Elevated DNA methylation across a 48-kb region spanning the HOXA gene cluster is associated with Alzheimer's disease neuropathology

Rebecca G. Smith; Eilis Hannon; Philip L. De Jager; Lori Chibnik; Simon J. Lott; Daniel Condliffe; Adam R. Smith; Vahram Haroutunian; Claire Troakes; Safa Al-Sarraj; David A. Bennett; John Powell; Simon Lovestone; Leonard Schalkwyk; Jonathan Mill; Katie Lunnon

doi:10.1016/j.jalz.2018.01.017

Elevated DNA methylation across a 48-kb region spanning the HOXA gene cluster is associated with Alzheimer's disease neuropathology

Rebecca G. Smith
, Eilis Hannon
, Philip L. De Jager
, Lori Chibnik
, Simon J. Lott
, Daniel Condliffe
, Adam R. Smith
, Vahram Haroutunian
, Claire Troakes
, Safa Al-Sarraj
, David A. Bennett
, John Powell
, Simon Lovestone
, Leonard Schalkwyk
, Jonathan Mill
, Katie Lunnon

Research output: Contribution to journal › Article › peer-review

146 Scopus citations

Abstract

Introduction: Alzheimer's disease is a neurodegenerative disorder that is hypothesized to involve epigenetic dysregulation of gene expression in the brain. Methods: We performed an epigenome-wide association study to identify differential DNA methylation associated with neuropathology in prefrontal cortex and superior temporal gyrus samples from 147 individuals, replicating our findings in two independent data sets (N = 117 and 740). Results: We identify elevated DNA methylation associated with neuropathology across a 48-kb region spanning 208 CpG sites within the HOXA gene cluster. A meta-analysis of the top-ranked probe within the HOXA3 gene (cg22962123) highlighted significant hypermethylation across all three cohorts (P = 3.11 × 10 ⁻¹⁸ ). Discussion: We present robust evidence for elevated DNA methylation associated with Alzheimer's disease neuropathology spanning the HOXA gene cluster on chromosome 7. These data add to the growing evidence highlighting a role for epigenetic variation in Alzheimer's disease, implicating the HOX gene family as a target for future investigation.

Original language	English
Pages (from-to)	1580-1588
Number of pages	9
Journal	Alzheimer's and Dementia
Volume	14
Issue number	12
DOIs	https://doi.org/10.1016/j.jalz.2018.01.017
State	Published - Dec 2018

Keywords

Alzheimer's disease (AD)
Braak stage
DNA methylation
Epigenetics
Epigenome-wide association study (EWAS)
HOXA
Illumina Infinium 450K BeadChip (450K array)
Meta-analysis
Neuropathology
Prefrontal cortex (PFC)
Superior temporal gyrus (STG)

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Smith, R. G., Hannon, E., De Jager, P. L., Chibnik, L., Lott, S. J., Condliffe, D., Smith, A. R., Haroutunian, V., Troakes, C., Al-Sarraj, S., Bennett, D. A., Powell, J., Lovestone, S., Schalkwyk, L., Mill, J., & Lunnon, K. (2018). Elevated DNA methylation across a 48-kb region spanning the HOXA gene cluster is associated with Alzheimer's disease neuropathology. Alzheimer's and Dementia, 14(12), 1580-1588. https://doi.org/10.1016/j.jalz.2018.01.017

@article{16b9eac9c34c453889676be4c2bc9294,

title = "Elevated DNA methylation across a 48-kb region spanning the HOXA gene cluster is associated with Alzheimer's disease neuropathology",

abstract = " Introduction: Alzheimer's disease is a neurodegenerative disorder that is hypothesized to involve epigenetic dysregulation of gene expression in the brain. Methods: We performed an epigenome-wide association study to identify differential DNA methylation associated with neuropathology in prefrontal cortex and superior temporal gyrus samples from 147 individuals, replicating our findings in two independent data sets (N = 117 and 740). Results: We identify elevated DNA methylation associated with neuropathology across a 48-kb region spanning 208 CpG sites within the HOXA gene cluster. A meta-analysis of the top-ranked probe within the HOXA3 gene (cg22962123) highlighted significant hypermethylation across all three cohorts (P = 3.11 × 10 −18 ). Discussion: We present robust evidence for elevated DNA methylation associated with Alzheimer's disease neuropathology spanning the HOXA gene cluster on chromosome 7. These data add to the growing evidence highlighting a role for epigenetic variation in Alzheimer's disease, implicating the HOX gene family as a target for future investigation.",

keywords = "Alzheimer's disease (AD), Braak stage, DNA methylation, Epigenetics, Epigenome-wide association study (EWAS), HOXA, Illumina Infinium 450K BeadChip (450K array), Meta-analysis, Neuropathology, Prefrontal cortex (PFC), Superior temporal gyrus (STG)",

author = "Smith, \{Rebecca G.\} and Eilis Hannon and \{De Jager\}, \{Philip L.\} and Lori Chibnik and Lott, \{Simon J.\} and Daniel Condliffe and Smith, \{Adam R.\} and Vahram Haroutunian and Claire Troakes and Safa Al-Sarraj and Bennett, \{David A.\} and John Powell and Simon Lovestone and Leonard Schalkwyk and Jonathan Mill and Katie Lunnon",

note = "Publisher Copyright: {\textcopyright} 2018 The Authors",

year = "2018",

month = dec,

doi = "10.1016/j.jalz.2018.01.017",

language = "English",

volume = "14",

pages = "1580--1588",

journal = "Alzheimer's and Dementia",

issn = "1552-5260",

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Smith, RG, Hannon, E, De Jager, PL, Chibnik, L, Lott, SJ, Condliffe, D, Smith, AR, Haroutunian, V, Troakes, C, Al-Sarraj, S, Bennett, DA, Powell, J, Lovestone, S, Schalkwyk, L, Mill, J & Lunnon, K 2018, 'Elevated DNA methylation across a 48-kb region spanning the HOXA gene cluster is associated with Alzheimer's disease neuropathology', Alzheimer's and Dementia, vol. 14, no. 12, pp. 1580-1588. https://doi.org/10.1016/j.jalz.2018.01.017

TY - JOUR

T1 - Elevated DNA methylation across a 48-kb region spanning the HOXA gene cluster is associated with Alzheimer's disease neuropathology

AU - Smith, Rebecca G.

AU - Hannon, Eilis

AU - De Jager, Philip L.

AU - Chibnik, Lori

AU - Lott, Simon J.

AU - Condliffe, Daniel

AU - Smith, Adam R.

AU - Haroutunian, Vahram

AU - Troakes, Claire

AU - Al-Sarraj, Safa

AU - Bennett, David A.

AU - Powell, John

AU - Lovestone, Simon

AU - Schalkwyk, Leonard

AU - Mill, Jonathan

AU - Lunnon, Katie

PY - 2018/12

Y1 - 2018/12

N2 - Introduction: Alzheimer's disease is a neurodegenerative disorder that is hypothesized to involve epigenetic dysregulation of gene expression in the brain. Methods: We performed an epigenome-wide association study to identify differential DNA methylation associated with neuropathology in prefrontal cortex and superior temporal gyrus samples from 147 individuals, replicating our findings in two independent data sets (N = 117 and 740). Results: We identify elevated DNA methylation associated with neuropathology across a 48-kb region spanning 208 CpG sites within the HOXA gene cluster. A meta-analysis of the top-ranked probe within the HOXA3 gene (cg22962123) highlighted significant hypermethylation across all three cohorts (P = 3.11 × 10 −18 ). Discussion: We present robust evidence for elevated DNA methylation associated with Alzheimer's disease neuropathology spanning the HOXA gene cluster on chromosome 7. These data add to the growing evidence highlighting a role for epigenetic variation in Alzheimer's disease, implicating the HOX gene family as a target for future investigation.

AB - Introduction: Alzheimer's disease is a neurodegenerative disorder that is hypothesized to involve epigenetic dysregulation of gene expression in the brain. Methods: We performed an epigenome-wide association study to identify differential DNA methylation associated with neuropathology in prefrontal cortex and superior temporal gyrus samples from 147 individuals, replicating our findings in two independent data sets (N = 117 and 740). Results: We identify elevated DNA methylation associated with neuropathology across a 48-kb region spanning 208 CpG sites within the HOXA gene cluster. A meta-analysis of the top-ranked probe within the HOXA3 gene (cg22962123) highlighted significant hypermethylation across all three cohorts (P = 3.11 × 10 −18 ). Discussion: We present robust evidence for elevated DNA methylation associated with Alzheimer's disease neuropathology spanning the HOXA gene cluster on chromosome 7. These data add to the growing evidence highlighting a role for epigenetic variation in Alzheimer's disease, implicating the HOX gene family as a target for future investigation.

KW - Alzheimer's disease (AD)

KW - Braak stage

KW - DNA methylation

KW - Epigenetics

KW - Epigenome-wide association study (EWAS)

KW - HOXA

KW - Illumina Infinium 450K BeadChip (450K array)

KW - Meta-analysis

KW - Neuropathology

KW - Prefrontal cortex (PFC)

KW - Superior temporal gyrus (STG)

UR - https://www.scopus.com/pages/publications/85049686390

U2 - 10.1016/j.jalz.2018.01.017

DO - 10.1016/j.jalz.2018.01.017

M3 - Article

C2 - 29550519

AN - SCOPUS:85049686390

SN - 1552-5260

VL - 14

SP - 1580

EP - 1588

JO - Alzheimer's and Dementia

JF - Alzheimer's and Dementia

IS - 12

ER -

Elevated DNA methylation across a 48-kb region spanning the HOXA gene cluster is associated with Alzheimer's disease neuropathology

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Keywords

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