title: Fine mapping and resequencing of the PARK16 locus in Parkinson's disease.
abstract: The PARK16 locus, spanning five genes on chromosome 1, was among the first genetic regions to show genome-wide association in Parkinson's disease (PD). Subsequent investigations have found variability in PARK16 top-hits and association patterns across populations, and the implicated genes and mechanisms are currently unclear. In the present study, we aimed to explore the contribution of PARK16 variability to PD risk in a Scandinavian population. We genotyped 17 single-nucleotide polymorphisms in a case-control sample set of 2570 individuals from Norway and Sweden to fine map the locus. Targeted resequencing of the full coding regions of SLC45A3, NUCKS1, RAB7L1, SLC41A1 and PM20D1 was performed in DNA pools from a subset of 387 patient samples. We find evidence for an association with PD for rs1775143 as well as a haplotype located around the 5' region of RAB7L1, implicating variants which are not in high linkage disequilibrium with the strongest signal from a recent large meta-analysis in Caucasians. We also provide suggestive support for epistasis between RAB7L1 and LRRK2 as previously hypothesized by others. Comparing our results with previous work, allelic heterogeneity at PARK16 appears likely, and further studies are warranted to disentangle the complex patterns of association and pinpoint the functionally relevant variants.
authors: 1] Department of Neurology, Oslo University Hospital, Oslo, Norway [2] University of Oslo, Institute of Clinical Medicine, Oslo, Norway.
authors: Lasse
authors: L
authors: Pihlstrøm
authors: Department of Neurology, Oslo University Hospital, Oslo, Norway.
authors: Aina
authors: A
authors: Rengmark
authors: Department of Neurology, Drammen Hospital, Drammen, Norway.
authors: Kari Anne
authors: KA
authors: Bjørnarå
authors: Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors: Nil
authors: N
authors: Dizdar
authors: Department of Pharmacology, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors: Camilla
authors: C
authors: Fardell
authors: Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
authors: Lars
authors: L
authors: Forsgren
authors: Department of Clinical Neuroscience and Rehabilitation, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors: Björn
authors: B
authors: Holmberg
authors: The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway.
authors: Jan Petter
authors: JP
authors: Larsen
authors: Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
authors: Jan
authors: J
authors: Linder
authors: Department of Pharmacology, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors: Hans
authors: H
authors: Nissbrandt
authors: Department of Neurology, Haukeland University Hospital, Bergen, Norway.
authors: Ole-Bjørn
authors: OB
authors: Tysnes
authors: 1] Department of Neurology, Oslo University Hospital, Oslo, Norway [2] University of Oslo, Institute of Clinical Medicine, Oslo, Norway.
authors: Espen
authors: E
authors: Dietrichs
authors: Department of Neurology, Oslo University Hospital, Oslo, Norway.
authors: Mathias
authors: M
authors: Toft
mesh_terms: D016022:Case-Control Studies; D002874:Chromosome Mapping; D004843:Epistasis, Genetic; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D015810:Linkage Disequilibrium; D010300:Parkinson Disease / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D017422:Sequence Analysis, DNA; D020691:rab GTP-Binding Proteins; D020761:rab1 GTP-Binding Proteins / Q000235:genetics
chemical_list: C000598762:Rab29 protein, human; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D020691:rab GTP-Binding Proteins; D020761:rab1 GTP-Binding Proteins