title: A GABBR2 gene variant modifies pathophysiology in Huntington's disease.
abstract: Striatal degeneration in Huntington's disease (HD) causes changes in cortico-subcortical pathways. Transcranial magnetic stimulation (TMS) is a valuable tool for assessing pathophysiology within these pathways, yet has had limited application in HD. As cortico-subcortical pathways are largely mediated by GABA and dopamine receptor genes, understanding how these genes modulate neurophysiology in HD may provide new insights into how underlying pathology maps onto clinical phenotype. Twenty-nine participants with HD underwent motor cortex stimulation, while corticospinal excitability, cortical inhibition and intracortical facilitation were indexed via peripheral electromyography. Single-nucleotide polymorphism mapping was performed across six genes that are known to modulate cortico-subcortical pathways (GABRA2, GABBR1, GABBR2, DRD1, DRD2, DRD4). Genetic associations with six TMS measures and age at onset were investigated. Our hierarchical multiple regression analysis, controlling for CAG and age, revealed that a GABBR2 variant, predicted to be disease-causative, was significantly associated with corticospinal excitability at corrected levels. A subsequent uncorrected exploratory analysis revealed associations between GABBR2, GABRA2 and DRD2 variants with TMS measures of corticospinal excitability and cortical inhibition in HD, as well as with age at onset. Our findings support the notion that uncovering genetic associations with pathophysiological measures and age at onset is an important way forward in terms of generating meaningful biomarkers with diagnostic and prognostic sensitivity, and identifying novel human-validated targets for future clinical trials.
authors.affiliation: School of Psychological Sciences and Monash Institute of Cognitive and Clinical Neurosciences, Monash University, Clayton, VIC 3800, Australia.
authors.forename: April L
authors.initials: AL
authors.lastname: Philpott
authors.affiliation: Monash Alfred Psychiatry Research Centre, Central Clinical School, Monash University and the Alfred, Melbourne, VIC 3004, Australia.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fitzgerald
authors.affiliation: Monash Alfred Psychiatry Research Centre, Central Clinical School, Monash University and the Alfred, Melbourne, VIC 3004, Australia.
authors.forename: Neil W
authors.initials: NW
authors.lastname: Bailey
authors.affiliation: Department of Neurology, Monash Medical Centre, Clayton, VIC 3800, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Churchyard
authors.affiliation: School of Psychological Sciences and Monash Institute of Cognitive and Clinical Neurosciences, Monash University, Clayton, VIC 3800, Australia. Electronic address: nellie.georgiou-karistianis@monash.edu.
authors.forename: Nellie
authors.initials: N
authors.lastname: Georgiou-Karistianis
authors.affiliation: School of Psychological Sciences and Monash Institute of Cognitive and Clinical Neurosciences, Monash University, Clayton, VIC 3800, Australia.
authors.forename: Tarrant D R
authors.initials: TD
authors.lastname: Cummins
mesh_terms: D000328:Adult; D017668:Age of Onset; D002540:Cerebral Cortex / Q000503:physiopathology; D003430:Cross-Sectional Studies; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D006816:Huntington Disease / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009473:Neuronal Plasticity; D020641:Polymorphism, Single Nucleotide; D017448:Receptors, Dopamine D2 / Q000235:genetics; D011963:Receptors, GABA-A / Q000235:genetics; D018080:Receptors, GABA-B / Q000235:genetics*; D013116:Spinal Cord / Q000503:physiopathology; D050781:Transcranial Magnetic Stimulation
chemical_list: C581293:DRD2 protein, human; C485503:GABBR2 protein, human; C484841:GABRA2 protein, human; D017448:Receptors, Dopamine D2; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B
keywords: Age at onset; Cortical excitability; Dopamine; GABA; Single-nucleotide polymorphism; Transcranial magnetic stimulation