The heterogeneity of drug response as the basis of identification of essential tremor subtypes

Muruzheva, Zamira M.; Магомедовна, Муружева Замира; Karpenko, Marina N.; Николаевна, Карпенко Марина; Клименко, В. М.; Матвеевич, Клименко Виктор

doi:10.17816/rcf16154-59

Cited by 2 publications

(1 citation statement)

References 27 publications

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“…The relationship of SHF with blood pressure medication from the pheWAS may suggest that beta-blockers interact with SHF . Beta-blockers such as propranolol can reduce kinetic tremor in certain ET patients 16 . The gene was clustered with the calcium-related genes such as CACNA1A , suggesting that beta-blockers may influence pathways identified from that cluster such as calcium channel activity.…”

Section: Discussionmentioning

confidence: 99%

Multi-omics integration of the phenome, transcriptome and genome highlights genes and pathways relevant to essential tremor

Liao

Sarayloo

Rochefort

et al. 2019

Preprint

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30The genetic factors predisposing to essential tremor (ET), of one of the most common movement 31 disorders, remains largely unknown. While current studies have examined the contribution of 32 both common and rare genetic variants, very few have investigated the ET transcriptome. To 33 understand pathways and genes relevant to ET, we used an RNA sequencing approach to 34 interrogate the transcriptome of two cerebellar regions, the dentate nucleus and cerebellar cortex, 35 in 16 cases and 16 age-and sex-matched controls. Additionally, a phenome-wide association 36 study (pheWAS) of the dysregulated genes was conducted, and a genome-wide gene association 37 study (GWGAS) was done to identify pathways overlapping with the transcriptomic data. We 38 identified several novel dysregulated genes including CACNA1A, a calcium voltage-gated 39 channel implicated in ataxia. Furthermore, several pathways including axon guidance, olfactory 40 loss, and calcium channel activity were significantly enriched. A subsequent examination of the 41 ET GWGAS data (N=7,154) also flagged genes involved in calcium ion-regulated exocytosis of 42 neurotransmitters to be significantly enriched. Interestingly, the pheWAS identified that the 43 dysregulated gene, SHF, is associated with a blood pressure medication (P=9.3E-08), which is 44 commonly used to reduce tremor in ET patients. Lastly, it is also notable that the dentate nucleus 45 and cerebellar cortex have different transcriptomes, suggesting that different regions of the 46 cerebellum have spatially different transcriptomes. 47

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Section: Discussionmentioning

confidence: 99%

Multi-omics integration of the phenome, transcriptome and genome highlights genes and pathways relevant to essential tremor

Liao

Sarayloo

Rochefort

et al. 2019

Preprint

View full text Add to dashboard Cite

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Multiomics Analyses Identify Genes and Pathways Relevant to Essential Tremor

et al. 2020

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IntroductionThe genetic factors and molecular mechanisms predisposing to essential tremor (ET) remains largely unknown.ObjectiveThe objective of this study was to identify pathways and genes relevant to ET by integrating multiomics approaches.MethodsCase‐control RNA sequencing of 2 cerebellar regions was done for 64 samples. A phenome‐wide association study (pheWAS) of the differentially expressed genes was conducted, and a genome‐wide gene association study (GWGAS) was done to identify pathways overlapping with the transcriptomic data. Finally, a transcriptome‐wide association study (TWAS) was done to identify novel risk genes for ET.ResultsWe identified several novel dysregulated genes, including CACNA1A and SHF. Pathways including axon guidance, olfactory loss, and calcium channel activity were significantly enriched. The ET GWGAS data found calcium ion‐regulated exocytosis of neurotransmitters to be significantly enriched. The TWAS also found calcium and olfactory pathways enriched. The pheWAS identified that the underexpressed differentially expressed gene, SHF, is associated with a blood pressure medication (P = 9.3E‐08), which is used to reduce tremor in ET patients. Treatment of cerebellar DAOY cells with the ET drug propranolol identified increases in SHF when treated, suggesting it may rescue the underexpression.ConclusionWe found that calcium‐related pathways were enriched across the GWGAS, TWAS, and transcriptome. SHF was shown to have significantly decreased expression, and the pheWAS showed it was associated with blood pressure medication. The treatment of cells with propranolol showed that the drug restored levels of SHF. Overall, our findings highlight the power of integrating multiple different approaches to prioritize ET pathways and genes. © 2020 International Parkinson and Movement Disorder Society

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The heterogeneity of drug response as the basis of identification of essential tremor subtypes

Cited by 2 publications

References 27 publications

Multi-omics integration of the phenome, transcriptome and genome highlights genes and pathways relevant to essential tremor

Multi-omics integration of the phenome, transcriptome and genome highlights genes and pathways relevant to essential tremor

Multiomics Analyses Identify Genes and Pathways Relevant to Essential Tremor

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