A Genome-Wide Association Study on Amyotrophic Lateral Sclerosis in the Taiwanese Han Population

Chen, Chi Jim; Chen, Chien‐Ming; Pai, Tun-Wen; Chang, Hao Teng; Hwang, Chi Shin

doi:10.2217/bmm.15.115

Cited by 10 publications

(4 citation statements)

References 73 publications

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“…Abundant Aβ pathology has also been found in LRRK2 mutation carriers and is consistent with comorbid AD pathology [41]. Besides AD and PD, RALYL showed single nucleotide polymorphism in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease, following a genome-wide association study (GWAS) [42]. In line with these findings, we now provide evidence that the RALYL gene plays a role in AD reserve, and it opens an avenue for investigating the association of RALYL with AD.…”

Section: Discussionsupporting

confidence: 77%

Exploring the role of RALYL in Alzheimer’s disease reserve by network-based approaches

et al. 2020

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Background Alzheimer’s disease (AD) reserve theory is based on specific individual characteristics that are associated with a higher resilience against neurodegeneration and its symptoms. A given degree of AD pathology may contribute to varying cognitive decline levels in different individuals. Although this phenomenon is attributed to reserve, the biological mechanisms that underpin it remain elusive, which restricts translational medicine research and treatment strategy development. Methods Network-based approaches were integrated to identify AD reserve related genes. Then, AD brain transcriptomics data were clustered into co-expression modules, and a Bayesian network was developed using these modules plus AD reserve related phenotypes. The directed acyclic graph suggested that the module was strongly associated with AD reserve. The hub gene of the module of interest was filtered using the topological method. Validation was performed in the multi-AD brain transcriptomic dataset. Results We revealed that the RALYL (RALY RNA Binding Protein-like) is the hub gene of the module which was highly associated with AD reserve related phenotypes. Pseudo-time projections of RALYL revealed the changes in relative expression drivers in the AD and control subjects over pseudo-time had distinct transcriptional states. Notably, the expression of RALYL decreased with the gradual progression of AD, and this corresponded to MMSE decline. Subjects with AD reserve exhibited significantly higher RALYL expression than those without AD reserve. Conclusion The present study suggests that RALYL may be associated with AD reserve, and it provides novel insights into the mechanisms of AD reserve and highlights the potential role of RALYL in this process.

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Section: Discussionsupporting

confidence: 77%

Exploring the role of RALYL in Alzheimer’s disease reserve by network-based approaches

et al. 2020

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“…A schematic overview of the study design is illustrated in Figure 1 . We conducted a survey of 26 GWASs ( Dunckley et al, 2007 ; Schymick et al, 2007 ; Van Es et al, 2007 ; Cronin et al, 2008 ; Van Es et al, 2008 ; Landers et al, 2009 ; van Es et al, 2009 ; Laaksovirta et al, 2010 ; Shatunov et al, 2010 ; Kwee et al, 2012 ; The ALSGEN Consortium, 2013 ; Deng et al, 2013 ; Diekstra et al, 2014 ; Fogh et al, 2014 ; Xie et al, 2014 ; McLaughlin et al, 2015 ; Chen et al, 2016 ; Fogh et al, 2016 ; van Rheenen et al, 2016 ; Benyamin et al, 2017 ; Nicolas et al, 2018 ; Dekker et al, 2019 ; Wei et al, 2019 ; Iacoangeli et al, 2020 ; Nakamura et al, 2020 ) of ALS in the NHGRI-EBI GWAS Catalog (till September 2021) and additionally included one most recent GWAS ( van Rheenen et al, 2021 ) and 3 recent post-GWASs ( Du et al, 2018 ; Xiao et al, 2020 ; Park et al, 2021 ) to summarize the current knowledge on the candidate genes of ALS ( Supplementary Table S1 ; Figure 2B ). We then based our post-GWAS analyses on ALS GWAS from Nicolas et al (2018) , which represents the largest-ever GWAS data for ALS, totaling 20,806 cases and 59,804 controls of European ancestry.…”

Section: Resultsmentioning

confidence: 99%

Causal Inference of Genetic Variants and Genes in Amyotrophic Lateral Sclerosis

Pan

Liu

et al. 2022

Front. Genet.

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Amyotrophic lateral sclerosis (ALS) is a fatal progressive multisystem disorder with limited therapeutic options. Although genome-wide association studies (GWASs) have revealed multiple ALS susceptibility loci, the exact identities of causal variants, genes, cell types, tissues, and their functional roles in the development of ALS remain largely unknown. Here, we reported a comprehensive post-GWAS analysis of the recent large ALS GWAS (n = 80,610), including functional mapping and annotation (FUMA), transcriptome-wide association study (TWAS), colocalization (COLOC), and summary data-based Mendelian randomization analyses (SMR) in extensive multi-omics datasets. Gene property analysis highlighted inhibitory neuron 6, oligodendrocytes, and GABAergic neurons (Gad1/Gad2) as functional cell types of ALS and confirmed cerebellum and cerebellar hemisphere as functional tissues of ALS. Functional annotation detected the presence of multiple deleterious variants at three loci (9p21.2, 12q13.3, and 12q14.2) and highlighted a list of SNPs that are potentially functional. TWAS, COLOC, and SMR identified 43 genes at 24 loci, including 23 novel genes and 10 novel loci, showing significant evidence of causality. Integrating multiple lines of evidence, we further proposed that rs2453555 at 9p21.2 and rs229243 at 14q12 functionally contribute to the development of ALS by regulating the expression of C9orf72 in pituitary and SCFD1 in skeletal muscle, respectively. Together, these results advance our understanding of the biological etiology of ALS, feed into new therapies, and provide a guide for subsequent functional experiments.

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“…Higher expression of this gene has been linked to greater AD reserve, a phenomenon where individuals have a high burden of disease pathology but limited cognitive decline ( 44 ). In addition, decreased Ralyl expression is associated with AD ( 45 ) and PD ( 45 , 46 ), and genetic mutations have been identified in amyotrophic lateral sclerosis (ALS) ( 47 ). Conversely, Lingo1 was down-regulated by AKST1220 but unchanged with SC57416A treatment.…”

Section: Resultsmentioning

confidence: 99%

Leukotriene A4 hydrolase inhibition improves age-related cognitive decline via modulation of synaptic function

Adams,

Rege,

Liu

et al. 2023

Sci. Adv.

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Leukotrienes, a class of inflammatory bioactive lipids, are well studied in the periphery, but less is known of their importance in the brain. We identified that the enzyme leukotriene A4 hydrolase (LTA4H) is expressed in healthy mouse neurons, and inhibition of LTA4H in aged mice improves hippocampal dependent memory. Single-cell nuclear RNA sequencing of hippocampal neurons after inhibition reveals major changes to genes important for synaptic organization, structure, and activity. We propose that LTA4H inhibition may act to improve cognition by directly inhibiting the enzymatic activity in neurons, leading to improved synaptic function. In addition, LTA4H plasma levels are increased in both aging and Alzheimer’s disease and correlated with cognitive impairment. These results identify a role for LTA4H in the brain, and we propose that LTA4H inhibition may be a promising therapeutic strategy to treat cognitive decline in aging related diseases.

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A Genome-Wide Association Study on Amyotrophic Lateral Sclerosis in the Taiwanese Han Population

Cited by 10 publications

References 73 publications

Exploring the role of RALYL in Alzheimer’s disease reserve by network-based approaches

Exploring the role of RALYL in Alzheimer’s disease reserve by network-based approaches

Causal Inference of Genetic Variants and Genes in Amyotrophic Lateral Sclerosis

Leukotriene A4 hydrolase inhibition improves age-related cognitive decline via modulation of synaptic function

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