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GWAS Links Gene Variant to Parkinson's Disease Risk in People of African Ancestry

NEW YORK — Through a genome-wide association study, an international team of researchers has found a novel Parkinson's disease gene variant among people of African ancestry that is not seen among Europeans.

The researchers believe that this variant in the GBA1 gene — which encodes β-glucocerebrosidase, a protein known to control how cells recycle proteins — could point to a mechanistic basis for Parkinson's disease in African populations.

"We were completely surprised," coauthor Sara Bandrés-Ciga, a staff scientist at the US National Institutes of Health's Center for Alzheimer's and Related Dementias (CARD), said in a statement. "The fact that the GBA1 variant had a significant association while others did not suggest that it is strongly tied to Parkinson's disease in this population."

The study was published in Lancet Neurology on Wednesday.

Most previous Parkinson's disease GWAS included people of European descent, and those studies have identified 90 independent genome-wide significant risk signals that explain 16 percent to 36 percent of the heritable risk of Parkinson's disease. However, as the researchers noted, very little is known about the genetics of Parkinson's disease in non-European populations.

For their study, they analyzed genetic data from 197,918 individuals with African or African admixed ancestry. Of these, 1,488 people had Parkinson's disease, and 196,430 did not. In addition, they used data from 9,230 cases and 4,966 controls of European ancestry for comparative analyses.

The participants came from several cohorts, including the Global Parkinson's Genetics Program, the International Parkinson's Disease Genomics Consortium Africa, and 23andMe.

Their meta-analysis pointed to a variant in GBA1, which had not been linked previously to Parkinson's risk. A gnomAD analysis indicated the variant rarely appears in people of European and Asian descent, suggesting it is almost exclusively related to African ancestry.

Within the African-ancestry cohort, the researchers found that those who carry one copy of the allele are about 1.5 times more likely to have Parkinson's disease than those who have no copies, while those who carry two copies are about 3.5 times more likely to have the condition.

According to the researchers, most of the variants previously associated with Parkinson's disease risk affect how the body manufactures glucocerebrosidase, an enzyme encoded by GBA1, which either disrupts the manufacturing process or alters the enzyme's activity. However, they said the new variant appears outside the coding region and might be responsible for changing lysosomal GBA1 activity in a previously unknown way.

Further, since this is an intronic variant that could affect gene expression, the researchers said RNA-based or other therapeutic interventions could be developed to reduce disease risk.

The authors pointed out, though, that two-thirds of the people with Parkinson's in this study were of Nigerian descent and that, because of that, the findings are not representative of the substantial genetic diversity found across Africa.

Still, this study underscores the need to include more diverse populations in genetic research. "These results support the idea that the genetic basis for a common disease can differ by ancestry, and understanding these differences may provide new insights into the biology of Parkinson's disease," coauthor Andrew Singleton, director of CARD, said in a statement.