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.

Assessment of the utility of a screening tool for COVID-19 diagnosis in an accident and emergency department in Lagos, Nigeria: A pilot study.

The use of reverse transcription-polymerase chain reaction (RT-PCR) is the gold standard laboratory test for diagnosing SARS-CoV-2 infection. However, it has the disadvantage of a long turnaround time and cost. The Nigeria Centre for Disease Control (NCDC) formulated a case definition for COVID-19. We sought to determine the utility of a 14-item, point-weighted clinical screening questionnaire adapted from the NCDC case definition in identifying patients more likely to have the disease. This was to aid prompt clinical decision-making. Methods: We retrospectively reviewed the data of 113 non-surgical patients presenting to the Accident and Emergency Department (A and E) of Lagos University Teaching Hospital, Lagos, Nigeria. Patients were stratified based on screening scores into low (0-2), moderate (3-5) and high (6) pre-test categories. Patients with low and high scores ≥6 were admitted to the A and E and the COVID-19 holding ward, respectively, while the moderate group had chest computed tomography scans to aid further decision-making, pending the outcome of their RT-PCR results. The validity of the triage score as compared to the RT-PCR test result was calculated and the kappa score of agreement was utilised to evaluate the concordance between two triage scores. The optimum cut-off score was also obtained based on the maximal Younden's index. Results: The frequencies of low, moderate and high pre-test scores were 34 (30%), 43 (38.1%) and 36 (31.9%), respectively. Overall, 38.1% (43/113) were RT-PCR positive. RT-PCR was positive in 26.5% (9/34) with low screening scores, 55.8% (24/43) with moderate scores and 27.8% (10/36) with high scores. The sensitivity and specificity of a high score of 6 were 25% and 92.86%, while the lower score of 3 had sensitivity and specificity of 62.5% and 58.6%, respectively. Conclusion: The screening tool showed a high specificity in its initial design, which suggests that anyone with a low score using this tool has a high probability of testing negative. We recommend a cut-off score of 4 (score A) or 6 (score B) of the current screening tool be used to increase the chances of identifying persons with COVID-19 for RT-PCR testing.