title: Genome-wide association study of neocortical Lewy-related pathology.
abstract: OBJECTIVE
  Dementia with Lewy bodies is an α-synucleinopathy characterized by neocortical Lewy-related pathology (LRP). We carried out a genome-wide association study (GWAS) on neocortical LRP in a population-based sample of subjects aged 85 or over.
  
  
  METHODS
  LRP was analyzed in 304 subjects in the Vantaa 85+ sample from Southern Finland. The GWAS included 41 cases with midbrain, hippocampal, and neocortical LRP and 177 controls without midbrain and hippocampal LRP. The Medical Research Council Cognitive Function and Ageing Study (CFAS) material was used for replication (51 cases and 131 controls).
  
  
  RESULTS
  By analyzing 327,010 markers the top signal was obtained at the HLA-DPA1/DPB1 locus (P = 1.29 × 10(-7)); five other loci on chromosomes 15q14, 2p21, 2q31, 18p11, and 5q23 were associated with neocortical LRP at P < 10(-5). Two loci were marked by multiple markers, 2p21 (P = 3.9 × 10(-6), upstream of the SPTBN1 gene), and HLA-DPA1/DPB1; these were tested in the CFAS material. Single marker (P = 0.0035) and haplotype (P = 0.04) associations on 2p21 were replicated in CFAS, whereas HLA-DPA1/DPB1 association was not. Bioinformatic analyses suggest functional effects for the HLA-DPA1/DPB1 markers as well as the 15q14 marker rs8037309.
  
  
  CONCLUSIONS
  We identified suggestive novel risk factors for neocortical LRP. SPTBN1 is the candidate on 2p21, it encodes beta-spectrin, an α-synuclein binding protein and a component of Lewy bodies. The HLA-DPA1/DPB1 association suggests a role for antigen presentation or alternatively, cis-regulatory effects, one of the regulated neighboring genes identified here (vacuolar protein sorting 52) plays a role in vesicular trafficking and has been shown to interact with α-synuclein in a yeast model.
authors.affiliation: Molecular Neurology, Research Program Unit, Biomedicum, University of Helsinki Helsinki, Finland.
authors.forename: Terhi
authors.initials: T
authors.lastname: Peuralinna
authors.affiliation: Department of Pathology, Haartman Institute, University of Helsinki and HUSLAB Helsinki, Finland ; Folkhalsan Institute of Genetics Helsinki, Finland.
authors.forename: Liisa
authors.initials: L
authors.lastname: Myllykangas
authors.affiliation: Department of Pathology, Haartman Institute, University of Helsinki and HUSLAB Helsinki, Finland ; Department of Neurosurgery, Helsinki University Central Hospital Helsinki, Finland.
authors.forename: Minna
authors.initials: M
authors.lastname: Oinas
authors.affiliation: Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, NIH Bethesda, Maryland.
authors.forename: Mike A
authors.initials: MA
authors.lastname: Nalls
authors.affiliation: School of Psychology, Social Work and Social Policy, University of South Australia Adelaide, Australia ; Department of Public Health and Primary Care, University of Cambridge Cambridge, United Kingdom.
authors.forename: Hannah A D
authors.initials: HA
authors.lastname: Keage
authors.affiliation: Molecular Neurology, Research Program Unit, Biomedicum, University of Helsinki Helsinki, Finland.
authors.forename: Veli-Matti
authors.initials: VM
authors.lastname: Isoviita
authors.affiliation: Molecular Neurology, Research Program Unit, Biomedicum, University of Helsinki Helsinki, Finland.
authors.forename: Miko
authors.initials: M
authors.lastname: Valori
authors.affiliation: Institute for Ageing and Health, Newcastle University Newcastle, United Kingdom.
authors.forename: Tuomo
authors.initials: T
authors.lastname: Polvikoski
authors.affiliation: Department of Pathology, Haartman Institute, University of Helsinki and HUSLAB Helsinki, Finland.
authors.forename: Anders
authors.initials: A
authors.lastname: Paetau
authors.affiliation: School of Public Health and Clinical Nutrition, University of Eastern Finland Kuopio, Finland.
authors.forename: Raimo
authors.initials: R
authors.lastname: Sulkava
authors.affiliation: Department of Neuroscience, University of Sheffield Sheffield, United Kingdom.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Ince
authors.affiliation: Department of Public Health and Primary Care, University of Cambridge Cambridge, United Kingdom.
authors.forename: Julia
authors.initials: J
authors.lastname: Zaccai
authors.affiliation: Department of Public Health and Primary Care, University of Cambridge Cambridge, United Kingdom.
authors.forename: Carol
authors.initials: C
authors.lastname: Brayne
authors.affiliation: Neuromuscular Diseases Research Group, Laboratory of Neurogenetics, National Institute on Aging, NIH Bethesda, Maryland.
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Traynor
authors.affiliation: Reta Lila Weston Research Laboratories, Departments of Molecular Neuroscience and of Clinical Neuroscience, UCL Institute of Neurology Queen Square, London, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.affiliation: Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, NIH Bethesda, Maryland.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Singleton
authors.affiliation: Molecular Neurology, Research Program Unit, Biomedicum, University of Helsinki Helsinki, Finland ; Department of Neurology, Helsinki University Central Hospital Helsinki, Finland.
authors.forename: Pentti J
authors.initials: PJ
authors.lastname: Tienari