title: Genetic variants associated with susceptibility to psychosis in late-onset Alzheimer's disease families.
abstract: Psychotic symptoms are frequent in late-onset Alzheimer's disease (LOAD) patients. Although the risk for psychosis in LOAD is genetically mediated, no genes have been identified. To identify loci potentially containing genetic variants associated with risk of psychosis in LOAD, a total of 263 families from the National Institute of Aging-LOAD cohort were classified into psychotic (LOAD+P, n = 215) and nonpsychotic (LOAD-P, n = 48) families based on the presence/absence of psychosis during the course of LOAD. The LOAD+P families yielded strong evidence of linkage on chromosome 19q13 (two-point [2-pt] ​logarithm of odds [LOD] = 3.8, rs2285513 and multipoint LOD = 2.7, rs541169). Joint linkage and association in 19q13 region detected strong association with rs2945988 (p = 8.7 × 10(-7)). Linkage results for the LOAD-P families yielded nonsignificant 19q13 LOD scores. Several 19q13 single-nucleotide polymorphisms generalized the association of LOAD+P in a Caribbean Hispanic (CH) cohort, and the strongest signal was rs10410711 (pmeta = 5.1 × 10(-5)). A variant located 24 kb upstream of rs10410711 and rs10421862 was strongly associated with LOAD+P (pmeta = 1.0 × 10(-5)) in a meta-analysis of the CH cohort and an additional non-Hispanic Caucasian dataset. Identified variants rs2945988 and rs10421862 affect brain gene expression levels. Our results suggest that genetic variants in genes on 19q13, some of which are involved in brain development and neurodegeneration, may influence the susceptibility to psychosis in LOAD patients.
authors.affiliation: Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center and New York Presbyterian Hospital, New York, NY, USA; Gertrude H. Sergievsky Center, Columbia University Medical Center and New York Presbyterian Hospital, New York, NY, USA; Department of Neurology, Columbia University Medical Center and New York Presbyterian Hospital, New York, NY, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Barral
authors.affiliation: Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center and New York Presbyterian Hospital, New York, NY, USA; Gertrude H. Sergievsky Center, Columbia University Medical Center and New York Presbyterian Hospital, New York, NY, USA; Department of Neurology, Columbia University Medical Center and New York Presbyterian Hospital, New York, NY, USA.
authors.forename: Badri N
authors.initials: BN
authors.lastname: Vardarajan
authors.affiliation: Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center and New York Presbyterian Hospital, New York, NY, USA; Gertrude H. Sergievsky Center, Columbia University Medical Center and New York Presbyterian Hospital, New York, NY, USA; Department of Neurology, Columbia University Medical Center and New York Presbyterian Hospital, New York, NY, USA.
authors.forename: Dolly
authors.initials: D
authors.lastname: Reyes-Dumeyer
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University, Indianapolis, IN, USA.
authors.forename: Kelley M
authors.initials: KM
authors.lastname: Faber
authors.affiliation: Department of Neurology, University of Washington, Seattle, WA, USA; Department of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Bird
authors.affiliation: Department of Neurology, University of Washington, Seattle, WA, USA; Department of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: Debby
authors.initials: D
authors.lastname: Tsuang
authors.affiliation: Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Bennett
authors.affiliation: Department of Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Roger
authors.initials: R
authors.lastname: Rosenberg
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Bradley F
authors.initials: BF
authors.lastname: Boeve
authors.affiliation: Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Neill R
authors.initials: NR
authors.lastname: Graff-Radford
authors.affiliation: Icanhn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Goate
authors.affiliation: Department of Neurology, Indiana University Center for Alzheimer's Disease and Related Disorders, Indianapolis, IN, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Farlow
authors.affiliation: Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center and New York Presbyterian Hospital, New York, NY, USA; Department of Medicine, Columbia University Medical Center and New York Presbyterian Hospital, New York, NY, USA.
authors.forename: Rafael
authors.initials: R
authors.lastname: Lantigua
authors.affiliation: Department of Geriatrics, Pontificia Universidad Católica Madre y Maestra, Santiago, Dominican Republic.
authors.forename: Martin Z
authors.initials: MZ
authors.lastname: Medrano
authors.affiliation: Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA; Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Xinbing
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: M Ilyas
authors.initials: MI
authors.lastname: Kamboh
authors.affiliation: Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Mahmud Muhiedine
authors.initials: MM
authors.lastname: Barmada
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Schaid
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University, Indianapolis, IN, USA.
authors.forename: Tatiana M
authors.initials: TM
authors.lastname: Foroud
authors.affiliation: Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Elise A
authors.initials: EA
authors.lastname: Weamer
authors.affiliation: Gertrude H. Sergievsky Center, Columbia University Medical Center and New York Presbyterian Hospital, New York, NY, USA; Department of Neurology, Columbia University Medical Center and New York Presbyterian Hospital, New York, NY, USA; Department of Epidemiology, Columbia University Medical Center and New York Presbyterian Hospital, New York, NY, USA; Division of Epidemiology, New York State Psychiatric Institute, New York, NY, USA.
authors.forename: Ruth
authors.initials: R
authors.lastname: Ottman
authors.affiliation: Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA; VISN 4 Mental Illness Research, Education and Clinical Center (MIRECC), VA Pittsburgh Healthcare System, Pittsburgh, PA, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Sweet
authors.affiliation: Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center and New York Presbyterian Hospital, New York, NY, USA; Gertrude H. Sergievsky Center, Columbia University Medical Center and New York Presbyterian Hospital, New York, NY, USA; Department of Neurology, Columbia University Medical Center and New York Presbyterian Hospital, New York, NY, USA. Electronic address: rpm2@cumc.columbia.edu.
authors.forename: Richard
authors.initials: R
authors.lastname: Mayeux
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics*; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics*; D015331:Cohort Studies; D066264:Datasets as Topic; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008297:Male; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011618:Psychotic Disorders / Q000209:etiology / Q000235:genetics*; D044465:White People
keywords: Association analysis; Genome-wide linkage analysis; Late-onset Alzheimer’s disease; Non-Hispanic Caucasian and Caribbean Hispanic ancestry populations; Psychosis