Exploring Genetic Differences in Parkinson’s Disease by Ancestry

A landmark international study has found that the genetic drivers of Parkinson’s disease can vary dramatically between populations, underscoring the need to include people of various ancestries in genetic research and clinical trials.

The study, published in The Lancet Neurology, analyzed genetic data from 99,783 participants in the Global Parkinson’s Genetics Program, including 58,559 people with Parkinson’s disease and 41,224 people without the disease. Investigators examined known Parkinson’s disease-causing mutations and high-risk variants across 11 ancestry groups, making it the largest and most genetically diverse Parkinson’s study conducted to date.

The findings have immediate implications for the newest generation of therapies targeting specific Parkinson’s-related genes as they move through clinical trials, said Niccolo Mencacci, MD, PhD, assistant professor in the Ken and Ruth Davee Department of Neurology’s Division of Movement Disorders, who was a co-author of the study.

“Scientists have learned a lot about the genetics of Parkinson’s disease over the past couple of decades, but there’s a big blind spot: almost all of that research has been done in people of European ancestry,” Mencacci said. “About three out of every four genetic studies of Parkinson’s disease have focused on this one group, even though Parkinson’s affects people all over the world.”  

In the study, investigators found that 2.1 percent of people with Parkinson’s carried a genetic variant known to directly cause the disease, while nearly 12 percent carried variants that increase disease risk. However, the frequency of variants differed substantially among ancestry groups. For example, disease-causing variants were identified in 10.7 percent of participants of Ashkenazi Jewish ancestry, but as few as 0.4 percent of participants of African ancestry. Based on the study data, risk-associated variants in the genes GBA1 and LRRK2 were detected in nearly 6,900 people with Parkinson’s disease.

One of the study’s major discoveries was that while the same genes often contribute to Parkinson’s disease across populations, the specific variants within those genes can differ markedly by ancestry, Mencacci said.

“The gene GBA1 turned out to be important in every single population studied, which is good news for treatments targeting it,” Mencacci said. “But the specific changes within that gene were often completely different from one group to another.”

Mencacci said that one GBA1 variant was found to be very common among people of African ancestry but is rarely seen in European populations.

“That variant would have been completely missed if research had stayed narrowly focused on European populations,” he said.

Similar patterns emerged for LRRK2, another key target of experimental Parkinson’s therapies. The well-known LRRK2 G2019S variant was especially common among Ashkenazi Jewish, Middle Eastern and Latino populations, while other different LRRK2 variants appeared to play a larger role in East Asian populations.

The study arrives as pharmaceutical companies pursue precision medicine approaches aimed at treating patients according to their unique genetic makeup.

“This matters a lot right now because new treatments are being developed that specifically target genes linked to Parkinson’s, like GBA1 and LRRK2,” Mencacci said. “If these treatments are only tested in, and designed around, people of European background, we don’t actually know whether they’ll be as relevant for people from other parts of the world.”

The research highlights that these treatments may be relevant to far more people with Parkinson’s than expected, Mencacci said, a discovery that would have been missed if research had focused on people of European ancestry alone.

Nearly 30 percent of study participants came from historically underrepresented populations, including individuals of African, Latin American, Central Asian and other ancestries. Investigators said expanding that representation even further will be critical for future discoveries.

“The big-picture message is that including diverse populations in genetics research isn’t just about fairness for its own sake,” Mencacci said. “It directly affects whether new Parkinson’s treatments will actually work for, and be available to, patients around the world.”

The study was supported by Aligning Science Across Parkinson’s (ASAP) through the Global Parkinson’s Genetics Program. Additional support was provided by the Intramural Research Program of the National Institutes of Health.