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000265764 005__ 20240112171355.0
000265764 0247_ $$2doi$$a10.1016/S1474-4422(23)00283-1
000265764 0247_ $$2pmid$$apmid:37633302
000265764 0247_ $$2pmc$$apmc:PMC10593199
000265764 0247_ $$2ISSN$$a1474-4422
000265764 0247_ $$2ISSN$$a1474-4465
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000265764 037__ $$aDZNE-2023-01035
000265764 041__ $$aEnglish
000265764 082__ $$a610
000265764 1001_ $$aRizig, Mie$$b0
000265764 245__ $$aIdentification of genetic risk loci and causal insights associated with Parkinson's disease in African and African admixed populations: a genome-wide association study.
000265764 260__ $$aLondon$$bLancet Publ. Group$$c2023
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000265764 520__ $$aAn 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.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.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 β=-2·00 [SE=0·57], p=0·0005, for African ancestry; and β=-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.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.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.
000265764 536__ $$0G:(DE-HGF)POF4-354$$a354 - Disease Prevention and Healthy Aging (POF4-354)$$cPOF4-354$$fPOF IV$$x0
000265764 588__ $$aDataset connected to CrossRef, PubMed, , Journals: pub.dzne.de
000265764 650_2 $$2MeSH$$aParkinson Disease: ethnology
000265764 650_2 $$2MeSH$$aHumans
000265764 650_2 $$2MeSH$$aParkinson Disease: genetics
000265764 650_2 $$2MeSH$$aGenome-Wide Association Study
000265764 650_2 $$2MeSH$$aGenetic Loci
000265764 650_2 $$2MeSH$$aLinkage Disequilibrium
000265764 650_2 $$2MeSH$$aBlack People: genetics
000265764 650_2 $$2MeSH$$aPolymorphism, Single Nucleotide: genetics
000265764 650_2 $$2MeSH$$aGenetic Predisposition to Disease: genetics
000265764 650_2 $$2MeSH$$aAfrican People: genetics
000265764 650_7 $$0EC 3.2.1.45$$2NLM Chemicals$$aGBA protein, human
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000265764 7001_ $$aNorcliffe-Kaufmann, Lucy$$b73
000265764 7001_ $$aNetwork, Nigeria Parkinson Disease Research$$b74$$eCollaboration Author
000265764 7001_ $$aAfrica, International Parkinson's Disease Genomics Consortium$$b75$$eCollaboration Author
000265764 7001_ $$aBlack$$b76
000265764 7001_ $$aGroup, African American Connections to Parkinson's Disease Study$$b77$$eCollaboration Author
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000265764 7001_ $$aOkubadejo, Njideka Ulunma$$b82
000265764 7001_ $$aProgram, Global Parkinson's Genetics$$b83$$eCollaboration Author
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