2 variants. Without representative data accounting for the broad differences seen across ancestries, precision medicine approaches will fail to be effective for the global population.
Standard genetic screening panels are mainly built using data from individuals of European ancestry, meaning certain variants more common in other populations might end up being overlooked. If key genetic drivers go undetected, patients from underrepresented populations are generally more likely to be locked out of targeted clinical trials evaluating the next generation of Parkinson’s therapeutics.
“Whereas clinical trials targeting GBA1 and LRRK2 variant carriers are primarily performed in Europe and the U.S.A., increased ancestral diversity in Parkinson’s disease research will be crucial to improve diagnostic accuracy, enhance our understanding of disease mechanisms across populations, and ensure equitable application of and access to emerging genetically informed therapies,” Klein and colleagues conclude.
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