RESUMO
Parkinson's disease (PD) is a debilitating neurodegenerative disorder and its rising global incidence highlights the need for the identification of modifiable risk factors. In a gene-based burden test of rare variants (8647 PD cases and 777,693 controls) we discovered a novel association between loss-of-function variants in ITSN1 and PD. This association was further supported with burden data from the Neurodegenerative Disease Knowledge Portal and the Accelerating Medicines Partnership Parkinson's Disease Knowledge Platform. Our findings show that Rho GTPases and disruptions in synaptic vesicle transport may be involved in the pathogenesis of PD, pointing to the possibility of novel therapeutic approaches.
Assuntos
Doença de Alzheimer , Glicoproteínas de Membrana , Receptores Imunológicos , Idoso , Feminino , Humanos , Masculino , Doença de Alzheimer/etnologia , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Apolipoproteínas E/metabolismo , LDL-Colesterol/metabolismo , Clusterina/metabolismo , Predisposição Genética para Doença/genética , Homozigoto , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Mutação de Sentido Incorreto , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismoRESUMO
Essential tremor (ET) is a prevalent neurological disorder with a largely unknown underlying biology. In this genome-wide association study meta-analysis, comprising 16,480 ET cases and 1,936,173 controls from seven datasets, we identify 12 sequence variants at 11 loci. Evaluating mRNA expression, splicing, plasma protein levels, and coding effects, we highlight seven putative causal genes at these loci, including CA3 and CPLX1. CA3 encodes Carbonic Anhydrase III and carbonic anhydrase inhibitors have been shown to decrease tremors. CPLX1, encoding Complexin-1, regulates neurotransmitter release. Through gene-set enrichment analysis, we identify a significant association with specific cell types, including dopaminergic and GABAergic neurons, as well as biological processes like Rho GTPase signaling. Genetic correlation analyses reveals a positive association between ET and Parkinson's disease, depression, and anxiety-related phenotypes. This research uncovers risk loci, enhancing our knowledge of the complex genetics of this common but poorly understood disorder, and highlights CA3 and CPLX1 as potential therapeutic targets.