title: APOE and BCHE as modulators of cerebral amyloid deposition: a florbetapir PET genome-wide association study.
abstract: Deposition of amyloid-β (Aβ) in the cerebral cortex is thought to be a pivotal event in Alzheimer's disease (AD) pathogenesis with a significant genetic contribution. Molecular imaging can provide an early noninvasive phenotype, but small samples have prohibited genome-wide association studies (GWAS) of cortical Aβ load until now. We employed florbetapir ((18)F) positron emission tomography (PET) imaging to assess brain Aβ levels in vivo for 555 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). More than six million common genetic variants were tested for association to quantitative global cortical Aβ load controlling for age, gender and diagnosis. Independent genome-wide significant associations were identified on chromosome 19 within APOE (apolipoprotein E) (rs429358, P=5.5 × 10(-14)) and on chromosome 3 upstream of BCHE (butyrylcholinesterase) (rs509208, P=2.7 × 10(-8)) in a region previously associated with serum BCHE activity. Together, these loci explained 15% of the variance in cortical Aβ levels in this sample (APOE 10.7%, BCHE 4.3%). Suggestive associations were identified within ITGA6, near EFNA5, EDIL3, ITGA1, PIK3R1, NFIB and ARID1B, and between NUAK1 and C12orf75. These results confirm the association of APOE with Aβ deposition and represent the largest known effect of BCHE on an AD-related phenotype. BCHE has been found in senile plaques and this new association of genetic variation at the BCHE locus with Aβ burden in humans may have implications for potential disease-modifying effects of BCHE-modulating agents in the AD spectrum.
authors: 1] Center for Neuroimaging, Department of Radiology and Imaging Sciences and Indiana Alzheimer's Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA [2] Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA [3] Medical Scientist Training Program, Indiana University School of Medicine, Indianapolis, IN, USA.
authors: V K
authors: VK
authors: Ramanan
authors: Center for Neuroimaging, Department of Radiology and Imaging Sciences and Indiana Alzheimer's Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA.
authors: S L
authors: SL
authors: Risacher
authors: Center for Neuroimaging, Department of Radiology and Imaging Sciences and Indiana Alzheimer's Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA.
authors: K
authors: K
authors: Nho
authors: 1] Center for Neuroimaging, Department of Radiology and Imaging Sciences and Indiana Alzheimer's Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA [2] Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors: S
authors: S
authors: Kim
authors: 1] Center for Neuroimaging, Department of Radiology and Imaging Sciences and Indiana Alzheimer's Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA [2] Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors: S
authors: S
authors: Swaminathan
authors: 1] Center for Neuroimaging, Department of Radiology and Imaging Sciences and Indiana Alzheimer's Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA [2] Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors: L
authors: L
authors: Shen
authors: 1] Center for Neuroimaging, Department of Radiology and Imaging Sciences and Indiana Alzheimer's Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA [2] Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA [3] Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors: T M
authors: TM
authors: Foroud
authors: Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors: H
authors: H
authors: Hakonarson
authors: The Translational Genomics Institute (TGen), Phoenix, AZ, USA.
authors: M J
authors: MJ
authors: Huentelman
authors: Department of Neuroscience, University of California, San Diego, CA, USA.
authors: P S
authors: PS
authors: Aisen
authors: Department of Neurology, Mayo Clinic Minnesota, Rochester, MN, USA.
authors: R C
authors: RC
authors: Petersen
authors: Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors: R C
authors: RC
authors: Green
authors: Department of Radiology, Mayo Clinic Minnesota, Rochester, MN, USA.
authors: C R
authors: CR
authors: Jack
authors: Department of Radiology, University of Michigan, Ann Arbor, MI, USA.
authors: R A
authors: RA
authors: Koeppe
authors: Department of Neurology, University of California, Berkeley, CA, USA.
authors: W J
authors: WJ
authors: Jagust
authors: 1] Departments of Radiology, Medicine, and Psychiatry, University of California, San Francisco, CA, USA [2] Department of Veterans Affairs Medical Center, San Francisco, CA, USA.
authors: M W
authors: MW
authors: Weiner
authors: 1] Center for Neuroimaging, Department of Radiology and Imaging Sciences and Indiana Alzheimer's Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA [2] Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA [3] Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors: A J
authors: AJ
authors: Saykin
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics*; D000814:Aniline Compounds; D001057:Apolipoproteins E / Q000235:genetics*; D002091:Butyrylcholinesterase / Q000235:genetics*; D002540:Cerebral Cortex / Q000000981:diagnostic imaging / Q000378:metabolism*; D060825:Cognitive Dysfunction / Q000235:genetics; D005026:Ethylene Glycols; D005260:Female; D059907:Functional Neuroimaging; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D058225:Plaque, Amyloid / Q000000981:diagnostic imaging / Q000378:metabolism*; D049268:Positron-Emission Tomography; D044465:White People / Q000235:genetics
chemical_list: D000814:Aniline Compounds; D001057:Apolipoproteins E; D005026:Ethylene Glycols; C545186:florbetapir; D002091:Butyrylcholinesterase