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 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 Petersen, Dennis W. Dickson, D. S. Knopman, Gil D. Rabinovici, Bruce Miller, Aida Suárez González, Eulogio Gil-NécigaJulie S. Snowden, Jenny Harris, Stuart Pickering-Brown, Eva Louwersheimer, Wiesje Van Der Flier, Philip Scheltens, Yolande A L Pijnenburg, Douglas Galasko, Marie Sarazin, Bruno Dubois, Eloi Magnin, Daniela Galimberti, Elio Angelo Scarpini, Stefano Cappa, John R. Hodges, Glenda M. Halliday, Lauren Bartley, Maria Carrillo, Jose T. Bras, J. Hardy, Martin N. Rossor, J. 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

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Atrophy
Alzheimer Disease
Odds Ratio
Genome-Wide Association Study

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

Cite this

Schott, J. M., Crutch, S. J., Carrasquillo, M. M., Uphill, J., Shakespeare, T., Ryan, N. 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

Genetic risk factors for the posterior cortical atrophy variant of Alzheimer's disease. / Schott, Jonathan M.; Crutch, Sebastian J.; Carrasquillo, Minerva M.; Uphill, James; Shakespeare, Tim; Ryan, Natalie S.; Yong, Keir X.; Lehmann, Manja; Ertekin-Taner, Nilufer; Graff-Radford, Neill R.; Boeve, Bradley F.; Murray, Melissa E.; Khan, Qurat ul Ain; Petersen, Ronald; Dickson, Dennis W.; Knopman, D. S.; Rabinovici, Gil D.; Miller, Bruce; González, Aida Suárez; Gil-Néciga, Eulogio; Snowden, Julie S.; Harris, Jenny; Pickering-Brown, Stuart; Louwersheimer, Eva; Van Der Flier, Wiesje; Scheltens, Philip; Pijnenburg, Yolande A L; Galasko, Douglas; Sarazin, Marie; Dubois, Bruno; Magnin, Eloi; Galimberti, Daniela; Scarpini, Elio Angelo; Cappa, Stefano; Hodges, John R.; Halliday, Glenda M.; Bartley, Lauren; Carrillo, Maria; Bras, Jose T.; Hardy, J.; Rossor, Martin N.; Collinge, J.; Fox, Nick C.; Mead, Simon.

In: Alzheimer's and Dementia, Vol. 12, No. 8, 01.08.2016, p. 862-871.

Research output: Contribution to journalArticle

Schott, JM, Crutch, SJ, Carrasquillo, MM, Uphill, J, Shakespeare, T, Ryan, NS, Yong, KX, Lehmann, M, Ertekin-Taner, N, Graff-Radford, NR, Boeve, BF, Murray, ME, Khan, QUA, Petersen, R, Dickson, DW, Knopman, DS, Rabinovici, GD, Miller, B, González, AS, Gil-Néciga, E, Snowden, JS, Harris, J, Pickering-Brown, S, Louwersheimer, E, Van Der Flier, W, Scheltens, P, Pijnenburg, YAL, Galasko, D, Sarazin, M, Dubois, B, Magnin, E, Galimberti, D, Scarpini, EA, Cappa, S, Hodges, JR, Halliday, GM, Bartley, L, Carrillo, M, Bras, JT, Hardy, J, Rossor, MN, Collinge, J, Fox, NC & Mead, S 2016, 'Genetic risk factors for the posterior cortical atrophy variant of Alzheimer's disease', Alzheimer's and Dementia, vol. 12, no. 8, pp. 862-871. https://doi.org/10.1016/j.jalz.2016.01.010
Schott JM, Crutch SJ, Carrasquillo MM, Uphill J, Shakespeare T, Ryan NS et al. Genetic risk factors for the posterior cortical atrophy variant of Alzheimer's disease. Alzheimer's and Dementia. 2016 Aug 1;12(8):862-871. https://doi.org/10.1016/j.jalz.2016.01.010
Schott, Jonathan M. ; Crutch, Sebastian J. ; Carrasquillo, Minerva M. ; Uphill, James ; Shakespeare, Tim ; Ryan, Natalie S. ; Yong, Keir X. ; Lehmann, Manja ; Ertekin-Taner, Nilufer ; Graff-Radford, Neill R. ; Boeve, Bradley F. ; Murray, Melissa E. ; Khan, Qurat ul Ain ; Petersen, Ronald ; Dickson, Dennis W. ; Knopman, D. S. ; Rabinovici, Gil D. ; Miller, Bruce ; González, Aida Suárez ; Gil-Néciga, Eulogio ; Snowden, Julie S. ; Harris, Jenny ; Pickering-Brown, Stuart ; Louwersheimer, Eva ; Van Der Flier, Wiesje ; Scheltens, Philip ; Pijnenburg, Yolande A L ; Galasko, Douglas ; Sarazin, Marie ; Dubois, Bruno ; Magnin, Eloi ; Galimberti, Daniela ; Scarpini, Elio Angelo ; Cappa, Stefano ; Hodges, John R. ; Halliday, Glenda M. ; Bartley, Lauren ; Carrillo, Maria ; Bras, Jose T. ; Hardy, J. ; Rossor, Martin N. ; Collinge, J. ; Fox, Nick C. ; Mead, Simon. / Genetic risk factors for the posterior cortical atrophy variant of Alzheimer's disease. In: Alzheimer's and Dementia. 2016 ; Vol. 12, No. 8. pp. 862-871.
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AU - Shakespeare, Tim

AU - Ryan, Natalie S.

AU - Yong, Keir X.

AU - Lehmann, Manja

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AU - Graff-Radford, Neill R.

AU - Boeve, Bradley F.

AU - Murray, Melissa E.

AU - Khan, Qurat ul Ain

AU - Petersen, Ronald

AU - Dickson, Dennis W.

AU - Knopman, D. S.

AU - Rabinovici, Gil D.

AU - Miller, Bruce

AU - González, Aida Suárez

AU - Gil-Néciga, Eulogio

AU - Snowden, Julie S.

AU - Harris, Jenny

AU - Pickering-Brown, Stuart

AU - Louwersheimer, Eva

AU - Van Der Flier, Wiesje

AU - Scheltens, Philip

AU - Pijnenburg, Yolande A L

AU - Galasko, Douglas

AU - Sarazin, Marie

AU - Dubois, Bruno

AU - Magnin, Eloi

AU - Galimberti, Daniela

AU - Scarpini, Elio Angelo

AU - Cappa, Stefano

AU - Hodges, John R.

AU - Halliday, Glenda M.

AU - Bartley, Lauren

AU - Carrillo, Maria

AU - Bras, Jose T.

AU - Hardy, J.

AU - Rossor, Martin N.

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AU - Fox, Nick C.

AU - Mead, Simon

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AB - 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.

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KW - APOE

KW - Genetics

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KW - Posterior cortical atrophy

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