title: Exonic Re-Sequencing of the Chromosome 2q24.3 Parkinson's Disease Locus.
abstract: Genome-wide association studies (GWAS) in Parkinson's disease (PD) have identified over 20 genomic regions associated with disease risk. Many of these loci include several candidate genes making it difficult to pinpoint the causal gene. The locus on chromosome 2q24.3 encompasses three genes: B3GALT1, STK39, and CERS6. In order to identify if the causal variants are simple missense changes, we sequenced all 31 exons of these three genes in 187 patients with PD. We identified 13 exonic variants including four non-synonymous and three insertion/deletion variants (indels). These non-synonymous variants and rs2102808, the GWAS tag SNP, were genotyped in three independent series consisting of a total of 1976 patients and 1596 controls. Our results show that the seven identified 2q24.3 coding variants are not independently responsible for the GWAS association signal at the locus; however, there is a haplotype, which contains both rs2102808 and a STK39 exon 1 6bp indel variant, that is significantly associated with PD risk (Odds Ratio [OR] = 1.35, 95% CI: 1.11-1.64, P = 0.003). This haplotype is more associated than each of the two variants independently (OR = 1.23, P = 0.005 and 1.10, P = 0.10, respectively). Our findings suggest that the risk variant is likely located in a non-coding region. Additional sequencing of the locus including promoter and regulatory regions will be needed to pinpoint the association at this locus that leads to an increased risk to PD.
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, United States of America.
authors.forename: Catherine
authors.initials: C
authors.lastname: Labbé
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, United States of America.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Ogaki
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, United States of America.
authors.forename: Oswaldo
authors.initials: O
authors.lastname: Lorenzo-Betancor
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, United States of America.
authors.forename: Minerva M
authors.initials: MM
authors.lastname: Carrasquillo
authors.affiliation: Section of Biostatistics, Mayo Clinic, Jacksonville, Florida, United States of America.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Heckman
authors.affiliation: Dublin Neurological Institute at the Mater Misericordiae University Hospital, Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Dublin, Ireland.
authors.forename: Allan
authors.initials: A
authors.lastname: McCarthy
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, United States of America.
authors.forename: Alexandra I
authors.initials: AI
authors.lastname: Soto-Ortolaza
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, United States of America.
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Walton
authors.affiliation: Dublin Neurological Institute at the Mater Misericordiae University Hospital, Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Dublin, Ireland.
authors.forename: Timothy
authors.initials: T
authors.lastname: Lynch
authors.affiliation: Department of Neurology, Medical University of Silesia, Katowice, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Siuda
authors.affiliation: Department of Neurology, Medical University of Silesia, Katowice, Poland.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Opala
authors.affiliation: Department of Neurology, Jagiellonian University, Krakow, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Krygowska-Wajs
authors.affiliation: Department of Neurodegenerative Disorders, Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Maria
authors.initials: M
authors.lastname: Barcikowska
authors.affiliation: Department of Neurology, Central Hospital of the Ministry of Interior and Administration, Warsaw, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Czyzewski
authors.affiliation: Department of Neurology, Mayo Clinic, Jacksonville, Florida, United States of America; Department of Pathology, Mayo Clinic, Jacksonville, Florida, United States of America.
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.affiliation: Department of Neurology, Mayo Clinic, Jacksonville, Florida, United States of America.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Uitti
authors.affiliation: Department of Neurology, Mayo Clinic, Jacksonville, Florida, United States of America.
authors.forename: Zbigniew K
authors.initials: ZK
authors.lastname: Wszolek
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, United States of America.
authors.forename: Owen A
authors.initials: OA
authors.lastname: Ross
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D016022:Case-Control Studies; D002889:Chromosomes, Human, Pair 2; D005091:Exons; D005260:Female; D056726:Genetic Association Studies; D055106:Genome-Wide Association Study; D006239:Haplotypes; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D054643:INDEL Mutation; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D040641:Quantitative Trait Loci
chemical_list: D017346:Protein Serine-Threonine Kinases; C486409:STK39 protein, human