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-Néciga; Julie 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

doi:10.1016/j.jalz.2016.01.010

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 journal › Article › peer-review

44 Scopus citations

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 language	English (US)
Pages (from-to)	862-871
Number of pages	10
Journal	Alzheimer's and Dementia
Volume	12
Issue number	8
DOIs	https://doi.org/10.1016/j.jalz.2016.01.010
State	Published - Aug 1 2016

Keywords

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

ASJC Scopus subject areas

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

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10.1016/j.jalz.2016.01.010

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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

Schott, JM, Crutch, SJ, Carrasquillo, MM, Uphill, J, Shakespeare, TJ, Ryan, NS, Yong, KX, Lehmann, M, Ertekin-Taner, N , Graff-Radford, NR , Boeve, BF , Murray, ME, Khan, QUA, Petersen, RC , Dickson, DW , Knopman, DS, Rabinovici, GD, Miller, BL, González, AS, Gil-Néciga, E, Snowden, JS, Harris, J, Pickering-Brown, SM, Louwersheimer, E, van der Flier, WM, Scheltens, P, Pijnenburg, YA, Galasko, D, Sarazin, M, Dubois, B, Magnin, E, Galimberti, D, Scarpini, E, Cappa, SF, Hodges, JR, Halliday, GM, Bartley, L, Carrillo, MC, 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

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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 = "Publisher Copyright: {\textcopyright} 2016 The Authors",

year = "2016",

month = aug,

day = "1",

doi = "10.1016/j.jalz.2016.01.010",

language = "English (US)",

volume = "12",

pages = "862--871",

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T1 - Genetic risk factors for the posterior cortical atrophy variant of Alzheimer's disease

AU - Schott, Jonathan M.

AU - Crutch, Sebastian J.

AU - Carrasquillo, Minerva M.

AU - Uphill, James

AU - Shakespeare, Tim J.

AU - Ryan, Natalie S.

AU - Yong, Keir X.

AU - Lehmann, Manja

AU - Ertekin-Taner, Nilufer

AU - Graff-Radford, Neill R.

AU - Boeve, Bradley F.

AU - Murray, Melissa E.

AU - Khan, Qurat ul Ain

AU - Petersen, Ronald C.

AU - Dickson, Dennis W.

AU - Knopman, David S.

AU - Rabinovici, Gil D.

AU - Miller, Bruce L.

AU - González, Aida Suárez

AU - Gil-Néciga, Eulogio

AU - Snowden, Julie S.

AU - Harris, Jenny

AU - Pickering-Brown, Stuart M.

AU - Louwersheimer, Eva

AU - van der Flier, Wiesje M.

AU - Scheltens, Philip

AU - Pijnenburg, Yolande A.

AU - Galasko, Douglas

AU - Sarazin, Marie

AU - Dubois, Bruno

AU - Magnin, Eloi

AU - Galimberti, Daniela

AU - Scarpini, Elio

AU - Cappa, Stefano F.

AU - Hodges, John R.

AU - Halliday, Glenda M.

AU - Bartley, Lauren

AU - Carrillo, Maria C.

AU - Bras, Jose T.

AU - Hardy, John

AU - Rossor, Martin N.

AU - Collinge, John

AU - Fox, Nick C.

AU - Mead, Simon

PY - 2016/8/1

Y1 - 2016/8/1

N2 - 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.

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.

KW - APOE

KW - Alzheimer's disease

KW - GWAS

KW - Genetics

KW - Posterior cortical atrophy

KW - Selective vulnerability

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SN - 1552-5260

VL - 12

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JO - Alzheimer's and Dementia

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

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Keywords

ASJC Scopus subject areas

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