@article{7e3393eee76443d5b6c0cea388554525,
title = "Genetic risk factors for the posterior cortical atrophy variant of Alzheimer's disease",
abstract = "Introduction The genetics underlying posterior cortical atrophy (PCA), typically a rare variant of Alzheimer's disease (AD), remain uncertain. Methods We genotyped 302 PCA patients from 11 centers, calculated risk at 24 loci for AD/DLB and performed an exploratory genome-wide association study. Results 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]). Discussion 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.",
keywords = "APOE, Alzheimer's disease, GWAS, Genetics, Posterior cortical atrophy, Selective vulnerability",
author = "Schott, {Jonathan M.} and Crutch, {Sebastian J.} and Carrasquillo, {Minerva M.} and James Uphill and Shakespeare, {Tim J.} and Ryan, {Natalie S.} and Yong, {Keir X.} and Manja Lehmann and Nilufer Ertekin-Taner and Graff-Radford, {Neill R.} and Boeve, {Bradley F.} and Murray, {Melissa E.} and Khan, {Qurat ul Ain} and Petersen, {Ronald C.} and Dickson, {Dennis W.} and Knopman, {David S.} and Rabinovici, {Gil D.} and Miller, {Bruce L.} and Gonz{\'a}lez, {Aida Su{\'a}rez} and Eulogio Gil-N{\'e}ciga and Snowden, {Julie S.} and Jenny Harris and Pickering-Brown, {Stuart M.} and Eva Louwersheimer and {van der Flier}, {Wiesje M.} and Philip Scheltens and Pijnenburg, {Yolande A.} and Douglas Galasko and Marie Sarazin and Bruno Dubois and Eloi Magnin and Daniela Galimberti and Elio Scarpini and Cappa, {Stefano F.} and Hodges, {John R.} and Halliday, {Glenda M.} and Lauren Bartley and Carrillo, {Maria C.} and Bras, {Jose T.} and John Hardy and Rossor, {Martin N.} and John Collinge and Fox, {Nick C.} and Simon Mead",
note = "Funding Information: We acknowledge the support of the Alzheimer's Association's International Society to Advance Alzheimer's Research and Treatment (ISTAART), Alzheimer's Research UK , the UK Alzheimer's Society and the Raena Frankel-Pollen Fund . This work was supported by the NIHR UCL/UCLH Biomedical Research Centre , the NIHR Queen Square Dementia Biomedical Research Unit , the Wolfson Foundation , and the UK Medical Research Council . The Dementia Research Centre is an Alzheimer's Research UK Coordinating Center. N.C.F. and M.N.R. are NIHR senior investigators. N.S.R. is in receipt of a Brain Exit Fellowship. J.T.B. receives funding from the UK Alzheimer's Society . This work was also supported by the Medical Research Council Dementias Platform UK ( MR/L023784/1 and MR/009076/1 ); Alzheimer's Research UK (Senior Research Fellowship to S.C., Research Fellowship to T.S.); the Dunhill Medical Trust (grant number R337/0214 to S.C.); ESRC/NIHR ( ES/K006711/1 to S.C.); EPSRC ( EP/M006093/1 to S.C.); Alzheimer's Association (MNIRGD 2013 award to M.M.C.); Mayo Alzheimer's Disease Research Center ( P50 AG0016574 to D.W.D., N.E.-T., N.R.G.-R., B.F.B., D.S.K., R.C.P.); National Institute on Aging ( R01 AG032990 and U01 AG046139 to N.E.-T.; R01-AG045611 to G.D.R.; and P50-AG023501 to B.L.M. and G.D.R.); National Institute of Neurological Disorders and Stroke ( R01 NS080820 to N.E.-T.); John Douglas French Alzheimer's Foundation (to G.D.R., B.L.M.); and State of California Department of Health Services Alzheimer's Disease Research Centre of California ( 04-33516 , B.L.M.). D.G. and E.S. are supported by Italian Ministry of Health (Ricerca Corrente). W.M.v.d.F., P.S. receive funding from PERADES-JPND . E.L. receives funding from Stichting Dioraphte . Case ascertainment in Australia was funded by grants from the National Health and Medical Research Council of Australia (NHMRC program grant # 1037746 ) and the Australian Research Council Centre of Excellence in Cognition and its Disorders Memory Node ( #CE110001021 ); G.H. is a NHMRC senior principal research fellow ( #1079679 ). We would like to thank the participants in the Framingham, Geisinger, WTCCC, and KORA studies used as controls in this article. The Framingham Heart Study is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with Boston University (Contract No. N01-HC-25195). This article was not prepared in collaboration with investigators of the Framingham Heart Study and does not necessarily reflect the opinions or views of the Framingham Heart Study, Boston University, or NHLBI. SHARe Illumina genotyping was provided under an agreement between Illumina and Boston University. Samples and data in this study were also provided by the Geisinger MyCode Project. Funding for the MyCode project was provided by a grant from Commonwealth of Pennsylvania and the Clinic Research Fund of Geisinger Clinic . Funding support for the genotyping of the MyCode cohort was provided by a Geisinger Clinic operating funds and an award from the Clinic Research Fund. The data sets used for the analyses described in this article were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000381.v1.p1. This study also makes use of the data generated by the Wellcome Trust Case Control Consortium. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk . Funding for the project was provided by the Wellcome Trust under award 076113 . ",
year = "2016",
month = aug,
day = "1",
doi = "10.1016/j.jalz.2016.01.010",
language = "English (US)",
volume = "12",
pages = "862--871",
journal = "Alzheimer's and Dementia",
issn = "1552-5260",
publisher = "Elsevier Inc.",
number = "8",
}