Parkinson's disease genetics across diverse ancestries: an observational genetic study of causal and risk variants with translational implications.

Causal and risk variants in GBA1, LRRK2, PRKN and other parkinsonism genes, whose frequencies and spectra differ substantially across genetically inferred ancestries.

The genetic architecture of Parkinson's disease varies across ancestries, yet most previous studies focused on European populations. This multi-ancestry observational cross-sectional study analysed genome and exome sequencing and array genotyping data from 99,783 individuals (58,559 patients and 41,224 controls) across 11 genetically inferred ancestries, in the parkinsonism genes endorsed by the MDS Task Force, including GBA1, LRRK2, SNCA, VPS35, RAB32, PINK1 and PRKN. A causal variant was carried by 1,217 patients (2.1%), with substantial variation across ancestries, from 10 patients (0.4%) of 2,844 of African ancestry to 251 (10.7%) of 2,343 of Ashkenazi Jewish ancestry. Risk variants in GBA1 and LRRK2 were found in 6,893 patients (11.8%) and 3,578 controls (8.7%), GBA1 risk variants ranging from 4.1% (195/4,773) in the east Asian group to 52.9% (1,505/2,844) in the African group. The authors stress that trials targeting GBA1 and LRRK2 variant carriers are run mainly in Europe and the USA, whereas 29% of participants came from under-represented populations.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The figure to remember is the contrast in GBA1 risk variant frequency across ancestries, which invalidates any extrapolation of genetic testing yield from one population to another. These frequencies must not be read as penetrance estimates: this is a cross-sectional allele frequency study, with no follow-up or individual risk estimation. In practice it strengthens the case for broad genetic testing in patients of non-European ancestry, currently the least likely to access targeted trials.

Analysis by Dr Thibaut Benquey