title: Fine-mapping the effects of Alzheimer's disease risk loci on brain morphology.
abstract: The neural substrate of genetic risk variants for Alzheimer's disease (AD) remains unknown. We studied their effect on healthy brain morphology to provide insight into disease etiology in the preclinical phase. We included 4071 nondemented, elderly participants of the population-based Rotterdam Study who underwent brain magnetic resonance imaging and genotyping. We performed voxel-based morphometry (VBM) on all gray-matter voxels for 19 previously identified, common AD risk variants. Whole-brain expression data from the Allen Human Brain Atlas was used to examine spatial overlap between VBM association results and expression of genes in AD risk loci regions. Brain regions most significantly associated with AD risk variants were the left postcentral gyrus with ABCA7 (rs4147929, p = 4.45 × 10-6), right superior frontal gyrus by ZCWPW1 (rs1476679, p = 5.12 × 10-6), and right postcentral gyrus by APOE (p = 6.91 × 10-6). Although no individual voxel passed multiple-testing correction, we found significant spatial overlap between the effects of AD risk loci on VBM and the expression of genes (MEF2C, CLU, and SLC24A4) in the Allen Brain Atlas. Results are available online on www.imagene.nl/ADSNPs/. In this single largest imaging genetics data set worldwide, we found that AD risk loci affect cortical gray matter in several brain regions known to be involved in AD, as well as regions that have not been implicated before.
authors.affiliation: Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, the Netherlands; Department of Medical Informatics, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Gennady V
authors.initials: GV
authors.lastname: Roshchupkin
authors.affiliation: Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, the Netherlands; Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Hieab H
authors.initials: HH
authors.lastname: Adams
authors.affiliation: Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Sven J
authors.initials: SJ
authors.lastname: van der Lee
authors.affiliation: Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, the Netherlands; Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Meike W
authors.initials: MW
authors.lastname: Vernooij
authors.affiliation: Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.affiliation: Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands; Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Andre G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Aad
authors.initials: A
authors.lastname: van der Lugt
authors.affiliation: Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.affiliation: Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, the Netherlands; Department of Medical Informatics, Erasmus MC, Rotterdam, the Netherlands; Faculty of Applied Sciences, Delft University of Technology, Delft, the Netherlands.
authors.forename: Wiro J
authors.initials: WJ
authors.lastname: Niessen
authors.affiliation: Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, the Netherlands; Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands; Department of Neurology, Erasmus MC, Rotterdam, the Netherlands. Electronic address: m.a.ikram@erasmusmc.nl.
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Ikram
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology*; D017920:Antiporters; D001921:Brain / Q000000981:diagnostic imaging* / Q000473:pathology*; D051152:Clusterin; D005260:Female; D015870:Gene Expression; D005838:Genotype; D006801:Humans; D064326:MEF2 Transcription Factors; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D059906:Neuroimaging; D012306:Risk
chemical_list: D017920:Antiporters; C495242:CLU protein, human; D051152:Clusterin; D064326:MEF2 Transcription Factors; C578040:MEF2C protein, human; C470570:SLC24A4 protein, human
keywords: Alzheimer's disease; Brain; Dementia; Genetics; Magnetic resonance imaging; Voxel-based morphometry