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A large study conducted by the Global Parkinson's Genetics Program (GP2) and published in The Lancet Neurology found significant ancestry-based variation in the genetic yield of established Parkinson's disease gene panels. The study included 99,783 participants, with 58,559 diagnosed with Parkinson's disease and 41,224 serving as controls, drawn from 144 cohorts across 129 sites and categorized into 11 genetically inferred ancestry groups. Approximately 29% of the participants belonged to under-represented populations, defined as non-European and non-Ashkenazi Jewish.
On average, 2.1% of individuals with Parkinson's disease carried a causal genetic variant, with rates ranging from 0.4% in individuals of African descent to 10.7% in those of Ashkenazi Jewish ancestry. The variants in the GBA1 and LRRK2 genes were found in 11.8% of individuals with Parkinson's disease and 8.7% of controls. Notably, GBA1 was the most frequently identified variant across all ancestry groups, with its prevalence varying significantly, from 4.1% in East Asian individuals to 52.9% in individuals of African descent.
The findings raise concerns about the applicability of current gene and variant lists for Parkinson's disease, which are primarily based on European-ancestry datasets and may not be universally applicable. The study highlights that insufficient ancestry-specific reference data can lead to some variants being classified as of uncertain significance in certain populations, limiting opportunities for counseling or participation in clinical trials.
The authors emphasize the need for greater ancestral diversity in Parkinson's disease research to enhance diagnostic accuracy, improve understanding of disease mechanisms across different populations, and ensure equitable access to emerging genetically informed therapies. However, they note that these findings require confirmation in certified diagnostic laboratories before implementation in clinical settings. The research was funded by Aligning Science Across Parkinson's through GP2.
