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Although large-scale genetic association studies have proven opportunistic for the delineation of neurodegenerative disease processes, we still lack a full understanding of the pathological mechanisms of these diseases, resulting in few appropriate treatment options and diagnostic challenges. To mitigate these gaps, the Neurodegenerative Disease Knowledge Portal (NDKP) was created as an open-science initiative with the aim to aggregate, enable analysis, and display all available genomic datasets of neurodegenerative disease, while protecting the integrity and confidentiality of the underlying datasets. The portal contains 218 genomic datasets, including genotyping and sequencing studies, of individuals across ten different phenotypic groups, including neurological conditions such as Alzheimer's disease, amyotrophic lateral sclerosis, Lewy body dementia, and Parkinson's disease. In addition to securely hosting large genomic datasets, the NDKP provides accessible workflows and tools to effectively utilize the datasets and assist in the facilitation of customized genomic analyses. Here, we summarize the genomic datasets currently included within the portal, the bioinformatics processing of the datasets, and the variety of phenotypes captured. We also present example use-cases of the various user interfaces and integrated analytic tools to demonstrate their extensive utility in enabling the extraction of high-quality results at the source, for both genomics experts and those in other disciplines. Overall, the NDKP promotes open-science and collaboration, maximizing the potential for discovery from the large-scale datasets researchers and consortia are expending immense resources to produce and resulting in reproducible conclusions to improve diagnostic and therapeutic care for neurodegenerative disease patients.
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Although over 90 independent risk variants have been identified for Parkinson's disease using genome-wide association studies, most studies have been performed in just one population at a time. Here we performed a large-scale multi-ancestry meta-analysis of Parkinson's disease with 49,049 cases, 18,785 proxy cases and 2,458,063 controls including individuals of European, East Asian, Latin American and African ancestry. In a meta-analysis, we identified 78 independent genome-wide significant loci, including 12 potentially novel loci (MTF2, PIK3CA, ADD1, SYBU, IRS2, USP8, PIGL, FASN, MYLK2, USP25, EP300 and PPP6R2) and fine-mapped 6 putative causal variants at 6 known PD loci. By combining our results with publicly available eQTL data, we identified 25 putative risk genes in these novel loci whose expression is associated with PD risk. This work lays the groundwork for future efforts aimed at identifying PD loci in non-European populations.
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Estudio de Asociación del Genoma Completo , Enfermedad de Parkinson , Humanos , Estudio de Asociación del Genoma Completo/métodos , Enfermedad de Parkinson/genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple/genética , Ubiquitina Tiolesterasa/genéticaRESUMEN
Parkinson's disease has a large heritable component and genome-wide association studies have identified over 90 variants with disease-associated common variants, providing deeper insights into the disease biology. However, there have not been large-scale rare variant analyses for Parkinson's disease. To address this gap, we investigated the rare genetic component of Parkinson's disease at minor allele frequencies <1%, using whole genome and whole exome sequencing data from 7184 Parkinson's disease cases, 6701 proxy cases and 51 650 healthy controls from the Accelerating Medicines Partnership Parkinson's disease (AMP-PD) initiative, the National Institutes of Health, the UK Biobank and Genentech. We performed burden tests meta-analyses on small indels and single nucleotide protein-altering variants, prioritized based on their predicted functional impact. Our work identified several genes reaching exome-wide significance. Two of these genes, GBA1 and LRRK2, have variants that have been previously implicated as risk factors for Parkinson's disease, with some variants in LRRK2 resulting in monogenic forms of the disease. We identify potential novel risk associations for variants in B3GNT3, AUNIP, ADH5, TUBA1B, OR1G1, CAPN10 and TREML1 but were unable to replicate the observed associations across independent datasets. Of these, B3GNT3 and TREML1 could provide new evidence for the role of neuroinflammation in Parkinson's disease. To date, this is the largest analysis of rare genetic variants in Parkinson's disease.
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Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/genética , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo/métodos , Factores de Riesgo , Frecuencia de los Genes , Receptores InmunológicosRESUMEN
Genome-wide association studies (GWAS) of Alzheimer's disease are predominantly carried out in European ancestry individuals despite the known variation in genetic architecture and disease prevalence across global populations. We leveraged published GWAS summary statistics from European, East Asian, and African American populations, and an additional GWAS from a Caribbean Hispanic population using previously reported genotype data to perform the largest multi-ancestry GWAS meta-analysis of Alzheimer's disease and related dementias to date. This method allowed us to identify two independent novel disease-associated loci on chromosome 3. We also leveraged diverse haplotype structures to fine-map nine loci with a posterior probability >0.8 and globally assessed the heterogeneity of known risk factors across populations. Additionally, we compared the generalizability of multi-ancestry- and single-ancestry-derived polygenic risk scores in a three-way admixed Colombian population. Our findings highlight the importance of multi-ancestry representation in uncovering and understanding putative factors that contribute to risk of Alzheimer's disease and related dementias.
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Enfermedad de Alzheimer , Predisposición Genética a la Enfermedad , Humanos , Enfermedad de Alzheimer/etnología , Enfermedad de Alzheimer/genética , Negro o Afroamericano/genética , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo/métodos , Genotipo , Polimorfismo de Nucleótido Simple/genética , Pueblos del Este de Asia/genética , Pueblo Europeo/genética , Pueblos Caribeños/genética , Hispánicos o Latinos/genética , Pueblos Sudamericanos/genéticaRESUMEN
BACKGROUND: GBA1 variants are among the most common genetic risk factors for Parkinson's disease (PD). GBA1 variants can be classified into three categories based on their role in Gaucher's disease (GD) or PD: severe, mild, and risk variant (for PD). OBJECTIVE: This review aims to generate and share a comprehensive database for GBA1 variants reported in PD to support future research and clinical trials. METHODS: We performed a literature search for all GBA1 variants that have been reported in PD. The data have been standardized and complemented with variant classification, odds ratio if available, and other data. RESULTS: We found 371 GBA1 variants reported in PD: 22 mild, 84 severe, 3 risk variants, and 262 of unknown status. We created a browser containing up-to-date information on these variants (https://pdgenetics.shinyapps.io/GBA1Browser/). CONCLUSIONS: The classification and browser presented in this work should inform and support basic, translational, and clinical research on GBA1-PD. © 2023 International Parkinson and Movement Disorder Society.
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Enfermedad de Gaucher , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/genética , Glucosilceramidasa/genética , Enfermedad de Gaucher/genética , MutaciónRESUMEN
Multiple genes have been associated with monogenic Parkinson's disease and Parkinsonism syndromes. Mutations in PINK1 (PARK6) have been shown to result in autosomal recessive early-onset Parkinson's disease. In the past decade, several studies have suggested that carrying a single heterozygous PINK1 mutation is associated with increased risk for Parkinson's disease. Here, we comprehensively assess the role of PINK1 variants in Parkinson's disease susceptibility using several large data sets totalling 376,558 individuals including 13,708 cases with Parkinson's disease and 362,850 control subjects. After combining these data, we did not find evidence to support a role for heterozygous PINK1 mutations as a robust risk factor for Parkinson's disease.
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Conjuntos de Datos como Asunto , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad/genética , Mutación , Resultados Negativos , Enfermedad de Parkinson/genética , Trastornos Parkinsonianos/genética , Proteínas Quinasas/genética , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Heterocigoto , Humanos , Masculino , Proteínas de la Membrana , Persona de Mediana Edad , Factores de Riesgo , Proteínas Supresoras de TumorRESUMEN
Multiple genes have been implicated in Parkinson's disease (PD), including causal gene variants and risk variants typically identified using genome-wide association studies. Variants in the alcohol dehydrogenase genes ADH1C and ADH1B are among the genes that have been associated with PD, suggesting that this family of genes may be important in PD. As part of the International Parkinson's Disease Genomics Consortium's efforts to scrutinize previously reported risk factors for PD, we explored genetic variation in the alcohol dehydrogenase genes ADH1A, ADH1B, ADH1C, ADH4, ADH5, ADH6, and ADH7 using imputed genome-wide association study data from 15,097 cases and 17,337 healthy controls. Rare-variant association tests and single-variant score tests did not show any statistically significant association of alcohol dehydrogenase genetic variation with the risk for PD.
