Fine-mapping the effects of Alzheimer's disease risk loci on brain morphology

Gennady V. Roshchupkin, Hieab H. Adams, Sven J. van der Lee, Meike W. Vernooij, Cornelia M. van Duijn, Andre G. Uitterlinden, Aad van der Lugt, Albert Hofman, Wiro J. Niessen, Mohammad A. Ikram

    Research output: Contribution to journalArticleScientificpeer-review

    18 Citations (Scopus)


    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 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.

    Original languageEnglish
    Pages (from-to)204-211
    Number of pages8
    JournalNeurobiology of Aging: age-related phenomena, neurodegeneration and neuropathology
    Publication statusPublished - 1 Dec 2016


    • Alzheimer's disease
    • Brain
    • Dementia
    • Genetics
    • Magnetic resonance imaging
    • Voxel-based morphometry


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