Genetic risk factors for the posterior cortical atrophy variant of Alzheimer's disease

Jonathan M. Schott, Sebastian J. Crutch, Minerva M. Carrasquillo, James Uphill, Tim J. Shakespeare, Natalie S. Ryan, Keir X. Yong, Manja Lehmann, Nilufer Ertekin-Taner, Neill R. Graff-Radford, Bradley F. Boeve, Melissa E. Murray, Qurat ul Ain Khan, Ronald C. Petersen, Dennis W. Dickson, David S. Knopman, Gil D. Rabinovici, Bruce L. Miller, Aida Suárez González, Eulogio Gil-NécigaJulie S. Snowden, Jenny Harris, Stuart M. Pickering-Brown, Eva Louwersheimer, Wiesje M. van der Flier, Philip Scheltens, Yolande A. Pijnenburg, Douglas Galasko, Marie Sarazin, Bruno Dubois, Eloi Magnin, Daniela Galimberti, Elio Scarpini, Stefano F. Cappa, John R. Hodges, Glenda M. Halliday, Lauren Bartley, Maria C. Carrillo, Jose T. Bras, John Hardy, Martin N. Rossor, John Collinge, Nick C. Fox, Simon Mead

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)862-871
Number of pages10
JournalAlzheimer's and Dementia
Volume12
Issue number8
DOIs
Publication statusPublished - Aug 1 2016

Keywords

  • Alzheimer's disease
  • APOE
  • Genetics
  • GWAS
  • Posterior cortical atrophy
  • Selective vulnerability

ASJC Scopus subject areas

  • Epidemiology
  • Health Policy
  • Developmental Neuroscience
  • Geriatrics and Gerontology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience
  • Psychiatry and Mental health

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  • Cite this

    Schott, J. M., Crutch, S. J., Carrasquillo, M. M., Uphill, J., Shakespeare, T. J., Ryan, N. S., Yong, K. X., Lehmann, M., Ertekin-Taner, N., Graff-Radford, N. R., Boeve, B. F., Murray, M. E., Khan, Q. U. A., Petersen, R. C., Dickson, D. W., Knopman, D. S., Rabinovici, G. D., Miller, B. L., González, A. S., ... Mead, S. (2016). Genetic risk factors for the posterior cortical atrophy variant of Alzheimer's disease. Alzheimer's and Dementia, 12(8), 862-871. https://doi.org/10.1016/j.jalz.2016.01.010