Alzheimer's disease-associated (hydroxy)methylomic changes in the brain and blood

Roy Lardenoije; Janou A.Y. Roubroeks; Ehsan Pishva; Markus Leber; Holger Wagner; Artemis Iatrou; Adam R. Smith; Rebecca G. Smith; Lars M.T. Eijssen; Luca Kleineidam; Amit Kawalia; Per Hoffmann; Tobias Luck; Steffi Riedel-Heller; Frank Jessen; Wolfgang Maier; Michael Wagner; René Hurlemann; Gunter Kenis; Muhammad Ali; Antonio Del Sol; Diego Mastroeni; Elaine Delvaux; Paul D. Coleman; Jonathan Mill; Bart P.F. Rutten; Katie Lunnon; Alfredo Ramirez; Daniël L.A. Van Den Hove

doi:10.1186/s13148-019-0755-5

Alzheimer's disease-associated (hydroxy)methylomic changes in the brain and blood

Roy Lardenoije, Janou A.Y. Roubroeks, Ehsan Pishva, Markus Leber, Holger Wagner, Artemis Iatrou, Adam R. Smith, Rebecca G. Smith, Lars M.T. Eijssen, Luca Kleineidam, Amit Kawalia, Per Hoffmann, Tobias Luck, Steffi Riedel-Heller, Frank Jessen, Wolfgang Maier, Michael Wagner, René Hurlemann, Gunter Kenis, Muhammad AliAntonio Del Sol, Diego Mastroeni, Elaine Delvaux, Paul D. Coleman, Jonathan Mill, Bart P.F. Rutten, Katie Lunnon, Alfredo Ramirez, Daniël L.A. Van Den Hove^*

^*Corresponding author for this work

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

74 Citations (Scopus)

Abstract

Background: Late-onset Alzheimer's disease (AD) is a complex multifactorial affliction, the pathogenesis of which is thought to involve gene-environment interactions that might be captured in the epigenome. The present study investigated epigenome-wide patterns of DNA methylation (5-methylcytosine, 5mC) and hydroxymethylation (5-hydroxymethylcytosine, 5hmC), as well as the abundance of unmodified cytosine (UC), in relation to AD. Results: We identified epigenetic differences in AD patients (n = 45) as compared to age-matched controls (n = 35) in the middle temporal gyrus, pertaining to genomic regions close to or overlapping with genes such as OXT (- 3.76% 5mC, p _Šidák = 1.07E-06), CHRNB1 (+ 1.46% 5hmC, p _Šidák = 4.01E-04), RHBDF2 (- 3.45% UC, p _Šidák = 4.85E-06), and C3 (- 1.20% UC, p _Šidák = 1.57E-03). In parallel, in an independent cohort, we compared the blood methylome of converters to AD dementia (n = 54) and non-converters (n = 42), at a preclinical stage. DNA methylation in the same region of the OXT promoter as found in the brain was found to be associated with subsequent conversion to AD dementia in the blood of elderly, non-demented individuals (+ 3.43% 5mC, p _Šidák = 7.14E-04). Conclusions: The implication of genome-wide significant differential methylation of OXT, encoding oxytocin, in two independent cohorts indicates it is a promising target for future studies on early biomarkers and novel therapeutic strategies in AD.

Original language	English
Article number	164
Journal	Clinical Epigenetics
Volume	11
Issue number	1
DOIs	https://doi.org/10.1186/s13148-019-0755-5
Publication status	Published - 27 Nov 2019

Keywords

Alzheimer's disease
Blood
Brain
DNA hydroxymethylation
DNA methylation
Epigenetics
Middle temporal gyrus

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10.1186/s13148-019-0755-5

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Lardenoije, R., Roubroeks, J. A. Y., Pishva, E., Leber, M., Wagner, H., Iatrou, A., Smith, A. R., Smith, R. G., Eijssen, L. M. T., Kleineidam, L., Kawalia, A., Hoffmann, P., Luck, T., Riedel-Heller, S., Jessen, F., Maier, W., Wagner, M., Hurlemann, R., Kenis, G., ... Van Den Hove, D. L. A. (2019). Alzheimer's disease-associated (hydroxy)methylomic changes in the brain and blood. Clinical Epigenetics, 11(1), Article 164. https://doi.org/10.1186/s13148-019-0755-5

@article{e1f794c8894b4b9eb87b134d05261a8f,

title = "Alzheimer's disease-associated (hydroxy)methylomic changes in the brain and blood",

abstract = "Background: Late-onset Alzheimer's disease (AD) is a complex multifactorial affliction, the pathogenesis of which is thought to involve gene-environment interactions that might be captured in the epigenome. The present study investigated epigenome-wide patterns of DNA methylation (5-methylcytosine, 5mC) and hydroxymethylation (5-hydroxymethylcytosine, 5hmC), as well as the abundance of unmodified cytosine (UC), in relation to AD. Results: We identified epigenetic differences in AD patients (n = 45) as compared to age-matched controls (n = 35) in the middle temporal gyrus, pertaining to genomic regions close to or overlapping with genes such as OXT (- 3.76% 5mC, p {\v S}id{\'a}k = 1.07E-06), CHRNB1 (+ 1.46% 5hmC, p {\v S}id{\'a}k = 4.01E-04), RHBDF2 (- 3.45% UC, p {\v S}id{\'a}k = 4.85E-06), and C3 (- 1.20% UC, p {\v S}id{\'a}k = 1.57E-03). In parallel, in an independent cohort, we compared the blood methylome of converters to AD dementia (n = 54) and non-converters (n = 42), at a preclinical stage. DNA methylation in the same region of the OXT promoter as found in the brain was found to be associated with subsequent conversion to AD dementia in the blood of elderly, non-demented individuals (+ 3.43% 5mC, p {\v S}id{\'a}k = 7.14E-04). Conclusions: The implication of genome-wide significant differential methylation of OXT, encoding oxytocin, in two independent cohorts indicates it is a promising target for future studies on early biomarkers and novel therapeutic strategies in AD.",

keywords = "Alzheimer's disease, Blood, Brain, DNA hydroxymethylation, DNA methylation, Epigenetics, Middle temporal gyrus",

author = "Roy Lardenoije and Roubroeks, {Janou A.Y.} and Ehsan Pishva and Markus Leber and Holger Wagner and Artemis Iatrou and Smith, {Adam R.} and Smith, {Rebecca G.} and Eijssen, {Lars M.T.} and Luca Kleineidam and Amit Kawalia and Per Hoffmann and Tobias Luck and Steffi Riedel-Heller and Frank Jessen and Wolfgang Maier and Michael Wagner and Ren{\'e} Hurlemann and Gunter Kenis and Muhammad Ali and {Del Sol}, Antonio and Diego Mastroeni and Elaine Delvaux and Coleman, {Paul D.} and Jonathan Mill and Rutten, {Bart P.F.} and Katie Lunnon and Alfredo Ramirez and {Van Den Hove}, {Dani{\"e}l L.A.}",

year = "2019",

month = nov,

day = "27",

doi = "10.1186/s13148-019-0755-5",

language = "English",

volume = "11",

journal = "Clinical Epigenetics",

issn = "1868-7075",

publisher = "Springer Verlag",

number = "1",

}

Lardenoije, R, Roubroeks, JAY, Pishva, E, Leber, M, Wagner, H, Iatrou, A, Smith, AR, Smith, RG, Eijssen, LMT, Kleineidam, L, Kawalia, A, Hoffmann, P, Luck, T, Riedel-Heller, S, Jessen, F, Maier, W, Wagner, M, Hurlemann, R, Kenis, G, Ali, M, Del Sol, A, Mastroeni, D, Delvaux, E, Coleman, PD, Mill, J, Rutten, BPF, Lunnon, K, Ramirez, A & Van Den Hove, DLA 2019, 'Alzheimer's disease-associated (hydroxy)methylomic changes in the brain and blood', Clinical Epigenetics, vol. 11, no. 1, 164. https://doi.org/10.1186/s13148-019-0755-5

TY - JOUR

T1 - Alzheimer's disease-associated (hydroxy)methylomic changes in the brain and blood

AU - Lardenoije, Roy

AU - Roubroeks, Janou A.Y.

AU - Pishva, Ehsan

AU - Leber, Markus

AU - Wagner, Holger

AU - Iatrou, Artemis

AU - Smith, Adam R.

AU - Smith, Rebecca G.

AU - Eijssen, Lars M.T.

AU - Kleineidam, Luca

AU - Kawalia, Amit

AU - Hoffmann, Per

AU - Luck, Tobias

AU - Riedel-Heller, Steffi

AU - Jessen, Frank

AU - Maier, Wolfgang

AU - Wagner, Michael

AU - Hurlemann, René

AU - Kenis, Gunter

AU - Ali, Muhammad

AU - Del Sol, Antonio

AU - Mastroeni, Diego

AU - Delvaux, Elaine

AU - Coleman, Paul D.

AU - Mill, Jonathan

AU - Rutten, Bart P.F.

AU - Lunnon, Katie

AU - Ramirez, Alfredo

AU - Van Den Hove, Daniël L.A.

PY - 2019/11/27

Y1 - 2019/11/27

N2 - Background: Late-onset Alzheimer's disease (AD) is a complex multifactorial affliction, the pathogenesis of which is thought to involve gene-environment interactions that might be captured in the epigenome. The present study investigated epigenome-wide patterns of DNA methylation (5-methylcytosine, 5mC) and hydroxymethylation (5-hydroxymethylcytosine, 5hmC), as well as the abundance of unmodified cytosine (UC), in relation to AD. Results: We identified epigenetic differences in AD patients (n = 45) as compared to age-matched controls (n = 35) in the middle temporal gyrus, pertaining to genomic regions close to or overlapping with genes such as OXT (- 3.76% 5mC, p Šidák = 1.07E-06), CHRNB1 (+ 1.46% 5hmC, p Šidák = 4.01E-04), RHBDF2 (- 3.45% UC, p Šidák = 4.85E-06), and C3 (- 1.20% UC, p Šidák = 1.57E-03). In parallel, in an independent cohort, we compared the blood methylome of converters to AD dementia (n = 54) and non-converters (n = 42), at a preclinical stage. DNA methylation in the same region of the OXT promoter as found in the brain was found to be associated with subsequent conversion to AD dementia in the blood of elderly, non-demented individuals (+ 3.43% 5mC, p Šidák = 7.14E-04). Conclusions: The implication of genome-wide significant differential methylation of OXT, encoding oxytocin, in two independent cohorts indicates it is a promising target for future studies on early biomarkers and novel therapeutic strategies in AD.

AB - Background: Late-onset Alzheimer's disease (AD) is a complex multifactorial affliction, the pathogenesis of which is thought to involve gene-environment interactions that might be captured in the epigenome. The present study investigated epigenome-wide patterns of DNA methylation (5-methylcytosine, 5mC) and hydroxymethylation (5-hydroxymethylcytosine, 5hmC), as well as the abundance of unmodified cytosine (UC), in relation to AD. Results: We identified epigenetic differences in AD patients (n = 45) as compared to age-matched controls (n = 35) in the middle temporal gyrus, pertaining to genomic regions close to or overlapping with genes such as OXT (- 3.76% 5mC, p Šidák = 1.07E-06), CHRNB1 (+ 1.46% 5hmC, p Šidák = 4.01E-04), RHBDF2 (- 3.45% UC, p Šidák = 4.85E-06), and C3 (- 1.20% UC, p Šidák = 1.57E-03). In parallel, in an independent cohort, we compared the blood methylome of converters to AD dementia (n = 54) and non-converters (n = 42), at a preclinical stage. DNA methylation in the same region of the OXT promoter as found in the brain was found to be associated with subsequent conversion to AD dementia in the blood of elderly, non-demented individuals (+ 3.43% 5mC, p Šidák = 7.14E-04). Conclusions: The implication of genome-wide significant differential methylation of OXT, encoding oxytocin, in two independent cohorts indicates it is a promising target for future studies on early biomarkers and novel therapeutic strategies in AD.

KW - Alzheimer's disease

KW - Blood

KW - Brain

KW - DNA hydroxymethylation

KW - DNA methylation

KW - Epigenetics

KW - Middle temporal gyrus

UR - http://www.scopus.com/inward/record.url?scp=85075776519&partnerID=8YFLogxK

U2 - 10.1186/s13148-019-0755-5

DO - 10.1186/s13148-019-0755-5

M3 - Article

C2 - 31775875

AN - SCOPUS:85075776519

SN - 1868-7075

VL - 11

JO - Clinical Epigenetics

JF - Clinical Epigenetics

IS - 1

M1 - 164

ER -

Alzheimer's disease-associated (hydroxy)methylomic changes in the brain and blood

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