Genetic Risk Loci for Parkinson Differ Slightly Between Asians and Europeans

By Will Boggs MD

May 04, 2020

NEW YORK (Reuters Health) - Genetic risk loci for Parkinson disease differ slightly between Asians and Europeans, according to the results of a genome-wide association study (GWAS).

"There is a lot of genetic similarity between Parkinson's disease in individuals of Asian and European ancestry, yet there are also important differences that may affect how accurately we can predict an Asian individual's risk of the disease in the presence or absence of Asian genetic data," Dr. Jia Nee Foo of Nanyang Technological University Singapore told Reuters Health by email.

"Most genetic studies so far are focused on European-ancestry samples," she said. "Genetic studies in diverse populations can provide new insights into the disease and point to new therapeutic targets."

Several dozen risk loci have been identified in GWASs in European populations. To identify potentially Asian-specific loci, Dr. Foo and colleagues undertook an East Asian meta-GWAS in more than 31,000 individuals and replicated the top single-nucleotide variants (SNVs) in cases and controls from the International Parkinson's Disease Genomics Consortium, the UK Biobank and Japan.

They identified 11 genome-wide significant loci, nine of which were previously described and two of which were newly identified. They also found a strong association with seven other loci that were previously reported to be associated with Parkinson disease in European individuals.

The new associations were at SV2C and WBSCR17. The variant within an intron of the SV2C gene showed consistent association with Parkinson disease across all five East Asian data sets.

SV2C is expressed in the basal ganglia and dopaminergic neurons and has previously been evaluated as a functional Parkinson disease candidate gene because of its restricted expression in brain regions relevant to Parkinson disease.

The second new variant was within an intron of the WBSCR17 gene and was also consistent across all five East Asian data sets, the researchers report in JAMA Neurology.

The SV2C variant was present at lower frequencies in European populations compared with Asian populations, whereas the WBSCR17 variant did not appear to be associated with Parkinson disease risk in European or Japanese cohorts.

A weighted polygenic risk score based on the 11 Asian SNVs significantly differentiated Parkinson disease cases from controls, and higher scores correlated significantly with younger age at onset in patients with Parkinson disease.

These 11 Asian SNVs accounted for an estimated 2.61% of the variance in Parkinson disease risk, whereas the previously reported 78 polymorphic European SNVs explained 2.57% of the variance in the same data set.

Combining the European and Asian loci resulted in a significant improvement of accuracy in differentiating East Asian cases from controls.

"SV2C is particularly interesting, as preliminary work in mouse models (by other groups, not ours) has shown that this gene affects dopamine release," Dr. Foo said. "This provides strong functional support for our finding."

"Compounds have already been designed to target a gene in the same family, SV2A, to treat epilepsy (levetiracetam)," she said. "Further work will be needed to determine if compounds targeting SV2C could be effective in Parkinson's disease patients."

Co-author Dr. Eng-King Tan of Duke-National University of Singapore Medical School told Reuters Health by email, "Physicians, geneticists, and scientists need to work more closely together to investigate why only certain at-risk individuals develop the disease while others do not, and how to bring these findings into the clinic to better manage patients with the disease."

"Characterizing and understanding the individual genetic architecture will facilitate the implementation of precision medicine, where we are able to define treatment strategies that are tailored to individual patients who live with Parkinson's disease," he said.

SOURCE: JAMA Neurology, online April 20, 2020.