Smoking is a cause of amyotrophic lateral sclerosis. High low‐density lipoprotein cholesterol levels? Unsure

Armon, Carmel

doi:10.1002/ana.25468

Cited by 8 publications

(3 citation statements)

References 43 publications

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“…Based on observational studies and MR analyses, conflicting evidence exists for lipid levels including cholesterol as a risk factor for ALS 48 – 50 . Potential selection bias, reverse causality and the subtype of cholesterol studied challenge the interpretation of these results.…”

Section: Discussionmentioning

confidence: 99%

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

et al. 2021

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.

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Section: Discussionmentioning

confidence: 99%

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

et al. 2021

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“…1), MR analyses were performed in R (version 3.6.1) with TwoSampleMR package (version 0.5.2) [11]. Causal inference by MR analysis requires three basic assumptions: 1) relevance, i.e., IVs have causal effects on the exposure (e.g., IgG); 2) exclusion restriction, i.e., IVs affect the outcome (e.g., ALS), only through the exposure; and 3) exchangeability or independence, i.e., no common causes exist between IVs and the outcome [12]. Lead SNPs from the genetic loci reported to be associated with each exposure were extracted from the GWAS of immunoglobulins [7].…”

Section: Methodsmentioning

confidence: 99%

Polygenic associations and causal inferences between serum immunoglobulins and amyotrophic lateral sclerosis

Chen

Shen

Zhang

et al. 2020

Preprint

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Chronic inflammation might contribute to the development of amyotrophic lateral sclerosis (ALS). The relationship between serum immunoglobulins and risk of ALS remains however greatly unknown. In order to overcome limitations like reverse causation and residual confounding commonly seen in observational studies, we applied polygenic risk score (PRS) and Mendelian randomization (MR) analyses on summary statistics from the large-scale genome-wide association studies (GWAS), to examine the polygenic and causal associations between three serum immunoglobulins (IgA, IgM, and IgG) and risk of ALS (first in a discovery phase and then in a replication phase). An inverse polygenic association was discovered between IgA and ALS as well as between IgM and ALS. Such associations were however not replicated using a larger ALS GWAS and no causal association was observed for either IgA-ALS or IgM-ALS. A positive polygenic association was both discovered [odds ratio (OR) = 1.18; 95% confidence interval (CI): 1.12-1.25, P=5.9e-7] and replicated (OR=1.13, 95% CI: 1.06-1.20, P=0.001) between IgG and ALS. A causal association between IgG and ALS was also suggested in both the discovery (OR=1.06, 95%CI: 1.02-1.10, P=0.009) and replication (OR=1.07, 95%CI: 0.90-1.24, P=0.420) analyses, although the latter was not statistically significant. This study suggests a shared polygenic risk between serum IgG (as a biomarker for chronic inflammation) and ALS.

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“…Utilizing the instrumental variable (IV) methods (Figure 1), MR analyses were performed in R (version 3.6.1) with TwoSampleMR package (version 0.5.2) [11]. Causal inference by MR analysis requires three basic assumptions: 1) relevance, i.e., IVs have causal effects on the exposure (e.g., IgG); 2) exclusion restriction, i.e., IVs affect the outcome (e.g., ALS), only through the exposure; and 3) exchangeability or independence, i.e., no common causes exist between IVs and the outcome [12]. Lead SNPs from the genetic loci reported to be associated with each exposure were extracted from the GWAS of immunoglobulins [7].…”

Section: Prs Analysesmentioning

confidence: 99%

Polygenic associations and causal inferences between serum immunoglobulins and amyotrophic lateral sclerosis

Chen

Shen

Zhang

et al. 2021

Clinica Chimica Acta

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Smoking is a cause of amyotrophic lateral sclerosis. High low‐density lipoprotein cholesterol levels? Unsure

Cited by 8 publications

References 43 publications

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Polygenic associations and causal inferences between serum immunoglobulins and amyotrophic lateral sclerosis

Polygenic associations and causal inferences between serum immunoglobulins and amyotrophic lateral sclerosis

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