Novel Genetic Risk Factor for Parkinson Disease Found in African Population

A genome-wide association study (GWAS) of people of African descent identified a novel genetic risk factor for Parkinson disease (PD). These findings were published in The Lancet Neurology.

To date, up to 36% of the heritable risk for PD has been identified among individuals with European ancestry. For non-European populations, however, little is known about the genetics of PD.

This study was the first GWAS assessing PD genetic risk among African and African admixed populations. Researchers from the Global Parkinson’s Genetics Program (GP2) sourced data from the International Parkinson’s Disease Genomics Consortium Africa (IPDGC Africa), the GP2, and 23andMe. Analyses were performed using 2 independent African cohorts, one African admixed cohort, and summary statistics from 23andMe.

Excluding the 23andMe dataset, the 3 cohorts comprised 1488 people with cases of PD and 196,430 control individuals. The mean age at PD onset ranged between 57.84 and 59.31. The researchers also included 9230 people with cases of PD and 4966 control individuals with European ancestry for comparison.

In the locus glucosylceramidase beta 1 (GBA1), 35 single nucleotide polymorphisms (SNPs) significantly associated with PD risk (odds ratio [OR], 1.58; 95% CI, 1.37-1.80; P =2.397×10^-14).

Conditional analyses indicated that only 1of the 35 SNPs, an intronic position at rs3115534, was driving the association. At that location, G was the more common allele among African and African admixed individuals relative to other populations, particularly for Nigerian populations. A linear regression analysis found rs3115534 was positively related with percentage of African ancestry (b, 0.0385; P =2.002×10^-9).

To test for additive effects, a linear regression analysis using 711 African cases and 185 African admixed cases indicated that rs3115534-G was an age-at-onset disease modifier among the African (b, -2.00; P =.0005) and African admixed (b, -4.15; P =.015) cohorts. Overall, each allele associated with a 3-year earlier onset of PD.

Fine mapping confirmed these findings, with a 71.4% posterior probability of rs3115534 being the causal variant.

In functional analyses, a strong signal between rs3115534 and the canonical transcription start site was observed (b, 0.238; P =9.99×10^-25), in which the risk allele associated with increased GBA1 expression. Furthermore, activity of glucocerebrosidase differed significantly between rs3115534-GG (mean, 762.50 U), -GT (mean, 2743.76 U; P =.00029), and -TT (mean, 1879.94 U; P =.00014) carriers.

The limitations of this study include the small sample size and the possibility that rare alleles or structural variants that may have been driving the observed signals were not considered in this analysis.

“Overall, by addressing the genetic complexity underlying these under-represented populations, our study represents a valuable resource for identifying and tracking GBA1 carriers that might prove to be relevant for enrolment in target-specific Parkinson’s disease clinical trials,” the researchers stated.

They concluded, “[W]e performed the largest genome-wide association study evaluating risk of Parkinson’s disease in individuals of African ancestry. We identified an intronic GBA1 variant, rs3115534, not previously associated with risk of Parkinson’s disease.”

Disclosures: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures,