title: Genome-wide copy-number variation study of psychosis in Alzheimer's disease.
abstract: About 40-60% of patients with late-onset Alzheimer's disease (AD) develop psychosis, which represents a distinct phenotype of more severe cognitive and functional deficits. The estimated heritability of AD+P is ~61%, which makes it a good target for genetic mapping. We performed a genome-wide copy-number variation (CNV) study on 496 AD cases with psychosis (AD+P), 639 AD subjects with intermediate psychosis (AD intermediate P) and 156 AD subjects without psychosis (AD-P) who were recruited at the University of Pittsburgh Alzheimer's Disease Research Center using over 1 million single-nucleotide polymorphisms (SNPs) and CNV markers. CNV load analysis found no significant difference in total and average CNV length and CNV number in the AD+P or AD intermediate P groups compared with the AD-P group. Our analysis revealed a marginally significant lower number of duplication events in AD+P cases compared with AD-P controls (P=0.059) using multivariable regression model. The most interesting finding was the presence of a genome-wide significant duplication in the APC2 gene on chromosome 19, which was protective against developing AD+P (odds ratio=0.42; P=7.2E-10). We also observed suggestive associations of duplications with AD+P in the SET (P=1.95E-06), JAG2 (P=5.01E-07) and ZFPM1 (P=2.13E-07) genes and marginal association of a deletion in CNTLN (P=8.87E-04). We have identified potential novel loci for psychosis in Alzheimer's disease that warrant follow-up in large-scale independent studies.
authors.affiliation: 1] Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA [2] Department of Pediatrics, School of Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: X
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: F Y
authors.initials: FY
authors.lastname: Demirci
authors.affiliation: Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Barmada
authors.affiliation: 1] Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA [2] Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: G A
authors.initials: GA
authors.lastname: Richardson
authors.affiliation: 1] Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA [2] VISN 4 Mental Illness Research, Education and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA, USA.
authors.forename: O L
authors.initials: OL
authors.lastname: Lopez
authors.affiliation: 1] Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA [2] Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA [3] VISN 4 Mental Illness Research, Education and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Sweet
authors.affiliation: 1] Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA [2] Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA [3] Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: M I
authors.initials: MI
authors.lastname: Kamboh
authors.affiliation: 1] Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA [2] Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Feingold
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000523:psychology; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000235:genetics; D056915:DNA Copy Number Variations; D004268:DNA-Binding Proteins; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D056488:Histone Chaperones / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D000072101:Jagged-2 Protein; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D015999:Multivariate Analysis; D009687:Nuclear Proteins / Q000235:genetics; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011618:Psychotic Disorders / Q000235:genetics* / Q000523:psychology; D012044:Regression Analysis; D012720:Severity of Illness Index; D014157:Transcription Factors / Q000235:genetics
chemical_list: C115681:APC2 protein, human; C579064:CNTLN protein, human; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D056488:Histone Chaperones; D036341:Intercellular Signaling Peptides and Proteins; C490504:JAG2 protein, human; D000072101:Jagged-2 Protein; D008565:Membrane Proteins; D009687:Nuclear Proteins; C513473:SET protein, human; D014157:Transcription Factors; C498432:ZFPM1 protein, human