title: Genetic risk factors for the posterior cortical atrophy variant of Alzheimer's disease.
abstract: The genetics underlying posterior cortical atrophy (PCA), typically a rare variant of Alzheimer's disease (AD), remain uncertain.
  
  
  
  We genotyped 302 PCA patients from 11 centers, calculated risk at 24 loci for AD/DLB and performed an exploratory genome-wide association study.
  
  
  
  We confirm that variation in/near APOE/TOMM40 (P = 6 × 10(-14)) alters PCA risk, but with smaller effect than for typical AD (PCA: odds ratio [OR] = 2.03, typical AD: OR = 2.83, P = .0007). We found evidence for risk in/near CR1 (P = 7 × 10(-4)), ABCA7 (P = .02) and BIN1 (P = .04). ORs at variants near INPP5D and NME8 did not overlap between PCA and typical AD. Exploratory genome-wide association studies confirmed APOE and identified three novel loci: rs76854344 near CNTNAP5 (P = 8 × 10(-10) OR = 1.9 [1.5-2.3]); rs72907046 near FAM46A (P = 1 × 10(-9) OR = 3.2 [2.1-4.9]); and rs2525776 near SEMA3C (P = 1 × 10(-8), OR = 3.3 [2.1-5.1]).
  
  
  
  We provide evidence for genetic risk factors specifically related to PCA. We identify three candidate loci that, if replicated, may provide insights into selective vulnerability and phenotypic diversity in AD.
authors.affiliation: Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK. Electronic address: j.schott@ucl.ac.uk.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Schott
authors.affiliation: Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK.
authors.forename: Sebastian J
authors.initials: SJ
authors.lastname: Crutch
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Minerva M
authors.initials: MM
authors.lastname: Carrasquillo
authors.affiliation: Department of Neurodegenerative Disease, MRC Prion Unit, UCL Institute of Neurology, London, UK.
authors.forename: James
authors.initials: J
authors.lastname: Uphill
authors.affiliation: Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK.
authors.forename: Tim J
authors.initials: TJ
authors.lastname: Shakespeare
authors.affiliation: Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK.
authors.forename: Natalie S
authors.initials: NS
authors.lastname: Ryan
authors.affiliation: Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK.
authors.forename: Keir X
authors.initials: KX
authors.lastname: Yong
authors.affiliation: Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK.
authors.forename: Manja
authors.initials: M
authors.lastname: Lehmann
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA; Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Nilufer
authors.initials: N
authors.lastname: Ertekin-Taner
authors.affiliation: Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Neill R
authors.initials: NR
authors.lastname: Graff-Radford
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Bradley F
authors.initials: BF
authors.lastname: Boeve
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Melissa E
authors.initials: ME
authors.lastname: Murray
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Qurat Ul Ain
authors.initials: QU
authors.lastname: Khan
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Petersen
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Knopman
authors.affiliation: UCSF, San Francisco, CA, USA.
authors.forename: Gil D
authors.initials: GD
authors.lastname: Rabinovici
authors.affiliation: UCSF, San Francisco, CA, USA.
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Miller
authors.affiliation: Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK; Memory Disorders Unit, Department of Neurology, University Hospital Virgen del Rocio, Seville, Spain.
authors.forename: Aida Suárez
authors.initials: AS
authors.lastname: González
authors.affiliation: Memory Disorders Unit, Department of Neurology, University Hospital Virgen del Rocio, Seville, Spain.
authors.forename: Eulogio
authors.initials: E
authors.lastname: Gil-Néciga
authors.affiliation: Institute of Brain, Behaviour and Mental Health, University of Manchester, UK.
authors.forename: Julie S
authors.initials: JS
authors.lastname: Snowden
authors.affiliation: Institute of Brain, Behaviour and Mental Health, University of Manchester, UK.
authors.forename: Jenny
authors.initials: J
authors.lastname: Harris
authors.affiliation: Institute of Brain, Behaviour and Mental Health, University of Manchester, UK.
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Pickering-Brown
authors.affiliation: Alzheimer Center, Department of Neurology, VU University Medical Center, Neuroscience Campus, Amsterdam, Netherlands.
authors.forename: Eva
authors.initials: E
authors.lastname: Louwersheimer
authors.affiliation: Alzheimer Center, Department of Neurology, VU University Medical Center, Neuroscience Campus, Amsterdam, Netherlands.
authors.forename: Wiesje M
authors.initials: WM
authors.lastname: van der Flier
authors.affiliation: Alzheimer Center, Department of Neurology, VU University Medical Center, Neuroscience Campus, Amsterdam, Netherlands.
authors.forename: Philip
authors.initials: P
authors.lastname: Scheltens
authors.affiliation: Alzheimer Center, Department of Neurology, VU University Medical Center, Neuroscience Campus, Amsterdam, Netherlands.
authors.forename: Yolande A
authors.initials: YA
authors.lastname: Pijnenburg
authors.affiliation: Department of Epidemiology & Biostatistics, VU University Medical Center, Amsterdam, The Netherlands; UC San Diego/VA San Diego Healthcare System, San Diego, CA, USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: Galasko
authors.affiliation: INSERM U610, Hôpital de la Salpêtrière, Paris, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Sarazin
authors.affiliation: Centre des Maladies Cognitives et Comportementales, IM2A, ICM, Paris 6 University, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Dubois
authors.affiliation: Regional Memory Centre (CMRR), CHU Besançon, Besançon, France.
authors.forename: Eloi
authors.initials: E
authors.lastname: Magnin
authors.affiliation: University of Milan, Fondazione Cà Granda, IRCCS Ospedale Policlinico, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Galimberti
authors.affiliation: University of Milan, Fondazione Cà Granda, IRCCS Ospedale Policlinico, Italy.
authors.forename: Elio
authors.initials: E
authors.lastname: Scarpini
authors.affiliation: Vita-Salute San Raffaele University, Milan, Italy.
authors.forename: Stefano F
authors.initials: SF
authors.lastname: Cappa
authors.affiliation: University of New South Wales, Sydney, Australia.
authors.forename: John R
authors.initials: JR
authors.lastname: Hodges
authors.affiliation: University of New South Wales, Sydney, Australia.
authors.forename: Glenda M
authors.initials: GM
authors.lastname: Halliday
authors.affiliation: University of New South Wales, Sydney, Australia.
authors.forename: Lauren
authors.initials: L
authors.lastname: Bartley
authors.affiliation: Alzheimer's Association, Chicago, IL, USA.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Carrillo
authors.affiliation: Department of Molecular Neurosciences, UCL Institute of Neurology, London, UK.
authors.forename: Jose T
authors.initials: JT
authors.lastname: Bras
authors.affiliation: Department of Molecular Neurosciences, UCL Institute of Neurology, London, UK.
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.affiliation: Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK.
authors.forename: Martin N
authors.initials: MN
authors.lastname: Rossor
authors.affiliation: Department of Neurodegenerative Disease, MRC Prion Unit, UCL Institute of Neurology, London, UK.
authors.forename: John
authors.initials: J
authors.lastname: Collinge
authors.affiliation: Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK.
authors.forename: Nick C
authors.initials: NC
authors.lastname: Fox
authors.affiliation: Department of Neurodegenerative Disease, MRC Prion Unit, UCL Institute of Neurology, London, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Mead
mesh_terms: D000367:Age Factors; D000368:Aged; D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics; D001284:Atrophy / Q000209:etiology; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics*; D002540:Cerebral Cortex / Q000473:pathology*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics; D008875:Middle Aged; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011062:Polynucleotide Adenylyltransferase; D011506:Proteins / Q000235:genetics*; D017463:Receptors, Complement 3b / Q000235:genetics; D012307:Risk Factors; D039961:Semaphorins / Q000235:genetics*
chemical_list: D001057:Apolipoproteins E; C513597:CNTNAP5 protein, human; C509991:CR1 protein, human; D015816:Cell Adhesion Molecules, Neuronal; D026901:Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D011506:Proteins; D017463:Receptors, Complement 3b; C543908:Sema3C protein, human; D039961:Semaphorins; C400783:TOMM40 protein, human; D011062:Polynucleotide Adenylyltransferase; C466099:TENT5A protein, human
keywords: APOE; Alzheimer's disease; GWAS; Genetics; Posterior cortical atrophy; Selective vulnerability