Multiomics Analyses Identify Genes and Pathways Relevant to Essential Tremor

Liao, Calwing; Sarayloo, Faezeh; Rochefort, Daniel; Houle, Gabrielle; Akçimen, Fulya; He, Qiaojun; Laporte, Alexandre D.; Spiegelman, Dan; Poewe, Werner; Berg, Daniela; Müller, Stefanie H.; Hopfner, Franziska; Deuschl, G.; Kuhlenbaeumer, Gregor; Rajput, Alex; Rouleau, Guy A.

doi:10.1002/mds.28031

Cited by 13 publications

(13 citation statements)

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“…Lastly, to explore for further potential evidence of shared genetic architecture, we reciprocally examined whether any of our top candidate variants ( p < 1 x 10 −5 ; n = 39 variants) associated with PD motor subtype confers susceptibility for ET, based on lookup of the top results in the largest GWAS completed to date (2807 ET cases/6,441 controls). 41 , 43 However, neither STK32B rs2301857 ( p = 0.18) nor any other top suggestive results from our PD motor subtype GWAS were significantly associated with ET susceptibility.…”

Section: Resultsmentioning

confidence: 62%

Genome-Wide Association Study Meta-Analysis for Parkinson Disease Motor Subtypes

et al. 2021

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ObjectiveTo discover genetic determinants of Parkinson disease (PD) motor subtypes, including tremor dominant (TD) and postural instability/gait difficulty (PIGD) forms.MethodsIn 3,212 PD cases of European ancestry, we performed a genome-wide association study (GWAS) examining 2 complementary outcome traits derived from the Unified Parkinson's Disease Rating Scale, including dichotomous motor subtype (TD vs PIGD) or a continuous tremor/PIGD score ratio. Logistic or linear regression models were adjusted for sex, age at onset, disease duration, and 5 ancestry principal components, followed by meta-analysis.ResultsAmong 71 established PD risk variants, we detected multiple suggestive associations with PD motor subtype, including GPNMB (rs199351, psubtype = 0.01, pratio = 0.03), SH3GL2 (rs10756907, psubtype = 0.02, pratio = 0.01), HIP1R (rs10847864, psubtype = 0.02), RIT2 (rs12456492, psubtype = 0.02), and FBRSL1 (rs11610045, psubtype = 0.02). A PD genetic risk score integrating all 71 PD risk variants was also associated with subtype ratio (p = 0.026, ß = −0.04, 95% confidence interval = −0.07–0). Based on top results of our GWAS, we identify a novel suggestive association at the STK32B locus (rs2301857, pratio = 6.6 × 10−7), which harbors an independent risk allele for essential tremor.ConclusionsMultiple PD risk alleles may also modify clinical manifestations to influence PD motor subtype. The discovery of a novel variant at STK32B suggests a possible overlap between genetic risk for essential tremor and tremor-dominant PD.

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Section: Resultsmentioning

confidence: 62%

Genome-Wide Association Study Meta-Analysis for Parkinson Disease Motor Subtypes

et al. 2021

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“…However, neither the STK32B variant nor any of the other 5 published ET risk variants 40 were associated with either of our PD motor subtype traits (table e- 5). Lastly, in order to explore for further potential evidence of shared genetic architecture, we reciprocally examined whether any of our top candidate variants (p < 1x10 -5 ; n=39 variants) associated with PD motor subtype confers susceptibility for ET, based on lookup of the top results in the largest GWAS completed to date (2807 ET cases / 6441 controls) 40,41 . However, neither STK32B rs2301857 (p=0.18) nor any other top suggestive results from our PD motor subtype GWAS were significantly associated with ET susceptibility.…”

Section: Resultsmentioning

confidence: 99%

Genome-Wide Association Study Meta-Analysis for Parkinson’s Disease Motor Subtypes

Alfradique-Dunham

Al‐Ouran

Coelln

et al. 2020

Preprint

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OBJECTIVE: To discover genetic determinants of Parkinson disease (PD) motor subtypes, including Tremor Dominant (TD) and Postural Instability/Gait Difficulty (PIGD) forms. METHODS: In 3,212 PD cases of European ancestry, we performed a genome-wide association study (GWAS) examining two complementary outcome traits derived from the Unified Parkinson's Disease Rating Scale (UPDRS), including dichotomous motor subtype (TD vs. PIGD) or a continuous tremor / PIGD score ratio. Logistic or linear regression models were adjusted for sex, age of onset, disease duration, and 5 ancestry principal components, followed by meta-analysis.RESULTS: Among 71 established PD risk variants, we detected multiple suggestive associations with PD motor subtype, including GPNMB (rs199347, p subtype = 0.01, p ratio = 0.03), SH3GL2 (rs10756907, p subtype = 0.02, p ratio = 0.01), HIP1R (rs10847864, p subtype = 0.02), RIT2 (rs12456492, p subtype = 0.02), and FBRSL1 (rs11610045, p subtype = 0.02). A PD genetic risk score integrating all 71 PD risk variants was also associated with subtype ratio (p = 0.026, ß = -0.04, 95% CI = -0.07, 0). Based on top results of our GWAS, we identify a novel suggestive association at the STK32B locus (rs2301857, p ratio = 6.6x10 -7 ), which harbors an independent risk allele for essential tremor.CONCLUSIONS: Multiple PD risk alleles may also modify clinical manifestations to influence PD motor subtype. The discovery of a novel variant at STK32B suggests a possible overlap between genetic risk for essential tremor and tremor-dominant PD.

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“…An ET gene-set was curated from genes associated with ET from linkage, whole-exome, GWAS and transcriptomic studies 2,10 . Drug gene-sets were made from convergent DEGs (FDR < 0.05) across different conditions (DAOY, NPC, propranolol, primidone, all conditions).…”

Section: Single Cell Enrichment Analysismentioning

confidence: 99%

“…The transcriptomic effects of primidone and propranolol in the context of ET remain poorly understood 10,11 . Propranolol increased the expression SHF, a gene that was shown to be downregulated in ET patient cerebellum 10 . Studying the effects of tremor-reducing drugs on transcription can inform us on mechanisms that reduce tremors.…”

Section: Introductionmentioning

confidence: 99%

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Convergent transcriptomic targets of propranolol and primidone identify potential biomarkers for essential tremor

Castonguay

Liao

Khayachi

et al. 2021

Preprint

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Essential tremor (ET) is one of the most common movement disorders, affecting nearly 5% of individuals over 65 years old. Despite its high heritability, few genetic risk loci for ET have been identified. Recent advances in pharmacogenomics have generated a wealth of data that led to the identification of molecular signatures in response to hundreds of chemical compounds. Among the different forms of data, gene expression has proven to be quite successful for the inference of drug response in cell models. We sought to leverage this approach in the context of ET where many patients are responsive two drugs: propranolol and primidone. Propranolol- and primidone-specific transcriptomic drug targets, as well as convergent gene targets across both drugs, could provide insights into the pathogenesis of ET and identify possible targets of interest for future treatments. In this study, cerebellar DAOY and neural progenitor cells were treated for 5 days with clinical concentrations of propranolol and primidone, after which RNA-sequencing was used to identify differentially expressed genes. The expression of genes previously implicated in genetic and transcriptomic studies of ET and other movement disorders, such as TRAPPC11, were significantly upregulated by propranolol. Pathway enrichment analysis identified multiple terms related to calcium signalling, endosomal sorting, axon guidance, and neuronal morphology. Convergent differentially expressed genes across all treatments and cell types were also found to be significantly more mutationally constrained, implying that they might harbour rare deleterious variants implicated in disease. Furthermore, these genes were enriched within cell types having high expression of ET related genes in both cortical and cerebellar tissues. Altogether, our results highlight potential cellular and molecular mechanisms associated with tremor reduction and identify relevant genetic biomarkers for drug-responsiveness in ET.

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Multiomics Analyses Identify Genes and Pathways Relevant to Essential Tremor

Cited by 13 publications

References 40 publications

Genome-Wide Association Study Meta-Analysis for Parkinson Disease Motor Subtypes

Genome-Wide Association Study Meta-Analysis for Parkinson Disease Motor Subtypes

Genome-Wide Association Study Meta-Analysis for Parkinson’s Disease Motor Subtypes

Convergent transcriptomic targets of propranolol and primidone identify potential biomarkers for essential tremor

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