Assessing Causal Relationship Between Human Blood Metabolites and Five Neurodegenerative Diseases With GWAS Summary Statistics.
Front Neurosci
; 15: 680104, 2021.
Article
em En
| MEDLINE
| ID: mdl-34955704
ABSTRACT
Background:
Neurodegenerative diseases (NDDs) are the leading cause of disability worldwide while their metabolic pathogenesis is unclear. Genome-wide association studies (GWASs) offer an unprecedented opportunity to untangle the relationship between metabolites and NDDs.Methods:
By leveraging two-sample Mendelian randomization (MR) approaches and relying on GWASs summary statistics, we here explore the causal association between 486 metabolites and five NDDs including Alzheimer's Disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Parkinson's disease (PD), and multiple sclerosis (MS). We validated our MR results with extensive sensitive analyses including MR-PRESSO and MR-Egger regression. We also performed linkage disequilibrium score regression (LDSC) and colocalization analyses to distinguish causal metabolite-NDD associations from genetic correlation and LD confounding of shared causal genetic variants. Finally, a metabolic pathway analysis was further conducted to identify potential metabolite pathways.Results:
We detected 164 metabolites which were suggestively associated with the risk of NDDs. Particularly, 2-methoxyacetaminophen sulfate substantially affected ALS (OR = 0.971, 95%CIs 0.961 â¼ 0.982, FDR = 1.04E-4) and FTD (OR = 0.924, 95%CIs 0.885 â¼ 0.964, FDR = 0.048), and X-11529 (OR = 1.604, 95%CIs 1.250 â¼ 2.059, FDR = 0.048) and X-13429 (OR = 2.284, 95%CIs 1.457 â¼ 3.581, FDR = 0.048) significantly impacted FTD. These associations were further confirmed by the weighted median and maximum likelihood methods, with MR-PRESSO and the MR-Egger regression removing the possibility of pleiotropy. We also observed that ALS or FTD can alter the metabolite levels, including ALS and FTD on 2-methoxyacetaminophen sulfate. The LDSC and colocalization analyses showed that none of the identified associations could be driven by genetic correlation or confounding by LD with common causal loci. Multiple metabolic pathways were found to be involved in NDDs, such as "urea cycle" (P = 0.036), "arginine biosynthesis" (P = 0.004) on AD and "phenylalanine, tyrosine and tryptophan biosynthesis" (P = 0.046) on ALS.Conclusion:
our study reveals robust bidirectional causal associations between servaral metabolites and neurodegenerative diseases, and provides a novel insight into metabolic mechanism for pathogenesis and therapeutic strategies of these diseases.
Texto completo:
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Coleções:
01-internacional
Base de dados:
MEDLINE
Tipo de estudo:
Clinical_trials
/
Prognostic_studies
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article