Calwing Liao1,2, Faezeh Sarayloo1,2, Daniel Rochefort2, Gabrielle Houle1,2, Fulya Akçimen1,2, Qin He3, Alexandre D Laporte2, Dan Spiegelman2, Werner Poewe4, Daniela Berg5, Stefanie Müller6, Franziska Hopfner7,8, Günther Deuschl9, Gregor Kuhlenbäeumer9, Alex Rajput10, Patrick A Dion2,11, Guy A Rouleau1,2,11. 1. Department of Human Genetics, McGill University, Montréal, Quebec, Canada. 2. Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada. 3. Department of Biomedical Sciences, Université de Montréal, Montréal, Quebec, Canada. 4. Department of Neurology, Medical University in Innsbruck, Innsbruck, Austria. 5. Department of Neurology, Christian-Albrechts-University, Kiel, Germany. 6. Institute of Health Informations, University College London, London, United Kingdom. 7. Department of Neurology, University Hospital Schleswig-Holstein, Christian-Albrechts-Universität zu Kiel, Kiel, Germany. 8. Department of Neurology, Hanover Medical School, Hanover, Germany. 9. Department of Neurology, Kiel University, Kiel, Germany. 10. Saskatchewan Movement Disorders Program, University of Saskatchewan, Saskatoon Health Region, Saskatoon, Canada. 11. Department of Neurology and Neurosurgery, McGill University, Montréal, Quebec, Canada.
Abstract
INTRODUCTION: The genetic factors and molecular mechanisms predisposing to essential tremor (ET) remains largely unknown. OBJECTIVE: The objective of this study was to identify pathways and genes relevant to ET by integrating multiomics approaches. METHODS: Case-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. RESULTS: We 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. CONCLUSION: We 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.
INTRODUCTION: The genetic factors and molecular mechanisms predisposing to essential tremor (ET) remains largely unknown. OBJECTIVE: The objective of this study was to identify pathways and genes relevant to ET by integrating multiomics approaches. METHODS: Case-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. RESULTS: We 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. CONCLUSION: We 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.
Authors: Regina T Martuscello; Karthigayini Sivaprakasam; Whitney Hartstone; Sheng-Han Kuo; Genevieve Konopka; Elan D Louis; Phyllis L Faust Journal: Cerebellum Date: 2022-10-15 Impact factor: 3.648
Authors: Isabel Alfradique-Dunham; Rami Al-Ouran; Rainer von Coelln; Cornelis Blauwendraat; Emily Hill; Lan Luo; Amanda Stillwell; Emily Young; Anita Kaw; Manuela Tan; Calwing Liao; Dena Hernandez; Lasse Pihlstrom; Donald Grosset; Lisa M Shulman; Zhandong Liu; Guy A Rouleau; Mike Nalls; Andrew B Singleton; Huw Morris; Joseph Jankovic; Joshua M Shulman Journal: Neurol Genet Date: 2021-01-28
Authors: Charles-Etienne Castonguay; Calwing Liao; Anouar Khayachi; Yumin Liu; Miranda Medeiros; Gabrielle Houle; Jay P Ross; Patrick A Dion; Guy A Rouleau Journal: NPJ Genom Med Date: 2022-08-04 Impact factor: 6.083
Authors: Félix Javier Jiménez-Jiménez; Hortensia Alonso-Navarro; Elena García-Martín; Ignacio Álvarez; Pau Pastor; José A G Agúndez Journal: Pharmaceuticals (Basel) Date: 2021-05-27