TY - JOUR
T1 - Fine-mapping the effects of Alzheimer's disease risk loci on brain morphology
AU - Roshchupkin, Gennady V.
AU - Adams, Hieab H.
AU - van der Lee, Sven J.
AU - Vernooij, Meike W.
AU - van Duijn, Cornelia M.
AU - Uitterlinden, Andre G.
AU - van der Lugt, Aad
AU - Hofman, Albert
AU - Niessen, Wiro J.
AU - Ikram, Mohammad A.
PY - 2016/12/1
Y1 - 2016/12/1
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - Brain
KW - Dementia
KW - Genetics
KW - Magnetic resonance imaging
KW - Voxel-based morphometry
UR - http://www.scopus.com/inward/record.url?scp=84990248698&partnerID=8YFLogxK
U2 - 10.1016/j.neurobiolaging.2016.08.024
DO - 10.1016/j.neurobiolaging.2016.08.024
M3 - Article
AN - SCOPUS:84990248698
SN - 0197-4580
VL - 48
SP - 204
EP - 211
JO - Neurobiology of Aging: age-related phenomena, neurodegeneration and neuropathology
JF - Neurobiology of Aging: age-related phenomena, neurodegeneration and neuropathology
ER -
