Identification of genetic risk loci and causal insights associated with Parkinson's disease in African and African admixed populations: a genome-wide association study.

BACKGROUND: An understanding of the genetic mechanisms underlying diseases in ancestrally diverse populations is an important step towards development of targeted treatments. Research in African and African admixed populations can enable mapping of complex traits, because of their genetic diversity, extensive population substructure, and distinct linkage disequilibrium patterns. We aimed to do a comprehensive genome-wide assessment in African and African admixed individuals to better understand the genetic architecture of Parkinson's disease in these underserved populations. METHODS: We performed a genome-wide association study (GWAS) in people of African and African admixed ancestry with and without Parkinson's disease. Individuals were included from several cohorts that were available as a part of the Global Parkinson's Genetics Program, the International Parkinson's Disease Genomics Consortium Africa, and 23andMe. A diagnosis of Parkinson's disease was confirmed clinically by a movement disorder specialist for every individual in each cohort, except for 23andMe, in which it was self-reported based on clinical diagnosis. We characterised ancestry-specific risk, differential haplotype structure and admixture, coding and structural genetic variation, and enzymatic activity. FINDINGS: We included 197 918 individuals (1488 cases and 196 430 controls) in our genome-wide analysis. We identified a novel common risk factor for Parkinson's disease (overall meta-analysis odds ratio for risk of Parkinson's disease 1·58 [95% CI 1·37-1·80], p=2·397 × 10-14) and age at onset at the GBA1 locus, rs3115534-G (age at onset ß=-2·00 [SE=0·57], p=0·0005, for African ancestry; and ß=-4·15 [0·58], p=0·015, for African admixed ancestry), which was rare in non-African or non-African admixed populations. Downstream short-read and long-read whole-genome sequencing analyses did not reveal any coding or structural variant underlying the GWAS signal. The identified signal seems to be associated with decreased glucocerebrosidase activity. INTERPRETATION: Our study identified a novel genetic risk factor in GBA1 in people of African ancestry, which has not been seen in European populations, and it could be a major mechanistic basis of Parkinson's disease in African populations. This population-specific variant exerts substantial risk on Parkinson's disease as compared with common variation identified through GWAS and it was found to be present in 39% of the cases assessed in this study. This finding highlights the importance of understanding ancestry-specific genetic risk in complex diseases, a particularly crucial point as the Parkinson's disease field moves towards targeted treatments in clinical trials. The distinctive genetics of African populations highlights the need for equitable inclusion of ancestrally diverse groups in future trials, which will be a valuable step towards gaining insights into novel genetic determinants underlying the causes of Parkinson's disease. This finding opens new avenues towards RNA-based and other therapeutic strategies aimed at reducing lifetime risk of Parkinson's disease. FUNDING: The Global Parkinson's Genetics Program, which is funded by the Aligning Science Across Parkinson's initiative, and The Michael J Fox Foundation for Parkinson's Research.

Garcinia kola seed biflavonoid fraction (Kolaviron), increases longevity and attenuates rotenone-induced toxicity in Drosophila melanogaster.

Rotenone, a naturally occurring and commonly used pesticide, has been established as a model for inducing Parkinson's Disease (PD) in rodents. Kolaviron is a biflavonoid complex from Garcinia kola seeds with anti-oxidative and anti-inflammatory properties. Here, we evaluated the ameliorative role of Kolaviron on rotenone-induced toxicity in Drosophila melanogaster. Flies for longevity study were exposed to Kolaviron (100-500mg/kg diet) throughout the lifespan. For biochemical study, Groups A, B and C flies were treated with ethanol (2.0%, control, vehicle), Kolaviron (200mg/kg diet) and rotenone (250µM) respectively. Flies in Group D were co-treated with both rotenone (250µM) and Kolaviron (200mg/kg diet) for 7days. Subsequently, selected markers of antioxidant status, inflammatory and neurotoxicity were evaluated in the flies. The results from longevity experiment showed that Kolaviron (200, 100, 300 and 400mg/kg) extended lifespan of flies by 38.2%, 20.6%, 11.8% and 2.9% respectively. Also, Kolaviron attenuated rotenone-induced inhibition of catalase, glutathione-S-transferase and acetylcholinesterase activities and depletion of total thiols content in flies. Moreover, Kolaviron prevented rotenone-induced increases in hydrogen peroxide and nitric oxide (nitrite and nitrate) levels and improved rotenone-induced decrease in locomotor performance of flies (p<0.05). Overall, this study evidenced for the first time, the lifespan extension property of Kolaviron and its chemoprotective role on rotenone-induced toxicity in D. melanogaster via anti-oxidative and anti-inflammatory mechanisms.

Falls and Their Associated Risks in Parkinson's Disease Patients in Nigeria.

OBJECTIVE: Falls are a devastating consequence of Parkinson's disease (PD) and are due to motor imbalance. However, the frequency of falls and their risk factors among Nigerians with PD is not known despite the significant increase in PD cases in the country. To assess fall risk factors and frequency in Nigerian PD patients. METHODS: Using an analytical design to compare falling versus non-falling patients, 81 PD patients were assessed for clinical factors, frequency of falls, and candidate risk factors for falls according to the Tinetti Balance and Gait, Unified Parkinson's Disease Rating Scale subsection 1, and Timed Up and Go Tests. Descriptive, bivariate, and multivariate analyses were performed at the 95% confidence level. RESULTS: The mean age of participants was 65.6 ± 9.7 years. Falls were about three times (p < 0.001) more common in PD patients. Of the falling patients, 67.7% sustained injuries, 67.7% had recurrent falls and 44.9% admitted to having a fear of falling. The independent statistical predictors of fall were fear of falling [odds ratio (OR): 3.86], disease severity (OR: 1.09) and disease duration (OR: 1.01). CONCLUSION: The frequency of falls in PD patients was significantly higher when compared with the healthy adult population, and the modifiable predictor was fear of falling with a potential to significantly reduce falls when strategically addressed.