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Alzheimer's disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci

Nature Neuroscience volume 17, pages 1156–1163 (2014)Cite this article

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Abstract

We used a collection of 708 prospectively collected autopsied brains to assess the methylation state of the brain's DNA in relation to Alzheimer's disease (AD). We found that the level of methylation at 71 of the 415,848 interrogated CpGs was significantly associated with the burden of AD pathology, including CpGs in the ABCA7 and BIN1 regions, which harbor known AD susceptibility variants. We validated 11 of the differentially methylated regions in an independent set of 117 subjects. Furthermore, we functionally validated these CpG associations and identified the nearby genes whose RNA expression was altered in AD: ANK1, CDH23, DIP2A, RHBDF2, RPL13, SERPINF1 and SERPINF2. Our analyses suggest that these DNA methylation changes may have a role in the onset of AD given that we observed them in presymptomatic subjects and that six of the validated genes connect to a known AD susceptibility gene network.

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Figure 1: Summary of the genome-wide brain DNA methylation scan for NP burden and its validation using independent DNA methylation data and brain RNA data.
Figure 2: Extent of differences in methylation levels at associated CpGs and regional distribution of associations.
Figure 3: Distribution of CpGs associated (P < 1.2 × 10−7) with NP among 11 chromatin states found in mid-frontal cortex.
Figure 4: Genes identified in our DNA methylation screen connect to a network of known AD susceptibility genes.

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Acknowledgements

We thank the National Institute for Health (NIHR) Biomedical Research Unit in Dementia in the South London and Maudsley NHS Foundation Trust (SLaM), Brains for Dementia Research (Alzheimer Brain Bank UK) and the donors and families who made this research possible. We also would like to thank the participants of the ROS and MAP studies for their participation in these studies. Support for this research was provided by grants from the US National Institutes of Health (R01 AG036042, R01AG036836, R01 AG17917,R01AG15819, R01 AG032990, R01 AG18023, RC2 AG036547, P30 AG10161, P50 AG016574, U01 ES017155, KL2 RR024151, K25 AG041906-01). Support was also provided by the Siragusa Foundation to N.E.-T., and the Robert and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program to N.E.-T., S.G.Y. and F.Z. This work was funded by US National Institutes of Health grant AG036039 to J.M. and an Equipment Grant from Alzheimer's Research UK.

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Authors and Affiliations

  1. Departments of Neurology and Psychiatry, Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Brigham and Women's Hospital, Boston, Massachusetts, USA

    Philip L De Jager, Gyan Srivastava, Brendan T Keenan, Anna Tang, Towfique Raj, Joseph Replogle & Lori B Chibnik

  2. Harvard Medical School, Boston, Massachusetts, USA

    Philip L De Jager, Towfique Raj, Joseph Replogle, Bradley E Bernstein & Lori B Chibnik

  3. Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA

    Philip L De Jager, Gyan Srivastava, Matthew L Eaton, Brendan T Keenan, Jason Ernst, Cristin McCabe, Towfique Raj, Joseph Replogle, Lori B Chibnik & Manolis Kellis

  4. University of Exeter Medical School, University of Exeter, Exeter, UK

    Katie Lunnon, Leonard C Schalkwyk & Jonathan Mill

  5. Institute of Psychiatry, King's College London, London, UK

    Katie Lunnon, Leonard C Schalkwyk & Jonathan Mill

  6. Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA

    Jeremy Burgess, High S Chai, Curtis Younkin, Steven G Younkin, Fanggeng Zou & Nilufer Ertekin-Taner

  7. Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA

    Jeremy Burgess, High S Chai & Nilufer Ertekin-Taner

  8. Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA

    Lei Yu, Julie A Schneider & David A Bennett

  9. Computer Science and Artificial Intelligence Laboratory (CSAIL), Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    Matthew L Eaton, Jason Ernst, Alex Meissner & Manolis Kellis

  10. Genetic Analysis Platform, Broad Institute, Cambridge, Massachusetts, USA

    Wendy Brodeur & Stacey Gabriel

  11. Department of Pharmacology and Therapeutics, McGill University, Montreal, Québec, Canada

    Moshe Szyf

  12. Epigenomics Program, Broad Institute, Cambridge, Massachusetts, USA

    Charles B Epstein, Bradley E Bernstein & Alex Meissner

  13. Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA

    Bradley E Bernstein

  14. Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA

    Alex Meissner

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  1. Philip L De Jager
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  29. David A Bennett
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Contributions

C.M., A.T., W.B., S.G., C.B.E., B.E.B., A.M. and J.A.S. collected, prepared and generated data from the samples. G.S., L.B.C., J.E., B.T.K., M.K., T.R., J.R. and L.Y. performed analyses on the resulting data. K.L., L.C.S. and J.M. generated and analyzed the replication data. N.E.-T., J.B., H.S.C., C.Y., F.Z. and S.G.Y. provided and analyzed RNA data from AD and non-AD brains. P.L.D. and D.A.B. designed the study. P.L.D., D.A.B. and L.B.C. wrote the manuscript. All of the authors critically reviewed the manuscript.

Corresponding authors

Correspondence to Philip L De Jager or David A Bennett.

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The authors declare no competing financial interests.

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De Jager, P., Srivastava, G., Lunnon, K. et al. Alzheimer's disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci. Nat Neurosci 17, 1156–1163 (2014). https://doi.org/10.1038/nn.3786

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