title: Association of Alzheimer's disease GWAS loci with MRI markers of brain aging.
abstract: Whether novel risk variants of Alzheimer's disease (AD) identified through genome-wide association studies also influence magnetic resonance imaging-based intermediate phenotypes of AD in the general population is unclear. We studied association of 24 AD risk loci with intracranial volume, total brain volume, hippocampal volume (HV), white matter hyperintensity burden, and brain infarcts in a meta-analysis of genetic association studies from large population-based samples (N = 8175-11,550). In single-SNP based tests, AD risk allele of APOE (rs2075650) was associated with smaller HV (p = 0.0054) and CD33 (rs3865444) with smaller intracranial volume (p = 0.0058). In gene-based tests, there was associations of HLA-DRB1 with total brain volume (p = 0.0006) and BIN1 with HV (p = 0.00089). A weighted AD genetic risk score was associated with smaller HV (beta ± SE = -0.047 ± 0.013, p = 0.00041), even after excluding the APOE locus (p = 0.029). However, only association of AD genetic risk score with HV, including APOE, was significant after multiple testing correction (including number of independent phenotypes tested). These results suggest that novel AD genetic risk variants may contribute to structural brain aging in nondemented older community persons.
authors: INSERM U897, University of Bordeaux, Bordeaux, France; University of Bordeaux, Bordeaux, FranceINSERM U897, University of Bordeaux, Bordeaux, France.
authors: Ganesh
authors: G
authors: Chauhan
authors: Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands; Department of Radiology, Erasmus Medical Center, Rotterdam, the Netherlands.
authors: Hieab H H
authors: HHH
authors: Adams
authors: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
authors: Joshua C
authors: JC
authors: Bis
authors: Department of Neurology, Boston University School of Medicine, Boston, MA, USA; The Framingham Heart Study, Boston, MA, USA.
authors: Galit
authors: G
authors: Weinstein
authors: Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA; Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
authors: Lei
authors: L
authors: Yu
authors: Institute of Molecular Biology and Biochemistry, Centre for Molecular Medicine, Medical University of Graz, Graz, Austria.
authors: Anna Maria
authors: AM
authors: Töglhofer
authors: Icelandic Heart Association, Iceland; Department of Medicine, University of Iceland, Reykjavik, Iceland.
authors: Albert Vernon
authors: AV
authors: Smith
authors: Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
authors: Sven J
authors: SJ
authors: van der Lee
authors: Department of Neurology, Johns Hopkins School of Medicine, Baltimore, USA; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, USA.
authors: Rebecca F
authors: RF
authors: Gottesman
authors: Menzies Research Institute Tasmania, University of Tasmania, Hobart, Tasmania, Australia.
authors: Russell
authors: R
authors: Thomson
authors: The Framingham Heart Study, Boston, MA, USA; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
authors: Jing
authors: J
authors: Wang
authors: The Framingham Heart Study, Boston, MA, USA; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
authors: Qiong
authors: Q
authors: Yang
authors: Department of Radiology, Erasmus Medical Center, Rotterdam, the Netherlands.
authors: Wiro J
authors: WJ
authors: Niessen
authors: Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors: Oscar L
authors: OL
authors: Lopez
authors: Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Psychology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors: James T
authors: JT
authors: Becker
authors: Stroke and Ageing Research Centre, Southern Clinical School, Department of Medicine, Monash University, Melbourne, Victoria, Australia.
authors: Thanh G
authors: TG
authors: Phan
authors: Stroke and Ageing Research Centre, Southern Clinical School, Department of Medicine, Monash University, Melbourne, Victoria, Australia; Developmental Imaging Group, Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, Victoria, Australia.
authors: Richard J
authors: RJ
authors: Beare
authors: Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA; Department of Biomedical Engineering, Illinois Institute of Technology, Chicago, IL, USA.
authors: Konstantinos
authors: K
authors: Arfanakis
authors: Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
authors: Debra
authors: D
authors: Fleischman
authors: Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands; Department of Radiology, Erasmus Medical Center, Rotterdam, the Netherlands.
authors: Meike W
authors: MW
authors: Vernooij
authors: Groupe d'Imagerie Neurofonctionnelle, UMR5296, CNRS, CEA, Université de Bordeaux, Bordeaux, France.
authors: Bernard
authors: B
authors: Mazoyer
authors: Institute of Molecular Biology and Biochemistry, Centre for Molecular Medicine, Medical University of Graz, Graz, Austria.
authors: Helena
authors: H
authors: Schmidt
authors: Stroke and Ageing Research Centre, Southern Clinical School, Department of Medicine, Monash University, Melbourne, Victoria, Australia; Menzies Research Institute Tasmania, University of Tasmania, Hobart, Tasmania, Australia.
authors: Velandai
authors: V
authors: Srikanth
authors: Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors: David S
authors: DS
authors: Knopman
authors: Department of Radiology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors: Clifford R
authors: CR
authors: Jack
authors: Department of Epidemiology and Public Health, Pasteur Institute of Lille, Lille, France; INSERM, U744, Lille, France; Université Lille 2, Lille, France.
authors: Philippe
authors: P
authors: Amouyel
authors: Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
authors: Albert
authors: A
authors: Hofman
authors: Department of Neurology, University of California at Davis, Davis, CA, USA.
authors: Charles
authors: C
authors: DeCarli
authors: INSERM U897, University of Bordeaux, Bordeaux, France.
authors: Christophe
authors: C
authors: Tzourio
authors: Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands; Netherlands Consortium for Healthy Aging, Leiden, the Netherlands; Center for Medical Systems Biology, Leiden, the Netherlands.
authors: Cornelia M
authors: CM
authors: van Duijn
authors: Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA; Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
authors: David A
authors: DA
authors: Bennett
authors: Department of Neurology, Clinical Division of Neurogeriatrics, Medical University of Graz, Austria.
authors: Reinhold
authors: R
authors: Schmidt
authors: Departments of Neurology and Epidemiology, University of Washington, Seattle, WA, USA.
authors: William T
authors: WT
authors: Longstreth
authors: Department of Medicine-Geriatrics/Gerontology, University of Mississippi Medical Center, Jackson, MS, USA.
authors: Thomas H
authors: TH
authors: Mosley
authors: The Human Genetics Center and Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, USA.
authors: Myriam
authors: M
authors: Fornage
authors: Laboratory of Epidemiology and Population Sciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
authors: Lenore J
authors: LJ
authors: Launer
authors: Department of Neurology, Boston University School of Medicine, Boston, MA, USA; The Framingham Heart Study, Boston, MA, USA.
authors: Sudha
authors: S
authors: Seshadri
authors: Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands; Department of Radiology, Erasmus Medical Center, Rotterdam, the Netherlands; Netherlands Consortium for Healthy Aging, Leiden, the Netherlands.
authors: M Arfan
authors: MA
authors: Ikram
authors: INSERM U897, University of Bordeaux, Bordeaux, France; University of Bordeaux, Bordeaux, FranceINSERM U897, University of Bordeaux, Bordeaux, France; Department of Neurology, Boston University School of Medicine, Boston, MA, USA; Department of Neurology, Bordeaux University Hospital, Bordeaux, France. Electronic address: sdebette@bu.edu.
authors: Stephanie
authors: S
authors: Debette
mesh_terms: D000375:Aging / Q000235:genetics* / Q000473:pathology*; D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology*; D001057:Apolipoproteins E / Q000235:genetics; D001921:Brain / Q000473:pathology*; D005260:Female; D055106:Genome-Wide Association Study; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009929:Organ Size / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D063268:Sialic Acid Binding Ig-like Lectin 3 / Q000235:genetics
chemical_list: D001057:Apolipoproteins E; D063268:Sialic Acid Binding Ig-like Lectin 3
keywords: Alzheimer; GWAS; Genetic risk score; Hippocampal volume; MRI-Markers