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

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.

[1]  A. Smith,et al.  Cerebral Amyloid Angiopathy, Subcortical White Matter Disease and Dementia: Literature Review and Study in OPTIMA , 2015, Brain pathology.

[2]  Benjamin F. J. Verhaaren,et al.  Alzheimer's Disease Genes and Cognition in the Nondemented General Population , 2013, Biological Psychiatry.

[3]  Stephen M. Smith,et al.  Threshold-free cluster enhancement: Addressing problems of smoothing, threshold dependence and localisation in cluster inference , 2009, NeuroImage.

[4]  Jason J. Corneveaux,et al.  Initial Assessment of the Pathogenic Mechanisms of the Recently Identified Alzheimer Risk Loci , 2013, Annals of human genetics.

[5]  A. Meyer-Lindenberg,et al.  Genetic interaction of PICALM and APOE is associated with brain atrophy and cognitive impairment in Alzheimer's disease , 2014, Alzheimer's & Dementia.

[6]  Neda Jahanshad,et al.  Whole-genome analyses of whole-brain data: working within an expanded search space , 2014, Nature Neuroscience.

[7]  C Xie,et al.  Decreased glutathione transferase activity in brain and ventricular fluid in Alzheimer's disease , 1998, Neurology.

[8]  Clifford R. Jack,et al.  Association of Alzheimer's disease GWAS loci with MRI markers of brain aging , 2015, Neurobiology of Aging.

[9]  Y. Liu,et al.  Association between NME8 Locus Polymorphism and Cognitive Decline, Cerebrospinal Fluid and Neuroimaging Biomarkers in Alzheimer's Disease , 2014, PLoS ONE.

[10]  A Hofman,et al.  Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53 949) , 2015, Molecular Psychiatry.

[11]  Vincent Frouin,et al.  Robust regression for large-scale neuroimaging studies , 2015, NeuroImage.

[12]  A. Singleton,et al.  Genetic variability in the regulation of gene expression in ten regions of the human brain , 2014, Nature Neuroscience.

[13]  Nick C Fox,et al.  Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease , 2013, Nature Genetics.

[14]  Alexander Hammers,et al.  Three‐dimensional maximum probability atlas of the human brain, with particular reference to the temporal lobe , 2003, Human brain mapping.

[15]  T. Funahashi,et al.  The Journal of Clinical Endocrinology & Metabolism Printed in U.S.A. Copyright © 2001 by The Endocrine Society Hypoadiponectinemia in Obesity and Type 2 Diabetes: Close Association with Insulin Resistance , 2022 .

[16]  R. Doerge,et al.  Empirical threshold values for quantitative trait mapping. , 1994, Genetics.

[17]  Karl J. Friston,et al.  A Voxel-Based Morphometric Study of Ageing in 465 Normal Adult Human Brains , 2001, NeuroImage.

[18]  P. Board,et al.  Polymorphisms in the human glutathione transferase Kappa (GSTK1) promoter alter gene expression. , 2010, Genomics.

[19]  Stephen M. Smith,et al.  Improved Optimization for the Robust and Accurate Linear Registration and Motion Correction of Brain Images , 2002, NeuroImage.

[20]  Monique M. B. Breteler,et al.  The Rotterdam Study: 2016 objectives and design update , 2015, European Journal of Epidemiology.

[21]  Albert Hofman,et al.  The potential for prevention of dementia across two decades: the prospective, population-based Rotterdam Study , 2015, BMC Medicine.

[22]  A. Goate,et al.  Expression of Novel Alzheimer’s Disease Risk Genes in Control and Alzheimer’s Disease Brains , 2012, PloS one.

[23]  B. Strooper,et al.  The role of G protein-coupled receptors in the pathology of Alzheimer's disease , 2011, Nature Reviews Neuroscience.

[24]  Mark W. Woolrich,et al.  Advances in functional and structural MR image analysis and implementation as FSL , 2004, NeuroImage.

[25]  Tyrone D. Cannon,et al.  Genetic influences on brain structure , 2001, Nature Neuroscience.

[26]  Wiro J. Niessen,et al.  Multi-spectral brain tissue segmentation using automatically trained k-Nearest-Neighbor classification , 2007, NeuroImage.

[27]  Wiro J. Niessen,et al.  The Rotterdam Scan Study: design and update up to 2012 , 2011, European Journal of Epidemiology.

[28]  Karl J. Friston,et al.  A Voxel-Based Method for the Statistical Analysis of Gray and White Matter Density Applied to Schizophrenia , 1995, NeuroImage.

[29]  Teri A Manolio,et al.  Genomewide association studies and assessment of the risk of disease. , 2010, The New England journal of medicine.

[30]  Paul M. Thompson,et al.  Common variants at 12q14 and 12q24 are associated with hippocampal volume , 2012, Nature Genetics.

[31]  Eric E. Smith,et al.  &bgr;-Amyloid, Blood Vessels, and Brain Function , 2009, Stroke.

[32]  M. Mattson Pathways towards and away from Alzheimer's disease , 2004, Nature.

[33]  David W Fardo,et al.  APOE-ε2 and APOE-ε4 correlate with increased amyloid accumulation in cerebral vasculature. , 2013, Journal of neuropathology and experimental neurology.

[34]  H. Stefánsson,et al.  Loss-of-function variants in ABCA7 confer risk of Alzheimer's disease , 2015, Nature Genetics.

[35]  A. Hofman,et al.  Genetic risk of neurodegenerative diseases is associated with mild cognitive impairment and conversion to dementia , 2015, Alzheimer's & Dementia.

[36]  John Suckling,et al.  Global, voxel, and cluster tests, by theory and permutation, for a difference between two groups of structural MR images of the brain , 1999, IEEE Transactions on Medical Imaging.

[37]  J. Ringman,et al.  Clinical predictors of severe cerebral amyloid angiopathy and influence of APOE genotype in persons with pathologically verified Alzheimer disease. , 2014, JAMA neurology.

[38]  A. Bird,et al.  Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals , 2003, Nature Genetics.

[39]  J. Gallacher,et al.  Convergent genetic and expression data implicate immunity in Alzheimer's disease , 2014, Alzheimer's & Dementia.

[40]  Mark E. Schmidt,et al.  The Alzheimer’s Disease Neuroimaging Initiative: A review of papers published since its inception , 2012, Alzheimer's & Dementia.

[41]  D. Stephan,et al.  A survey of genetic human cortical gene expression , 2007, Nature Genetics.