title: Genetic variation associated with the occurrence and progression of neurological disorders.
abstract: This paper presents an overview of genetic variation associated with the onset and progression of 14 neurological disorders, focusing primarily on association studies. The 14 disorders are heterogeneous in terms of their frequency, age of onset, etiology and progression. There is substantially less evidence on progression than onset. With regard to onset, the conditions are diverse in terms of their epidemiology and patterns of familial aggregation. While the muscular dystrophies and Huntington's disease are monogenic diseases, for the other 12 conditions only a small proportion of cases is associated with specific genetic syndromes or mutations. Excluding these, some familial aggregation remains for the majority of cases. There is considerable variation in the volume of evidence by condition, and by gene within condition. The volume of evidence is greatest for Alzheimer's disease, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis. As for common complex chronic diseases, genome wide association studies have found that validated genomic regions account for a low proportion of heritability. Apart from multiple sclerosis, which shares several susceptibility loci with other immune-related disorders, variation at HLA-DRB5 being associated both with Parkinson's disease and Alzheimer's disease, and the association of the C9orf72 repeat expansion with ALS and frontotemporal degeneration, there was little evidence of gene loci being consistently associated with more than one neurological condition or with other conditions. With the exception of spina bifida, for which maternal MTHFR genotype is associated with risk in the offspring, and corroborates other evidence of the importance of folate in etiology, there was little evidence that the pathways influenced by genetic variation are related to known lifestyle or environmental exposures.
authors.affiliation: School of Epidemiology, Public Health and Preventive Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Canada. Electronic address: jlittle@uottawa.ca.
authors.forename: Julian
authors.initials: J
authors.lastname: Little
authors.affiliation: Faculty of Health Sciences, University of Ontario Institute of Technology, Canada.
authors.forename: Caroline
authors.initials: C
authors.lastname: Barakat-Haddad
authors.affiliation: Department of Speech-Language Pathology, University of Toronto, Canada; Health Care and Outcomes Research, Krembil Research Institute, University Health Network, Canada; Rehabilitation Sciences Institute, University of Toronto, Canada.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Martino
authors.affiliation: University of Calgary and the Hotchkiss Brain Institute, Calgary, AB, Canada.
authors.forename: Tamara
authors.initials: T
authors.lastname: Pringsheim
authors.affiliation: Faculty of Medicine (Neurology), Djavad Mowafaghian Centre for Brain Health, Vancouver Coastal Health Research Institute, University of British Columbia, Canada.
authors.forename: Helen
authors.initials: H
authors.lastname: Tremlett
authors.affiliation: Faculty of Medicine (Neurology), Djavad Mowafaghian Centre for Brain Health, Vancouver Coastal Health Research Institute, University of British Columbia, Canada.
authors.forename: Kyla A
authors.initials: KA
authors.lastname: McKay
authors.affiliation: Department of Speech-Language Pathology, University of Toronto, Canada; Rehabilitation Sciences Institute, University of Toronto, Canada; Department of Psychology, University of Toronto, Canada; Toronto Rehabilitation Institute, University Health Network, Canada.
authors.forename: Pascal
authors.initials: P
authors.lastname: van Lieshout
authors.affiliation: Newfoundland and Labrador Centre for Health Information, 70 O'Leary Avenue, St. John's, NL, Canada.
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Walsh
authors.affiliation: Interdisciplinary School of Health Sciences, University of Ottawa, Ottawa, ON, Canada.
authors.forename: James
authors.initials: J
authors.lastname: Gomes
authors.affiliation: School of Epidemiology, Public Health and Preventive Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Canada; McLaughlin Centre for Population Health Risk Assessment, University of Ottawa, Ottawa, Ontario, Canada; Risk Sciences International, Ottawa, Ontario, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Krewski
mesh_terms: D000073885:C9orf72 Protein / Q000235:genetics; D018450:Disease Progression; D014644:Genetic Variation / Q000235:genetics*; D055106:Genome-Wide Association Study; D059847:HLA-DRB5 Chains / Q000235:genetics; D006801:Humans; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D009422:Nervous System Diseases / Q000453:epidemiology* / Q000235:genetics*
chemical_list: D000073885:C9orf72 Protein; D059847:HLA-DRB5 Chains; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2)
keywords: Familial association; Genetic variation; Genome wide association; Neurological condition; Onset; Progression