medwireNews: Researchers have identified a major genetic risk factor for Parkinson’s disease in GBA1 that appears to be specific to people of African ancestry.
In their genome-wide association study involving 197,918 individuals of African or African admixed ancestry with and without Parkinson’s disease, the genetic variant (rs3115534-G) in GBA1 was present in 39% of the 1488 people with Parkinson’s disease.
The rs3115534-G was the leading single nucleotide polymorphism of 35 within the GBA1 locus significantly associated with Parkinson’s disease risk and was associated with a 58% increased risk for the condition among carriers relative to people without the variant.
By contrast, the genetic variant was very rare in a comparative analysis of individuals of European ancestry – 9230 patients with Parkinson’s disease and 4966 without.
This finding emphasizes “the importance of understanding ancestry-specific genetic risk in complex diseases, a particularly crucial point as the Parkinson’s disease field moves towards targeted treatments in clinical trials,” say the researchers in The Lancet Neurology.
Njideka Okubadejo (University of Lagos, Idi Araba, Nigeria) and colleagues add: “Deciphering causal and genetic risk factors in people of African ancestries will help to determine whether interventions, potential targets for disease-modifying treatments, and prevention strategies that are being studied in the European populations are relevant to African and African admixed populations.”
Among the study participants, there were 589 of Nigerian origin from the IPDGC Africa cohort, 1722 of broad unspecified African origin from the GP2 dataset), and 195,607 of African admixed origin – 1334 from the GP2 dataset and 194,273 from the 23andMe dataset.
In both the IPDGC Africa and GP2 datasets, Parkinson's disease was diagnosed according to criteria set by the Parkinson's UK Brain Bank.
In the 23andMe dataset, Parkinson's disease was diagnosed based on participants' self-reports, which were reliant on previous clinical diagnoses.
Linear regression analyses showed that the GBA1 rs3115534-G variant was positively associated with increasing percentage of African ancestry and had an additive effect, with homozygotes being between 1.92 and 3.80 times more likely to have Parkinson’s disease than not, while heterozygotes were between 1.17 and 1.38 more likely.
Further, in a linear regression analysis among 711 African ancestry cases and 185 African admixed ancestry cases, researchers found that “GBA1 rs3115534-G was also an age-at-onset disease modifier,” resulting in Parkinson’s disease onset occurring approximately 3 years earlier in individuals carrying one risk allele compared with those carrying none.
Genome sequencing analyses did not identify any coding or structural variations underlying the GBA1 genetic variant. However, the rs3115534-G risk allele was associated with increased GBA1 expression in whole blood and paradoxically, it was also linked to a trend toward decreased glucocerebrosidase activity, which is encoded by GBA1, particularly among homozygous carriers of the variant.
The researchers speculate that this could be due to transcript diversity and may lead to “new avenues towards efficient RNA-based therapeutic strategies, such as antisense oligonucleotides or short interfering RNAs, aimed at reducing lifetime risk.”
They conclude: “The distinctive genetics of African populations highlights the need for equitable inclusion of ancestrally diverse groups in future trials, which will be a valuable step towards gaining insights into novel genetic determinants underlying the causes of Parkinson’s disease.”
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