title: Investigating the role of rare coding variability in Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP) in late-onset Alzheimer's disease.
abstract: The overlapping clinical and neuropathologic features between late-onset apparently sporadic Alzheimer's disease (LOAD), familial Alzheimer's disease (FAD), and other neurodegenerative dementias (frontotemporal dementia, corticobasal degeneration, progressive supranuclear palsy, and Creutzfeldt-Jakob disease) raise the question of whether shared genetic risk factors may explain the similar phenotype among these disparate disorders. To investigate this intriguing hypothesis, we analyzed rare coding variability in 6 Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP), in 141 LOAD patients and 179 elderly controls, neuropathologically proven, from the UK. In our cohort, 14 LOAD cases (10%) and 11 controls (6%) carry at least 1 rare variant in the genes studied. We report a novel variant in PSEN1 (p.I168T) and a rare variant in PSEN2 (p.A237V), absent in controls and both likely pathogenic. Our findings support previous studies, suggesting that (1) rare coding variability in PSEN1 and PSEN2 may influence the susceptibility for LOAD and (2) GRN, MAPT, and PRNP are not major contributors to LOAD. Thus, genetic screening is pivotal for the clinical differential diagnosis of these neurodegenerative dementias.
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, UK; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. Electronic address: celeste.sassi.10@ucl.ac.uk.
authors.forename: Celeste
authors.initials: C
authors.lastname: Sassi
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, UK; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Rita
authors.initials: R
authors.lastname: Guerreiro
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, UK; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Raphael
authors.initials: R
authors.lastname: Gibbs
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Jinhui
authors.initials: J
authors.lastname: Ding
authors.affiliation: King's College London Institute of Psychiatry, London, UK.
authors.forename: Michelle K
authors.initials: MK
authors.lastname: Lupton
authors.affiliation: King's College London Institute of Psychiatry, London, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Troakes
authors.affiliation: King's College London Institute of Psychiatry, London, UK.
authors.forename: Safa
authors.initials: S
authors.lastname: Al-Sarraj
authors.affiliation: King's College London Institute of Psychiatry, London, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Niblock
authors.affiliation: King's College London Institute of Psychiatry, London, UK.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Gallo
authors.affiliation: King's College London Institute of Psychiatry, London, UK.
authors.forename: Jihad
authors.initials: J
authors.lastname: Adnan
authors.affiliation: King's College London Institute of Psychiatry, London, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Killick
authors.affiliation: Translation Cell Sciences-Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK.
authors.forename: Kristelle S
authors.initials: KS
authors.lastname: Brown
authors.affiliation: Translation Cell Sciences-Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Medway
authors.affiliation: Translation Cell Sciences-Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK.
authors.forename: Jenny
authors.initials: J
authors.lastname: Lord
authors.affiliation: Translation Cell Sciences-Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK.
authors.forename: James
authors.initials: J
authors.lastname: Turton
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, UK.
authors.forename: Jose
authors.initials: J
authors.lastname: Bras
authors.affiliation: Translation Cell Sciences-Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK.
authors.forename: Kevin
authors.initials: K
authors.lastname: Morgan
authors.affiliation: King's College London Institute of Psychiatry, London, UK.
authors.forename: John F
authors.initials: JF
authors.lastname: Powell
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Singleton
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, UK.
authors.forename: John
authors.initials: J
authors.lastname: Hardy
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000175:diagnosis / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D015331:Cohort Studies; D003704:Dementia / Q000175:diagnosis / Q000235:genetics; D003937:Diagnosis, Differential; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D053764:Presenilin-1 / Q000235:genetics*; D053766:Presenilin-2 / Q000235:genetics*; D000072002:Prion Proteins; D011328:Prions / Q000235:genetics*; D000077153:Progranulins; D016875:tau Proteins / Q000235:genetics*
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; C054369:MAPT protein, human; C512656:PRNP protein, human; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D000072002:Prion Proteins; D011328:Prions; D000077153:Progranulins; D016875:tau Proteins
keywords: APP; Alzheimer's disease; Exome sequencing; GRN; MAPT; Neurodegenerative dementia; PRNP; PSEN1; PSEN2
references.citation: J Biol Chem. 2008 Jan 18;283(3):1744-1753
references.pmid: 17984093
references.citation: PLoS Genet. 2013;9(8):e1003685
references.pmid: 23990795
references.citation: Am J Med Genet. 1995 Feb 27;60(1):12-8
references.pmid: 7485229
references.citation: Arch Gen Psychiatry. 1997 Mar;54(3):264-70
references.pmid: 9075467
references.citation: Nucleic Acids Res. 2010 Sep;38(16):e164
references.pmid: 20601685
references.citation: Genome Res. 2009 Sep;19(9):1665-74
references.pmid: 19602640
references.citation: Neurosci Lett. 2001 Jun 29;306(3):203-5
references.pmid: 11406330
references.citation: Lancet. 1996 Mar 2;347(9001):573-8
references.pmid: 8596319
references.citation: JAMA. 2010 May 12;303(18):1832-40
references.pmid: 20460622
references.citation: Nature. 1991 Jul 25;352(6333):340-2
references.pmid: 1677164
references.citation: N Engl J Med. 2013 Jan 10;368(2):117-27
references.pmid: 23150934
references.citation: N Engl J Med. 2012 Jan 19;366(3):283-4
references.pmid: 22216764
references.citation: Hum Mutat. 2010 Feb;31(2):E1126-40
references.pmid: 20020531
references.citation: Nat Genet. 2009 Oct;41(10):1094-9
references.pmid: 19734903
references.citation: Nat Genet. 2011 May;43(5):436-41
references.pmid: 21460841
references.citation: Bioinformatics. 2009 Jul 15;25(14):1754-60
references.pmid: 19451168
references.citation: Nat Genet. 2013 Dec;45(12):1452-8
references.pmid: 24162737
references.citation: Hum Mol Genet. 1998 Jan;7(1):43-51
references.pmid: 9384602
references.citation: Neurology. 2003 Jan 28;60(2):235-9
references.pmid: 12552037
references.citation: Nat Genet. 2011 May;43(5):429-35
references.pmid: 21460840
references.citation: Nat Genet. 2009 Oct;41(10):1088-93
references.pmid: 19734902
references.citation: Nature. 2012 Aug 2;488(7409):96-9
references.pmid: 22801501
references.citation: J Neuropathol Exp Neurol. 2012 Apr;71(4):266-73
references.pmid: 22437338
references.citation: Genome Res. 2010 Sep;20(9):1297-303
references.pmid: 20644199
references.citation: Hum Mol Genet. 1993 May;2(5):541-4
references.pmid: 8100163
references.citation: Am J Hum Genet. 1999 Sep;65(3):664-70
references.pmid: 10441572
references.citation: Mol Cell Biol. 2006 Nov;26(22):8357-70
references.pmid: 16982696
references.citation: Neurology. 2008 Aug 26;71(9):656-64
references.pmid: 18565828
references.citation: PLoS One. 2012;7(2):e31039
references.pmid: 22312439
references.citation: Nature. 2014 Jan 23;505(7484):550-554
references.pmid: 24336208
references.citation: Neurobiol Aging. 2010 May;31(5):725-31
references.pmid: 18667258
references.citation: Neurology. 2001 Aug 28;57(4):621-5
references.pmid: 11524469
references.citation: Arch Gen Psychiatry. 2006 Feb;63(2):168-74
references.pmid: 16461860