GBA variants influence cognitive status in amyotrophic lateral sclerosis

Canosa, Antonio; Grassano, Maurizio; Moglia, Cristina; Iazzolino, Barbara; Peotta, Laura; Gallone, Salvatore; Brunetti, Maura; Barberis, Marco; Sbaiz, Luca; Palumbo, Francesca; Cabras, Sara; Manera, Umberto; Vasta, Rosario; Traynor, Bryan J.; Corrado, Lucia; D’Alfonso, Sandra; Mazzini, Letizia; Calvo, Andrea; Chiò, Adriano

doi:10.1136/jnnp-2021-327426

Cited by 4 publications

(6 citation statements)

References 5 publications

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“…Similarly, a previous study reported that a SNP, rs1564282, in the GAK intronic region was associated with susceptibility to PD 27 . For ALS, evidence suggests that endolysosomal dysfunction plays a role, and variants in GBA (glucocerebrosidase‐encoding gene) affect the cognitive status of patients with ALS 28 . Thus, we speculate that variants in the TMEM175 / GAK region are associated with shared genetic mechanisms of ALS and PD, such as the pleiotropic SNP rs873785 located near the TMEM175 and GAK genes.…”

Section: Discussionmentioning

confidence: 83%

Shared Genetics and Comorbid Genes of Amyotrophic Lateral Sclerosis and Parkinson's Disease

Tian

et al. 2023

Movement Disorders

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BackgroundComorbidity exists between amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD), but the role of genetic factors is unclear.ObjectiveWe aim to investigate genetic correlation, causal relationship, and comorbid genes between ALS and PD.MethodsLeveraging the largest genome‐wide association study data (ALS: 27,205 cases, 110,881 controls; PDG: 33,674 cases, 449,056 controls), we used linkage disequilibrium score regression and Mendelian randomization analysis for genetic correlation and causal inference. We performed genome‐wide cross‐trait analysis via Multi‐Trait Analysis of Genome‐Wide Association Studies and Cross‐Phenotype Association to identify specific single‐nucleotide polymorphisms, followed by functional mapping and annotation. Integrating expression quantitative trait loci data from 13 brain regions, we conducted a transcriptome‐wide association study via functional summary‐based imputation and joint‐tissue imputation to explore comorbid genes, followed by pathway enrichment analysis.ResultsWe found that PD positively correlates with ALS (rg = 0.144, P = 0.026) and confers a causal effect (odds ratio = 1.09, 95% confidence interval: 1.03–1.15, P = 3.00 × 10−3). We identified nine single‐nucleotide polymorphisms (eight new), associating with three risk loci (chromosomes 4, 10, and 17) and seven genes (TMEM175, MAPT, NSF, LRRC37A2, ARHGAP27, GAK, and FGFRL1). In transcriptome‐wide association study analysis, we showed six previously unreported pleiotropic genes (KANSL1, ARL17B, EFNA1, WNT3, ERCC8, and ADAM15), and we found these candidate genes are mainly enriched in negative regulation of neuron projection development (GO:0010977).ConclusionsOur work demonstrates shared genetic architecture between ALS and PD, reports new pleiotropic genes, and sheds light on the comorbid mechanism. © 2023 International Parkinson and Movement Disorder Society.

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Section: Discussionmentioning

confidence: 83%

Shared Genetics and Comorbid Genes of Amyotrophic Lateral Sclerosis and Parkinson's Disease

Tian

et al. 2023

Movement Disorders

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“…GBA variants were more frequent in AD than in ALS patients, but both frequencies were quite similar to those in healthy controls [ 16 ]. Three ALS patients (ALS-2, ALS-25 and ALS-98) carried more than one PD-related variant ( Table 2 ), while another patient (ALS-102) carried two GBA variants (c.1093G>A, c.882T>G).…”

Section: Resultsmentioning

confidence: 99%

“…In addition, more frequent cognitive decline and alterations in executive function and language processing were observed in patients carrying these variants [ 42 ]. Interestingly, pathogenic variants in GBA have also been found in FTD [ 31 ], and ALS patients show in the latter a more compromised cognitive profile [ 16 ]. Our results are in line with previous studies [ 16 , 43 ], confirming that the frequency of GBA variants in the ALS cohort is similar to that of European population controls in the gnomAD database.…”

Section: Discussionmentioning

confidence: 99%

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Frequency of Parkinson’s Disease Genes and Role of PARK2 in Amyotrophic Lateral Sclerosis: An NGS Study

Vacchiano

Bartoletti-Stella

Rizzo

et al. 2022

Genes

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Amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease (AD) patients show a higher prevalence of Lewy body disease than the general population. Additionally, parkinsonian features were found in about 30% of ALS patients. We aimed to explore the frequency of Parkinson’s disease (PD)-causative genes in ALS patients, compared to AD and healthy controls (HCs). We used next-generation sequencing multigene panels by analyzing SNCA, LRRK2, PINK1, PARK2, PARK7, SYNJ1, CHCHD2, PLA2G6, GCH1, ATP13A2, DNAJC6 and FBXO genes. GBA gene, a risk factor for PD, was also analyzed. In total, 130 ALS and 100 AD patients were investigated. PD-related genes were found to be altered in 26.2% of ALS, 20% of AD patients and 19.2% of HCs. Autosomal recessive genes were significantly more involved in ALS as compared to AD and HCs (p = 0.021). PARK2 variants were more frequent in ALS than in AD and HCs, although not significantly. However, the p.Arg402Cys variant was increased in ALS than in HCs (p = 0.025). This finding is consistent with current literature, as parkin levels were found to be decreased in ALS animal models and patients. Our results confirm the possible role of PD-related genes as risk modifier in ALS pathogenesis.

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“…Recent studies on the evaluation of the impact of Hungtingtin (HTT) pathologic expansions in the ALS-FTD spectrum suggest an ethiopathological link ( 77 ). Similarly, rare variants in the GBA gene encoding glucocerebrosidase (previously described as a potential risk factor of cognitive impairment in Parkinson's disease) are also overrepresented in patients with FTD-ALS and ALScbi compared to patients with ALS and having no cognitive impairment ( 78 ).…”

Section: Extra-motor Involvement In Alsmentioning

confidence: 99%

Pathophysiological Underpinnings of Extra-Motor Neurodegeneration in Amyotrophic Lateral Sclerosis: New Insights From Biomarker Studies

et al. 2022

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Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) lie at opposing ends of a clinical, genetic, and neuropathological continuum. In the last decade, it has become clear that cognitive and behavioral changes in patients with ALS are more frequent than previously recognized. Significantly, these non-motor features can impact the diagnosis, prognosis, and management of ALS. Partially overlapping neuropathological staging systems have been proposed to describe the distribution of TAR DNA-binding protein 43 (TDP-43) aggregates outside the corticospinal tract. However, the relationship between TDP-43 inclusions and neurodegeneration is not absolute and other pathophysiological processes, such as neuroinflammation (with a prominent role of microglia), cortical hyperexcitability, and synaptic dysfunction also play a central role in ALS pathophysiology. In the last decade, imaging and biofluid biomarker studies have revealed important insights into the pathophysiological underpinnings of extra-motor neurodegeneration in the ALS-FTLD continuum. In this review, we first summarize the clinical and pathophysiological correlates of extra-motor neurodegeneration in ALS. Next, we discuss the diagnostic and prognostic value of biomarkers in ALS and their potential to characterize extra-motor neurodegeneration. Finally, we debate about how biomarkers could improve the diagnosis and classification of ALS. Emerging imaging biomarkers of extra-motor neurodegeneration that enable the monitoring of disease progression are particularly promising. In addition, a growing arsenal of biofluid biomarkers linked to neurodegeneration and neuroinflammation are improving the diagnostic accuracy and identification of patients with a faster progression rate. The development and validation of biomarkers that detect the pathological aggregates of TDP-43 in vivo are notably expected to further elucidate the pathophysiological underpinnings of extra-motor neurodegeneration in ALS. Novel biomarkers tracking the different aspects of ALS pathophysiology are paving the way to precision medicine approaches in the ALS-FTLD continuum. These are essential steps to improve the diagnosis and staging of ALS and the design of clinical trials testing novel disease-modifying treatments.

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GBA variants influence cognitive status in amyotrophic lateral sclerosis

Cited by 4 publications

References 5 publications

Shared Genetics and Comorbid Genes of Amyotrophic Lateral Sclerosis and Parkinson's Disease

Shared Genetics and Comorbid Genes of Amyotrophic Lateral Sclerosis and Parkinson's Disease

Frequency of Parkinson’s Disease Genes and Role of PARK2 in Amyotrophic Lateral Sclerosis: An NGS Study

Pathophysiological Underpinnings of Extra-Motor Neurodegeneration in Amyotrophic Lateral Sclerosis: New Insights From Biomarker Studies

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