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

Nature Neuroscience 17, 1156–1163 (2014) | Download Citation

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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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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.

Author information

Affiliations

  1. Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, 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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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.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Philip L De Jager or David A Bennett.

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DOI

https://doi.org/10.1038/nn.3786

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