title: A survey of ABCA1 sequence variation confirms association with dementia.
abstract: We and others have conducted targeted genetic association analyses of ABCA1 in relation to Alzheimer disease risk with a resultant mixture of both support and refutation, but all previous studies have been based upon only a few markers. Here, a detailed survey of genetic variation in the ABCA1 region has been performed in a total of 1,567 Swedish dementia cases (including 1,275 with Alzheimer disease) and 2,203 controls, providing evidence of association with maximum significance at marker rs2230805 (odds ratio [OR]=1.39; 95% confidence interval [CI] 1.23-1.57, p=7.7x10(-8)). Haplotype-based tests confirmed association of this genomic region after excluding rs2230805, and imputation did not reveal additional markers with greater support. Significantly associating markers reside in two distinct linkage disequilibrium blocks with maxima near the promoter and in the terminal exon of a truncated ABCA1 splice form. The putative risk allele of rs2230805 was also found to be associated with reduced cerebrospinal fluid levels of beta-amyloid. The strongest evidence of association was obtained when all forms of dementia were considered together, but effect sizes were similar when only confirmed Alzheimer disease cases were assessed. Results further implicate ABCA1 in dementia, reinforcing the putative involvement of lipid transport in neurodegenerative disease.
authors.affiliation: Department of Psychology, University of California at Riverside, Riverside, California, USA.
authors.forename: Chandra A
authors.initials: CA
authors.lastname: Reynolds
authors.forename: Mun-Gwan
authors.initials: MG
authors.lastname: Hong
authors.forename: Ulrika K
authors.initials: UK
authors.lastname: Eriksson
authors.forename: Kaj
authors.initials: K
authors.lastname: Blennow
authors.forename: Anna M
authors.initials: AM
authors.lastname: Bennet
authors.forename: Boo
authors.initials: B
authors.lastname: Johansson
authors.forename: Bo
authors.initials: B
authors.lastname: Malmberg
authors.forename: Stig
authors.initials: S
authors.lastname: Berg
authors.forename: Fredrik
authors.initials: F
authors.lastname: Wiklund
authors.forename: Margaret
authors.initials: M
authors.lastname: Gatz
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Pedersen
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Prince
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D016022:Case-Control Studies; D003625:Data Collection; D003704:Dementia / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters