Assessing Causal Relationship Between Human Blood Metabolites and Five Neurodegenerative Diseases With GWAS Summary Statistics

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 ∼ 0.982, FDR = 1.04E-4) and FTD (OR = 0.924, 95%CIs: 0.885 ∼ 0.964, FDR = 0.048), and X-11529 (OR = 1.604, 95%CIs: 1.250 ∼ 2.059, FDR = 0.048) and X-13429 (OR = 2.284, 95%CIs: 1.457 ∼ 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.

A multimodal intervention for Alzheimer’s disease results in multifaceted systemic effects reflected in blood and ameliorates functional and cognitive outcomes

“…Sun et al (2019) report increases associated with increased stroke risk, possibly due to increased blood pressure. Chen et al (2021) see a negative correlation with AD but a positive correlation with frontotemporal dementia (FTD). The relationship of hexadecanedioate with AD amelioration may be important, complex, and non-linear.…”

“…For example, one might expect a gene implicated by AD GWAS to have its gene product identified, or an analyte functionally associated with that gene. None of the candidate COCOA mediators intersect with a list of GWAS-implicated genes (Seto et al, 2021) (Chen et al, 2021). They suggestively associated 164 metabolites with the risk of at least one neurodegenerative disease.…”

“…Albumin and urea. Albumin and urea are particularly interesting because: (1) they very commonly measured as part of routine clinical labs -urea is one of eight assays in a typical basic metabolic panel, (2) they are very inexpensive to measure, (3) they are part of nitrogen metabolism pathways implicated by other significant mediator candidates, and (4) urea has been previously associated with AD (Ramdane, 2017;Chen et al, 2021). Albumin changes -but possibly in the opposite effect direction -have been reported to impact aging and neurodegeneration.…”

“…Subsystems. Chen et al leveraged two-sample Mendelian randomization and GWAS summary statistics to explore the causal association between 486 metabolites and five neurodegenerative diseases (NDDs) including AD (Chen et al, 2021). They suggestively associated 164 metabolites with the risk of at least one neurodegenerative disease.…”

The mechanism of palmatine-mediated intestinal flora and host metabolism intervention in OA-OP comorbidity rats

“…N-acetylcysteine can regulate a variety of pathophysiological processes, including oxidative stress, apoptosis, mitochondrial dysfunction, and imbalance of glutamate and dopamine neurotransmitter systems ( 31 ). Other studies have shown that 2-methoxy acetaminophen sulfate has an intervention effect on neurodegenerative diseases (such as amyotrophic lateral sclerosis and frontotemporal dementia) ( 32 ). Phenylalanine is one of the essential aromatic amino acids of the human body and can only be obtained from the outside world by food, because there is no relevant synthesis pathway in the human body.…”