A meta-analysis of epigenome-wide association studies in Alzheimer’s disease highlights novel differentially methylated loci across cortex

Rebecca G. Smith; Ehsan Pishva; Gemma Shireby; Adam R. Smith; Janou A.Y. Roubroeks; Eilis Hannon; Gregory Wheildon; Diego Mastroeni; Gilles Gasparoni; Matthias Riemenschneider; Armin Giese; Andrew J. Sharp; Leonard Schalkwyk; Vahram Haroutunian; Wolfgang Viechtbauer; Daniel L.A. van den Hove; Michael Weedon; Danielle Brokaw; Paul T. Francis; Alan J. Thomas; Seth Love; Kevin Morgan; Jörn Walter; Paul D. Coleman; David A. Bennett; Philip L. De Jager; Jonathan Mill; Katie Lunnon

doi:10.1038/s41467-021-23243-4

A meta-analysis of epigenome-wide association studies in Alzheimer’s disease highlights novel differentially methylated loci across cortex

Rebecca G. Smith, Ehsan Pishva, Gemma Shireby, Adam R. Smith, Janou A.Y. Roubroeks, Eilis Hannon, Gregory Wheildon, Diego Mastroeni, Gilles Gasparoni, Matthias Riemenschneider, Armin Giese, Andrew J. Sharp, Leonard Schalkwyk, Vahram Haroutunian, Wolfgang Viechtbauer, Daniel L.A. van den Hove, Michael Weedon, Danielle Brokaw, Paul T. Francis, Alan J. ThomasSeth Love, Kevin Morgan, Jörn Walter, Paul D. Coleman, David A. Bennett, Philip L. De Jager, Jonathan Mill, Katie Lunnon

ASU-Banner Neurodegenerative Disease Research Center (NDRC)

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

38 Scopus citations

Abstract

Epigenome-wide association studies of Alzheimer’s disease have highlighted neuropathology-associated DNA methylation differences, although existing studies have been limited in sample size and utilized different brain regions. Here, we combine data from six DNA methylomic studies of Alzheimer’s disease (N = 1453 unique individuals) to identify differential methylation associated with Braak stage in different brain regions and across cortex. We identify 236 CpGs in the prefrontal cortex, 95 CpGs in the temporal gyrus and ten CpGs in the entorhinal cortex at Bonferroni significance, with none in the cerebellum. Our cross-cortex meta-analysis (N = 1408 donors) identifies 220 CpGs associated with neuropathology, annotated to 121 genes, of which 84 genes have not been previously reported at this significance threshold. We have replicated our findings using two further DNA methylomic datasets consisting of a further >600 unique donors. The meta-analysis summary statistics are available in our online data resource (www.epigenomicslab.com/ad-meta-analysis/).

Original language	English (US)
Article number	3517
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-23243-4
State	Published - Dec 1 2021

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
General
Physics and Astronomy(all)

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Smith, R. G., Pishva, E., Shireby, G., Smith, A. R., Roubroeks, J. A. Y., Hannon, E., Wheildon, G., Mastroeni, D., Gasparoni, G., Riemenschneider, M., Giese, A., Sharp, A. J., Schalkwyk, L., Haroutunian, V., Viechtbauer, W., van den Hove, D. L. A., Weedon, M., Brokaw, D., Francis, P. T., ... Lunnon, K. (2021). A meta-analysis of epigenome-wide association studies in Alzheimer’s disease highlights novel differentially methylated loci across cortex. Nature communications, 12(1), Article 3517. https://doi.org/10.1038/s41467-021-23243-4

Smith, RG, Pishva, E, Shireby, G, Smith, AR, Roubroeks, JAY, Hannon, E, Wheildon, G, Mastroeni, D, Gasparoni, G, Riemenschneider, M, Giese, A, Sharp, AJ, Schalkwyk, L, Haroutunian, V, Viechtbauer, W, van den Hove, DLA, Weedon, M, Brokaw, D, Francis, PT, Thomas, AJ, Love, S, Morgan, K, Walter, J, Coleman, PD, Bennett, DA, De Jager, PL, Mill, J & Lunnon, K 2021, 'A meta-analysis of epigenome-wide association studies in Alzheimer’s disease highlights novel differentially methylated loci across cortex', Nature communications, vol. 12, no. 1, 3517. https://doi.org/10.1038/s41467-021-23243-4

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title = "A meta-analysis of epigenome-wide association studies in Alzheimer{\textquoteright}s disease highlights novel differentially methylated loci across cortex",

abstract = "Epigenome-wide association studies of Alzheimer{\textquoteright}s disease have highlighted neuropathology-associated DNA methylation differences, although existing studies have been limited in sample size and utilized different brain regions. Here, we combine data from six DNA methylomic studies of Alzheimer{\textquoteright}s disease (N = 1453 unique individuals) to identify differential methylation associated with Braak stage in different brain regions and across cortex. We identify 236 CpGs in the prefrontal cortex, 95 CpGs in the temporal gyrus and ten CpGs in the entorhinal cortex at Bonferroni significance, with none in the cerebellum. Our cross-cortex meta-analysis (N = 1408 donors) identifies 220 CpGs associated with neuropathology, annotated to 121 genes, of which 84 genes have not been previously reported at this significance threshold. We have replicated our findings using two further DNA methylomic datasets consisting of a further >600 unique donors. The meta-analysis summary statistics are available in our online data resource (www.epigenomicslab.com/ad-meta-analysis/).",

author = "Smith, {Rebecca G.} and Ehsan Pishva and Gemma Shireby and Smith, {Adam R.} and Roubroeks, {Janou A.Y.} and Eilis Hannon and Gregory Wheildon and Diego Mastroeni and Gilles Gasparoni and Matthias Riemenschneider and Armin Giese and Sharp, {Andrew J.} and Leonard Schalkwyk and Vahram Haroutunian and Wolfgang Viechtbauer and {van den Hove}, {Daniel L.A.} and Michael Weedon and Danielle Brokaw and Francis, {Paul T.} and Thomas, {Alan J.} and Seth Love and Kevin Morgan and J{\"o}rn Walter and Coleman, {Paul D.} and Bennett, {David A.} and {De Jager}, {Philip L.} and Jonathan Mill and Katie Lunnon",

note = "Funding Information: This work was funded by a major project grant from the Alzheimer{\textquoteright}s Society UK (AS-PG-14-038) to K.L., an Alzheimer{\textquoteright}s Association US New Investigator Research Grant (NIRG-14-320878) to K.L. and a project grant from the Medical Research Council (MRC) (MR/N027973/1) to K.L. as part of a larger collaborative project funded to K.L. and D.L.A.v.d.H. for the EPI-AD consortium through the Joint Programme—Neurodegenerative Disease Research (JPND) initiative. This work was also supported through a ZonMw Memorabel Grant (733050516) to E.P. Data analysis was undertaken using high-performance computing supported by a Medical Research Council (MRC) Clinical Infrastructure Award (M008924) to J.M. The project was also supported through PhD studentships from the Alzheimer{\textquoteright}s Society (G.S.), BRACE (Bristol Research into Alzheimer{\textquoteright}s and Care of the Elderly) (G.W.) and the MRC GW4 Doctoral Training Program (DTP) (J.A.Y.R.). BDR is jointly funded by Alzheimer{\textquoteright}s Research UK and the Alzheimer{\textquoteright}s Society in association with the MRC. DNA methylation data generated in the Brains for Dementia Research cohort was supported by the Alzheimer{\textquoteright}s Society and Alzheimer{\textquoteright}s Research UK (ARUK). Research reported in this publication was also supported by the National Institute of Aging of the National Institutes of Health under award numbers P30AG19610, P30AG10161, R01AG15819, R01AG17917, R01AG36042, R01AG036039, R01AG036400 and R01AG067015. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We thank the donors and families who have made this research possible. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

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doi = "10.1038/s41467-021-23243-4",

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T1 - A meta-analysis of epigenome-wide association studies in Alzheimer’s disease highlights novel differentially methylated loci across cortex

AU - Smith, Rebecca G.

AU - Pishva, Ehsan

AU - Shireby, Gemma

AU - Smith, Adam R.

AU - Roubroeks, Janou A.Y.

AU - Hannon, Eilis

AU - Wheildon, Gregory

AU - Mastroeni, Diego

AU - Gasparoni, Gilles

AU - Riemenschneider, Matthias

AU - Giese, Armin

AU - Sharp, Andrew J.

AU - Schalkwyk, Leonard

AU - Haroutunian, Vahram

AU - Viechtbauer, Wolfgang

AU - van den Hove, Daniel L.A.

AU - Weedon, Michael

AU - Brokaw, Danielle

AU - Francis, Paul T.

AU - Thomas, Alan J.

AU - Love, Seth

AU - Morgan, Kevin

AU - Walter, Jörn

AU - Coleman, Paul D.

AU - Bennett, David A.

AU - De Jager, Philip L.

AU - Mill, Jonathan

AU - Lunnon, Katie

N1 - Funding Information: This work was funded by a major project grant from the Alzheimer’s Society UK (AS-PG-14-038) to K.L., an Alzheimer’s Association US New Investigator Research Grant (NIRG-14-320878) to K.L. and a project grant from the Medical Research Council (MRC) (MR/N027973/1) to K.L. as part of a larger collaborative project funded to K.L. and D.L.A.v.d.H. for the EPI-AD consortium through the Joint Programme—Neurodegenerative Disease Research (JPND) initiative. This work was also supported through a ZonMw Memorabel Grant (733050516) to E.P. Data analysis was undertaken using high-performance computing supported by a Medical Research Council (MRC) Clinical Infrastructure Award (M008924) to J.M. The project was also supported through PhD studentships from the Alzheimer’s Society (G.S.), BRACE (Bristol Research into Alzheimer’s and Care of the Elderly) (G.W.) and the MRC GW4 Doctoral Training Program (DTP) (J.A.Y.R.). BDR is jointly funded by Alzheimer’s Research UK and the Alzheimer’s Society in association with the MRC. DNA methylation data generated in the Brains for Dementia Research cohort was supported by the Alzheimer’s Society and Alzheimer’s Research UK (ARUK). Research reported in this publication was also supported by the National Institute of Aging of the National Institutes of Health under award numbers P30AG19610, P30AG10161, R01AG15819, R01AG17917, R01AG36042, R01AG036039, R01AG036400 and R01AG067015. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We thank the donors and families who have made this research possible. Publisher Copyright: © 2021, The Author(s).

PY - 2021/12/1

Y1 - 2021/12/1

N2 - Epigenome-wide association studies of Alzheimer’s disease have highlighted neuropathology-associated DNA methylation differences, although existing studies have been limited in sample size and utilized different brain regions. Here, we combine data from six DNA methylomic studies of Alzheimer’s disease (N = 1453 unique individuals) to identify differential methylation associated with Braak stage in different brain regions and across cortex. We identify 236 CpGs in the prefrontal cortex, 95 CpGs in the temporal gyrus and ten CpGs in the entorhinal cortex at Bonferroni significance, with none in the cerebellum. Our cross-cortex meta-analysis (N = 1408 donors) identifies 220 CpGs associated with neuropathology, annotated to 121 genes, of which 84 genes have not been previously reported at this significance threshold. We have replicated our findings using two further DNA methylomic datasets consisting of a further >600 unique donors. The meta-analysis summary statistics are available in our online data resource (www.epigenomicslab.com/ad-meta-analysis/).

AB - Epigenome-wide association studies of Alzheimer’s disease have highlighted neuropathology-associated DNA methylation differences, although existing studies have been limited in sample size and utilized different brain regions. Here, we combine data from six DNA methylomic studies of Alzheimer’s disease (N = 1453 unique individuals) to identify differential methylation associated with Braak stage in different brain regions and across cortex. We identify 236 CpGs in the prefrontal cortex, 95 CpGs in the temporal gyrus and ten CpGs in the entorhinal cortex at Bonferroni significance, with none in the cerebellum. Our cross-cortex meta-analysis (N = 1408 donors) identifies 220 CpGs associated with neuropathology, annotated to 121 genes, of which 84 genes have not been previously reported at this significance threshold. We have replicated our findings using two further DNA methylomic datasets consisting of a further >600 unique donors. The meta-analysis summary statistics are available in our online data resource (www.epigenomicslab.com/ad-meta-analysis/).

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A meta-analysis of epigenome-wide association studies in Alzheimer’s disease highlights novel differentially methylated loci across cortex

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