Research Identifies Novel Genetic Risk Factor of Parkinson Disease in African Populations

Author(s):

Findings of a new novel genetic risk factor could inform future GBA1 clinical trials, improving patient stratification and the odds of designing trials that are more likely to produce meaningful and actionable answers.

Mie Rizig, MD

A recently published genome-wide association study (GWAS) of nearly 200,000 individuals found a novel genetic risk factor affecting GBA1 in people of African ancestry, which had not been seen in European populations, and could be a major mechanistic basis of Parkinson disease (PD) in African populations.^1,2

The variant on the GBA1 gene was identified by researchers from the Global Genetics Program (GP2), led by those at the National Institutes of Health, the University of Lagos in Nigeria, and University College London (UCL). From the 3 cohorts, 1488 cases of PD and 196,430 controls of African and African admixed ancestry were included in the GWAS meta-analyses. In the overall meta-analysis, the odds ratio (OR) for risk of PD was 1.58 (95% CI, 1.37-1.80; P = 2.397 x 10-14).

"Genetics study in people of European descent has led to a wave of treatment approaches in development," first author Mie Rizig, MD, lead coordinator, International Parkinson’s Disease Genomics Consortium (IPDGC) Africa, and a senior clinical research fellow, UCL, said in statement.¹ "It has been our hope in organizing genetic data from African populations, and in contributing to complementary datasets with GP2, that findings would indicate those therapies have broader application or would illuminate novel targets for a next generation of strategies."

In the study, investigators pulled individual-level data from the IPDGC and GP2 cohorts, and GWAS summary statistics from 23andMe. The IPDGC Africa and GP2 blood or saliva samples were genotyped using 2 different genotyping platforms—NeuroBooster and NeuroChip. To further dissect the novel identified GWAS signal, whole-genome sequencing (WGS) was performed. In addition to the meta-analyses, the study also included a comparative population of 9230 cases and 4966 controls with European ancestry.

A total of 35 single nucleotide polymorphisms (SNP) within the GBA1 locus were significantly associated with PD risk, with consistent directionality of effect across all cohorts, the 2 most distant SNPs being 639 773 bp apart from each other. Linear regression analyses showed that the GBA1 rs3115534 variant was positively associated with a higher percentage of African ancestry (ß = 0.0385 [SE, 0.0064]; P = 2.002 x 10^-9).

In a follow-up analysis evaluating whether the effect of the risk allele was additive, linear regression models showed that GBA1 rs3115534-G was also an age-at-onset disease modifier (African ancestry: ß = 2.00 [SE, 0.57]; P = .0005; African admixed ancestry: ß = –4.15 [SE, 0.58]; P = .015; mean ß = –3.06 [SE, 0.40]; P = .0077). Comprised of 711 African ancestry cases and 185 African admixed ancestry cases, the presence of this allele resulted in an onset of PD 3 years earlier per risk allele.

"As researchers and clinicians, our shared responsibility is to make sure Parkinson's science is representative of all communities around the world,” Njideka Okubadejo, MD, professor of neurology, University of Lagos College of Medicine, said in a statement.¹ "This GBA1 result is a step toward that future, where the research field is prioritizing, learning from, and treating all people with Parkinson's disease."

According to 1000 Genomes, larger sub-African population haplotypes spanning the rs3115534 variant were identified in the Esan and the Yoruba in Ibadan populations, suggesting a founder effect, and “underscoring the significance once again of ancestral diversity in genetic studies,” Rizig et al wrote. Fine mapping of this locus showed the lead SNP had a posterior probability of being the causal variant of 71.4%. “Because of the intronic nature of this variant, gene expression is potentially modified, paving the way for explorations in RNA-based or other therapeutic interventions that target the reduction of lifetime risk,” the study authors concluded.

Short-read WGS analyses were conducted in 206 individuals (141 cases and 65 controls), of whom 39 individuals were GBA1 rs3115534-GG carriers, 69 were rs3115534-GT carriers, and 98 were rs3115543-TT carriers. Between short-read WGS and imputed genotyped data for rs3115534, a 96.6% correlation was observed, further validating the high quality of the imputed data.

By leveraging expression quantitative trait locus data predominantly of African American ancestry, the rs3115534-G risk allele to be associated with increased GBA1 expression in the whole blood, but paradoxically linked with a trend towards decreased glucocerebrosidase activity. Overall, the data suggested a decreasing trend in glucocerebrosidase activity estimates when comparing rs3115534-GG homozygous risk allele carriers (mean, 762.50 U [SD, 273.50] vs rs115534-GT heterozygous carriers (2743.76 U [SE, 1960.83]; Welch 2-sample t test for GG vs GT: t = 4.3138; df = 21.583; P = .00029) and rs3115534-TT homozygous non-risk allele carriers (1879·94 U [1010·84]) versus rs3115534-GG homozygous risk allele carrier (GG vs TT: t= –4·7564, df = 18.363, P = 0.00014).

REFERENCES
1. Global consortium identifies novel Parkinson’s genetic risk factor in African populations. The Michael J Fox Foundation for Parkinson’s Research; Aligning Science Across Parkinson’s Disease. News release. August 24, 2023. Accessed August 25, 2023. https://www.prnewswire.com/news-releases/global-consortium-identifies-novel-parkinsons-genetic-risk-factor-in-african-populations-301908803.html
2. Rixig M, Bandres-Ciga S, Makarious MB, et al. Identification of genetic risk loci and causal insights associated with Parkinson’s disease in African and African admixed populations: a genome-wide association study. Published online August 23, 2023. doi:10.1016/S1474-4422(23)00283-1