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.
INTERPRETATION: 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.