title: Variants in GBA, SNCA, and MAPT influence Parkinson disease risk, age at onset, and progression.
abstract: Multiple genetic variants have been linked to risk of Parkinson disease (PD), but known mutations do not explain a large proportion of the total PD cases. Similarly, multiple loci have been associated with PD risk by genome-wide association studies (GWAS). The influence that genetic factors confer on phenotypic diversity remains unclear. Few studies have been performed to determine whether the GWAS loci are also associated with age at onset (AAO) or motor progression. We used 2 PD case-control data sets (Washington University and the Parkinson's Progression Markers Initiative) to determine whether polymorphisms located at the GWAS top hits (GBA, ACMSD/TMEM163, STK39, MCCC1/LAMP3, GAK/TMEM175, SNCA, and MAPT) show association with AAO or motor progression. We found associations between single nucleotide polymorphisms at the GBA and MAPT loci and PD AAO and progression. These findings reinforce the complex genetic basis of PD and suggest that distinct genes and variants explain the genetic architecture of PD risk, onset, and progression.
authors.affiliation: Department of Neurology, Washington University, St. Louis, MO, USA.
authors.forename: Albert A
authors.initials: AA
authors.lastname: Davis
authors.affiliation: Department of Neurology, Washington University, St. Louis, MO, USA.
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Andruska
authors.affiliation: Department of Psychiatry, Washington University, School of Medicine, St. Louis, MO, USA.
authors.forename: Bruno A
authors.initials: BA
authors.lastname: Benitez
authors.affiliation: Department of Neurology, Washington University, St. Louis, MO, USA; Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University, St. Louis, MO, USA; School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Parktown, South Africa.
authors.forename: Brad A
authors.initials: BA
authors.lastname: Racette
authors.affiliation: Department of Neurology, Washington University, St. Louis, MO, USA; Department of Radiology, Washington University, St. Louis, MO, USA; Department of Anatomy and Neurobiology, Washington University, St. Louis, MO, USA; Programs in Physical Therapy and Occupational Therapy, Washington University, St. Louis, MO, USA; Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University, St. Louis, MO, USA.
authors.forename: Joel S
authors.initials: JS
authors.lastname: Perlmutter
authors.affiliation: Department of Psychiatry, Washington University, School of Medicine, St. Louis, MO, USA; Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University, St. Louis, MO, USA. Electronic address: cruchagac@psychiatry.wustl.edu.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cruchaga
mesh_terms: D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D066264:Datasets as Topic; D018450:Disease Progression; D005260:Female; D055106:Genome-Wide Association Study; D060005:Genotyping Techniques; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D009043:Motor Activity / Q000235:genetics; D010300:Parkinson Disease / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012306:Risk; D051844:alpha-Synuclein / Q000235:genetics*; D001617:beta-Glucosidase / Q000235:genetics*; D016875:tau Proteins / Q000235:genetics*
chemical_list: C054369:MAPT protein, human; C497604:SNCA protein, human; D051844:alpha-Synuclein; D016875:tau Proteins; D001617:beta-Glucosidase
keywords: Age at onset; GBA; MAPT; Motor progression; Parkinson disease; SNCA