scholarly journals An Integrative Transcriptome-Wide Analysis of Amyotrophic Lateral Sclerosis for the Identification of Potential Genetic Markers and Drug Candidates

2021 ◽  
Vol 22 (6) ◽  
pp. 3216
Author(s):  
Sungmin Park ◽  
Daeun Kim ◽  
Jaeseung Song ◽  
Jong Wha J. Joo
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Small Molecules ◽  
Expression Profiles ◽  
Association Studies ◽  
Enrichment Analysis ◽  
Genome Wide Association Studies ◽  
Summary Statistic ◽  
Drug Candidates ◽  
Causal Genes ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative neuromuscular disease. Although genome-wide association studies (GWAS) have successfully identified many variants significantly associated with ALS, it is still difficult to characterize the underlying biological mechanisms inducing ALS. In this study, we performed a transcriptome-wide association study (TWAS) to identify disease-specific genes in ALS. Using the largest ALS GWAS summary statistic (n = 80,610), we identified seven novel genes using 19 tissue reference panels. We conducted a conditional analysis to verify the genes’ independence and to confirm that they are driven by genetically regulated expressions. Furthermore, we performed a TWAS-based enrichment analysis to highlight the association of important biological pathways, one in each of the four tissue reference panels. Finally, utilizing a connectivity map, a database of human cell expression profiles cultured with bioactive small molecules, we discovered functional associations between genes and drugs to identify 15 bioactive small molecules as potential drug candidates for ALS. We believe that, by integrating the largest ALS GWAS summary statistic with gene expression to identify new risk loci and causal genes, our study provides strong candidates for molecular basis experiments in ALS.

scholarly journals Multiple-Tissue Integrative Transcriptome-Wide Association Studies Discovered New Genes Associated With Amyotrophic Lateral Sclerosis

2020 ◽  
Vol 11 ◽  
Author(s):  
Lishun Xiao ◽  
Zhongshang Yuan ◽  
Siyi Jin ◽  
Ting Wang ◽  
Shuiping Huang ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Type I Error ◽  
Association Studies ◽  
Type I ◽  
Genome Wide Association Studies ◽  
Combination Strategy ◽  
New Genes ◽  
Genome Wide ◽  
Causal Genes ◽  
Lateral Sclerosis

Genome-wide association studies (GWAS) have identified multiple causal genes associated with amyotrophic lateral sclerosis (ALS); however, the genetic architecture of ALS remains completely unknown and a large number of causal genes have yet been discovered. To full such gap in part, we implemented an integrative analysis of transcriptome-wide association study (TWAS) for ALS to prioritize causal genes with summary statistics from 80,610 European individuals and employed 13 GTEx brain tissues as reference transcriptome panels. The summary-level TWAS analysis with single brain tissue was first undertaken and then a flexible p-value combination strategy, called summary data-based Cauchy Aggregation TWAS (SCAT), was proposed to pool association signals from single-tissue TWAS analysis while protecting against highly positive correlation among tests. Extensive simulations demonstrated SCAT can produce well-calibrated p-value for the control of type I error and was often much more powerful to identify association signals across various scenarios compared with single-tissue TWAS analysis. Using SCAT, we replicated three ALS-associated genes (i.e., ATXN3, SCFD1, and C9orf72) identified in previous GWASs and discovered additional five genes (i.e., SLC9A8, FAM66D, TRIP11, JUP, and RP11-529H20.6) which were not reported before. Furthermore, we discovered the five associations were largely driven by genes themselves and thus might be new genes which were likely related to the risk of ALS. However, further investigations are warranted to verify these results and untangle the pathophysiological function of the genes in developing ALS.

scholarly journals Evidence for GRN as part of a neuroinflammatory mechanism connecting common neurodegenerative diseases

2020 ◽  
Author(s):  
Mike A. Nalls ◽  
Cornelis Blauwendraat ◽  
Lana Sargent ◽  
Dan Vitale ◽  
Hampton Leonard ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Neurodegenerative Diseases ◽  
Genetic Risk ◽  
Association Studies ◽  
Molecular Data ◽  
Genome Wide Association Studies ◽  
Data Types ◽  
Genome Wide ◽  
Trait Locus ◽  
Lateral Sclerosis

SUMMARYBackgroundPrevious research using genome wide association studies (GWAS) has identified variants that may contribute to lifetime risk of multiple neurodegenerative diseases. However, whether there are common mechanisms that link neurodegenerative diseases is uncertain. Here, we focus on one gene, GRN, encoding progranulin, and the potential mechanistic interplay between genetic risk, gene expression in the brain and inflammation across multiple common neurodegenerative diseases.MethodsWe utilized GWAS, expression quantitative trait locus (eQTL) mapping and Bayesian colocalization analyses to evaluate potential causal and mechanistic inferences. We integrate various molecular data types from public resources to infer disease connectivity and shared mechanisms using a data driven process.FindingseQTL analyses combined with GWAS identified significant functional associations between increasing genetic risk in the GRN region and decreased expression of the gene in Parkinson’s, Alzheimer’s and amyotrophic lateral sclerosis. Additionally, colocalization analyses show a connection between blood based inflammatory biomarkers relating to platelets and GRN expression in the frontal cortex.InterpretationGRN expression mediates neuroinflammation function related to general neurodegeneration. This analysis suggests shared mechanisms for Parkinson’s, Alzheimer’s and amyotrophic lateral sclerosis.FundingNational Institute on Aging, National Institute of Neurological Disorders and Stroke, and the Michael J. Fox Foundation.

scholarly journals Leukocyte telomere length and amyotrophic lateral sclerosis: a Mendelian randomization study

2021 ◽  
Author(s):  
Kailin Xia ◽  
Linjing Zhang ◽  
Gan Zhang ◽  
Yajun Wang ◽  
Tao Huang ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Telomere Length ◽  
Causal Relationship ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Sensitivity Analyses ◽  
Genome Wide Association Studies ◽  
Leukocyte Telomere Length ◽  
Weighted Median ◽  
Lateral Sclerosis

Abstract Background Observational studies have suggested that telomere length is associated with amyotrophic lateral sclerosis (ALS). However, it remains unclear whether this association is causal. We employed a two-sample Mendelian randomization (MR) approach to explore the causal relationship between leukocyte telomere length (LTL) and ALS based on the most cited and most recent and largest LTL genome-wide association studies (GWASs) that measured LTL with the Southern blot method (n = 9190) and ALS GWAS summary data (n = 80,610). We adopted the inverse variance weighted (IVW) method to examine the effect of LTL on ALS and used the weighted median method, simple median method, MR Egger method and MR PRESSO method to perform sensitivity analyses. Results We found that genetically determined longer LTL was inversely associated with the risk of ALS (OR = 0.846, 95% CI: 0.744–0.962, P = 0.011), which was mainly driven by rs940209 in the OBFC1 gene, suggesting a potential effect of OBFC1 on ALS. In sensitivity analyses, that was confirmed in MR Egger method (OR = 0.647,95% CI = 0.447–0.936, P = 0.050), and a similar trend was shown with the weighted median method (OR = 0.893, P = 0.201) and simple median method (OR = 0.935 P = 0.535). The MR Egger analyses did not suggest directional pleiotropy, showing an intercept of 0.025 (P = 0.168). Neither the influence of instrumental outliers nor heterogeneity was found. Conclusions Our results suggest that genetically predicted longer LTL has a causal relationship with a lower risk of ALS and underscore the importance of protecting against telomere loss in ALS.

scholarly journals Genetically Predicted Circulating Concentrations of Micronutrients and Risk of Amyotrophic Lateral Sclerosis: A Mendelian Randomization Study

2022 ◽  
Vol 12 ◽  
Author(s):  
Changqing Mu ◽  
Yating Zhao ◽  
Chen Han ◽  
Dandan Tian ◽  
Na Guo ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Large Scale ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Inverse Variance ◽  
Effective Role ◽  
Copper Zinc ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive and devastating neurodegenerative disease with increasing incidence and high mortality, resulting in a considerable socio-economic burden. Till now, plenty of studies have explored the potential relationship between circulating levels of various micronutrients and ALS risk. However, the observations remain equivocal and controversial. Thus, we conducted a two-sample Mendelian randomization (MR) study to investigate the causality between circulating concentrations of 9 micronutrients, including retinol, folate acid, vitamin B12, B6 and C, calcium, copper, zinc as well as magnesium, and ALS susceptibility. In our analysis, several single nucleotide polymorphisms were collected as instrumental variables from large-scale genome-wide association studies of these 9 micronutrients. Then, inverse variance weighted (IVW) approach as well as alternative MR-Egger regression, weighted median and MR-pleiotropy residual sum and outlier (MR-PRESSO) analyses were performed to evaluate causal estimates. The results from IVW analysis showed that there was no causal relationship of 9 micronutrients with ALS risk. Meanwhile, the three complementary approaches obtained similar results. Thus, our findings indicated that supplementation of these 9 micronutrients may not play a clinically effective role in preventing the occurrence of ALS.

scholarly journals Loss of nucleoporin Nup50 is a risk factor for amyotrophic lateral sclerosis

2021 ◽  
Author(s):  
Salim Megat ◽  
Natalia Mora ◽  
Jason Sanogo ◽  
Alberto Catanese ◽  
Najwa Ouali ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Association Studies ◽  
Nuclear Pore ◽  
Genome Wide Association Studies ◽  
Gene Encoding ◽  
Pathogenic Variants ◽  
Or Gene ◽  
Lateral Sclerosis

The genetic basis of amyotrophic lateral sclerosis (ALS) is still incompletely understood. Using two independent genetic strategies, we show here that a large part of ALS heritability lies in genes expressed in inhibitory and excitatory neurons, especially at splicing sites regulated by a defined set of RNA binding proteins including TDP-43 and FUS. We conducted a transcriptome wide association study (TWAS) and identified 59 loci associated with ALS, including 14 previously identified genes, some of them not previously reaching significance in genome wide association studies. Among the 45 novel genes, several genes are involved in pathways known to be affected in ALS such as mitochondrial metabolism (including ATP5H, ATP5D, BCS1L), proteostasis (including COPS7A, G2E3, TMEM175, USP35) or gene expression and RNA metabolism (including ARID1B, ATXN3, PTBP2, TAF10). Interestingly, decreased expression of NUP50, a constrained gene encoding a nuclear pore basket protein, was associated with ALS in TWAS (Zscore = -4, FDR = 0.034). 11 potentially pathogenic variants (CADD score > 20) in 23 patients were identified in the NUP50 gene, most of them in the region of the protein mediating interaction with Importin alpha, and including 2 frameshift mutations. In cells from two patients carrying NUP50 variants, we showed decreased levels of NUP50 protein. Importantly, knocking down Nup50 led to increased neuronal death associated with p62 and nucleoporin inclusions in cultured neurons, and motor defects in Drosophila and zebrafish models. In all, our study identifies alterations in splicing in neurons as a critical pathogenic process in ALS, uncovers several new loci potentially contributing to ALS missing heritability, and provides genetic evidence linking nuclear pore defects to ALS.

scholarly journals Assessing the role of blood pressure in amyotrophic lateral sclerosis: a Mendelian randomization study

2021 ◽  
Author(s):  
Kailin Xia ◽  
Linjing Zhang ◽  
Lu Tang ◽  
Tao Huang ◽  
Dongsheng Fan
Keyword(s):  
Blood Pressure ◽  
Amyotrophic Lateral Sclerosis ◽  
Protective Factor ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Sensitivity Analyses ◽  
Genome Wide Association Studies ◽  
Inverse Variance ◽  
High Level ◽  
Lateral Sclerosis

Abstract Background Observational studies have suggested a close but controversial relationship between blood pressure (BP) and amyotrophic lateral sclerosis (ALS). However, it remains unclear whether this association is causal. The authors employed a bidirectional two-sample Mendelian randomization (MR) approach to investigate whether there is a causal relationship between BP and ALS. Genetic proxies for systolic blood pressure (SBP), diastolic blood pressure (DBP), antihypertension drugs (AHDs), ALS, and their corresponding genome-wide association studies (GWAS) summary datasets were obtained from the updated largest studies. Inverse variance weighted (IVW) method was adopted as the main approach to examine the effect of BP on ALS and four other MR methods for sensitivity analyses. To exclude the interference between SBP and DBP, multivariable MR was used. Results We found that genetically determined increased DBP was a protective factor for ALS (OR = 0.978, 95% CI 0.960–0.996, P = 0.017), and increased SBP was an independent risk factor for ALS (OR = 1.014, 95% CI 1.003–1.025, P = 0.015). The high level of targeted protein of Calcium channel blocker (CCB) showed a causative relationship with ALS (OR = 0.985, 95% CI 0.971-1.000, P = 0.049). No evidence was revealed that ALS caused results change of BP measurements. Conclusions This study demonstrated that an increase in DBP is a protective factor for ALS, and increased SBP is independently risk for ALS, which may be related to sympathetic excitability. Blood pressure management is important in ALS, in which CCB may be a promising candidate.

scholarly journals Immunity in amyotrophic lateral sclerosis: blurred lines between excessive inflammation and inefficient immune responses

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Louis-Charles Béland ◽  
Andrea Markovinovic ◽  
Hrvoje Jakovac ◽  
Fabiola De Marchi ◽  
Ervina Bilic ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Immune System ◽  
T Cell ◽  
Immune Responses ◽  
Association Studies ◽  
Common Finding ◽  
Genome Wide Association Studies ◽  
Immune System Activation ◽  
Immune Mediated ◽  
Lateral Sclerosis

Abstract Despite wide genetic, environmental and clinical heterogeneity in amyotrophic lateral sclerosis, a rapidly fatal neurodegenerative disease targeting motoneurons, neuroinflammation is a common finding. It is marked by local glial activation, T cell infiltration and systemic immune system activation. The immune system has a prominent role in the pathogenesis of various chronic diseases, hence some of them, including some types of cancer, are successfully targeted by immunotherapeutic approaches. However, various anti-inflammatory or immunosuppressive therapies in amyotrophic lateral sclerosis have failed. This prompted increased scrutiny over the immune-mediated processes underlying amyotrophic lateral sclerosis. Perhaps the biggest conundrum is that amyotrophic lateral sclerosis pathogenesis exhibits features of three otherwise distinct immune dysfunctions—excessive inflammation, autoimmunity and inefficient immune responses. Epidemiological and genome-wide association studies show only minimal overlap between amyotrophic lateral sclerosis and autoimmune diseases, so excessive inflammation is usually thought to be secondary to protein aggregation, mitochondrial damage or other stresses. In contrast, several recently characterized amyotrophic lateral sclerosis-linked mutations, including those in TBK1, OPTN, CYLD and C9orf72, could lead to inefficient immune responses and/or damage pile-up, suggesting that an innate immunodeficiency may also be a trigger and/or modifier of this disease. In such cases, non-selective immunosuppression would further restrict neuroprotective immune responses. Here we discuss multiple layers of immune-mediated neuroprotection and neurotoxicity in amyotrophic lateral sclerosis. Particular focus is placed on individual patient mutations that directly or indirectly affect the immune system, and the mechanisms by which these mutations influence disease progression. The topic of immunity in amyotrophic lateral sclerosis is timely and relevant, because it is one of the few common and potentially malleable denominators in this heterogenous disease. Importantly, amyotrophic lateral sclerosis progression has recently been intricately linked to patient T cell and monocyte profiles, as well as polymorphisms in cytokine and chemokine receptors. For this reason, precise patient stratification based on immunophenotyping will be crucial for efficient therapies.

scholarly journals deTS: tissue-specific enrichment analysis to decode tissue specificity

2019 ◽  
Vol 35 (19) ◽  
pp. 3842-3845 ◽  
Author(s):  
Guangsheng Pei ◽  
Yulin Dai ◽  
Zhongming Zhao ◽  
Peilin Jia
Keyword(s):  
Expression Profiles ◽  
Association Studies ◽  
Gene Expression Profiles ◽  
Enrichment Analysis ◽  
R Package ◽  
Supplementary Information ◽  
Genome Wide Association Studies ◽  
Tissue Specific ◽  
Genome Wide ◽  
Specific Regulation

Abstract Motivation Diseases and traits are under dynamic tissue-specific regulation. However, heterogeneous tissues are often collected in biomedical studies, which reduce the power in the identification of disease-associated variants and gene expression profiles. Results We present deTS, an R package, to conduct tissue-specific enrichment analysis with two built-in reference panels. Statistical methods are developed and implemented for detecting tissue-specific genes and for enrichment test of different forms of query data. Our applications using multi-trait genome-wide association studies data and cancer expression data showed that deTS could effectively identify the most relevant tissues for each query trait or sample, providing insights for future studies. Availability and implementation https://github.com/bsml320/deTS and CRAN https://cran.r-project.org/web/packages/deTS/ Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals Polygenic Associations and Causal Inferences between Serum Immunoglobulins and Amyotrophic Lateral Sclerosis

2020 ◽  
Author(s):  
Xu Chen ◽  
Xiaojun Shen ◽  
Yiqiang Zhan ◽  
Fang Fang
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Chronic Inflammation ◽  
Large Scale ◽  
Association Studies ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Causal Association ◽  
Polygenic Risk ◽  
Serum Immunoglobulins ◽  
Lateral Sclerosis

AbstractChronic 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=5.9×10−7] 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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