TY - JOUR
T1 - Genetic variants associated with susceptibility to psychosis in late-onset Alzheimer's disease families
AU - NIA-LOAD/NCRAD Family Study Group
AU - Barral, Sandra
AU - Vardarajan, Badri N.
AU - Reyes-Dumeyer, Dolly
AU - Faber, Kelley M.
AU - Bird, Thomas D.
AU - Tsuang, Debby
AU - Bennett, David A.
AU - Rosenberg, Roger
AU - Boeve, Bradley F.
AU - Graff-Radford, Neill R.
AU - Goate, Alison M.
AU - Farlow, Martin
AU - Lantigua, Rafael
AU - Medrano, Martin Z.
AU - Wang, Xinbing
AU - Kamboh, M. Ilyas
AU - Barmada, Mahmud Muhiedine
AU - Schaid, Daniel J.
AU - Foroud, Tatiana M.
AU - Weamer, Elise A.
AU - Ottman, Ruth
AU - Sweet, Robert A.
AU - Mayeux, Richard
N1 - Funding Information:
S.B. is funded by NIH grants U01 AG023749, 1U01AG032984, UF1AG047133 and P50 AG08702; B.N.V. receives support from NIMH TRANSFORM K12 Mentored Career Development Award; K.M.F. has received research support from the NIH through U24AG021886 and U01AG032984; T.D.B. receives support from NIH grant P50AG005136 and from the Department of Veterans Affairs, the McCaffrey Foundation; D.T. is supported by NIH/NIA U0 AG032984 and P50AG05136-22 and also receives support from the Research and Development, VA Puget Sound Health Care System; D.A.B. is supported by NIH R01AG017917, P30AG010161, R01AG015819, U01AG46152, R01AG036042 and Zinfandel, Inc. He serves on the editorial board of Neurology, Current Alzheimer’s Research, and Neuroepidemiology; has received honoraria for non-industry sponsored lectures; serves on the adjudication committee for Takeda, Inc., and has served as a consultant to Enzymotic, Ltd., and Vigorous Minds, Inc.; R.R. discloses he is PI on the NIH/NIA Alzheimer’s Disease Center Grant P30AG12300-20. He is Editor of JAMA Neurology and Editorial Board Member of JAMA. He is listed as Inventor on the US Patent for “Amyloid Beta Gene Vaccines”; B.F.B has served as an investigator for a clinical trial sponsored by GE Healthcare. He receives royalties from the publication of a book entitled Behavioral Neurology Of Dementia (Cambridge Medicine, 2009). He has received honoraria from the American Academy of Neurology. He serves on the Scientific Advisory Board of the Tau Consortium. He receives research support from the NIH (U01 AG045390, P50 AG016574, U01 AG006786, RO1 AG032306, RO1 AG041797) and the Mangurian Foundation.; N.R.G. is taking part in a multicenter study for treatment of mild Alzheimer disease funded by Eli Lilly. He is taking part in a treatment of bvFTD study funded by TauRx and has consulted for Cytox. He is funded by NIH grants U01AG24904, P50AG 16574, U01AG032438, R01AG041797 and R01AG039389; A.M.G. is funded by NIHNIA grants: R01AG041797, U24AG026395, R37AG015473, and U24AG21886. She also serves as consultant for Cognition Therapeutics and receives license income from Taconic Industries; M.F. receives research support from Accera, Biogen, Chase Pharmaceuticals, Eisai, Eli Lilly, Genentech, Lundbeck, MedAvante/AstraZeneca, Navidea and Roche. He also receives research support from the following NIH/NIA grants: U24AG021886, P30AG10133, U01AG042791, UL1RR001106-01NIH, KL2TR025760-01, TL1RR025759-01, U24AG021886, R01AG041797, P30AG10133, U01AG024904; he is part of the speaker’s bureau of Eisai, Pfizer, Forest, Novartis, Eli Lilly & Company, serves on the consultant/advisory boards at Accera, Alltech, Avanir, Eisai Med Res, Inc., EnVivo Pharmaceuticals, Grifols, Helicon, Inc Research, Medavante, Medivation, Inc., Merck and Co. Inc., Novartis, Pfizer, Prana Biotech, QR Pharma, Roche, Sanofi-Aventis, Schering-Plough, Toyama Pharm., Lilly, UCB Pharma and Elan; X.W., M.I.K. and M.M.B. receive support from NIH grants AG030653, AG041718 and AG005133. D.J.S. receives support from NIH grant 5R01GM065450-11; T.M.F. is funded by NIH grants R01AG041797 and U24AG0218860. She is a member of the Washington University Alzheimer’s Disease Research Center External Advisory Board; E.A.W. is supported by NIH grants AG026395, AG05133 and AG027224; RO serves on the scientific advisory board for and holds stock options in Trigeminal Solutions, Inc; received funding for travel from the École des Hautes Etudes en Santé Publique, the University of Bologna, and the University of Calgary; and receives research support from the NIH through U01NS077276, U01NS077367, R01NS078419, P50 HG007257, R01NS073872 and R01AG041797; R.A.S. receives support from USPHS grants MH071533, AG027224, AG041797, AG05133, MH094564, HHSN271201300032C, MH103204 and VHA grant 1BX000452; RM receives support from the NIH/NIA through P50AG0870, U01AG023749-05, R37 AG015473-12, 1R01AG036040-01, 1U01AG032984-01, R01AG037212, R01AG035020-01, R01AG041797. He is also funded by the Department of Defense W81XWH.
Publisher Copyright:
© 2015 The Authors.
PY - 2015/11
Y1 - 2015/11
N2 - 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.
AB - 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.
KW - Association analysis
KW - Genome-wide linkage analysis
KW - Late-onset Alzheimer's disease
KW - Non-Hispanic Caucasian and Caribbean Hispanic ancestry populations
KW - Psychosis
UR - http://www.scopus.com/inward/record.url?scp=84947045063&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84947045063&partnerID=8YFLogxK
U2 - 10.1016/j.neurobiolaging.2015.08.006
DO - 10.1016/j.neurobiolaging.2015.08.006
M3 - Article
C2 - 26359528
AN - SCOPUS:84947045063
SN - 0197-4580
VL - 36
SP - 3116.e9-3116.e16
JO - Neurobiology of aging
JF - Neurobiology of aging
IS - 11
ER -