Alzheimer's Disease: Early Alterations in Brain DNA Methylation at ANK1, BIN1, RHBDF2 and Other Loci

Overview

Journal Nat Neurosci

Date 2014 Aug 18

PMID 25129075

Citations 480

Authors

Philip L De Jager

Gyan Srivastava

Katie Lunnon

Jeremy Burgess

Leonard C Schalkwyk

Lei Yu

Matthew L Eaton

Brendan T Keenan

Jason Ernst

Cristin McCabe

Anna Tang

Towfique Raj

Joseph Replogle

Wendy Brodeur

Stacey Gabriel

High S Chai

Curtis Younkin

Steven G Younkin

Fanggeng Zou

Moshe Szyf

Charles B Epstein

Julie A Schneider

Bradley E Bernstein

Alex Meissner

Nilufer Ertekin-Taner

Lori B Chibnik

Manolis Kellis

Jonathan Mill

David A Bennett

Affiliations

Soon will be listed here.

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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References

Bennett D, Wilson R, Arvanitakis Z, Boyle P, de Toledo-Morrell L, Schneider J . Selected findings from the Religious Orders Study and Rush Memory and Aging Project. J Alzheimers Dis. 2012; 33 Suppl 1:S397-403. PMC: 3434299. DOI: 10.3233/JAD-2012-129007. View

Renner N, Sansing H, Inglis F, Mehra S, Kaushal D, Lackner A . Transient acidification and subsequent proinflammatory cytokine stimulation of astrocytes induce distinct activation phenotypes. J Cell Physiol. 2012; 228(6):1284-94. PMC: 3582839. DOI: 10.1002/jcp.24283. View

Shulman J, Chen K, Keenan B, Chibnik L, Fleisher A, Thiyyagura P . Genetic susceptibility for Alzheimer disease neuritic plaque pathology. JAMA Neurol. 2013; 70(9):1150-7. PMC: 3773291. DOI: 10.1001/jamaneurol.2013.2815. View

Rossin E, Lage K, Raychaudhuri S, Xavier R, Tatar D, Benita Y . Proteins encoded in genomic regions associated with immune-mediated disease physically interact and suggest underlying biology. PLoS Genet. 2011; 7(1):e1001273. PMC: 3020935. DOI: 10.1371/journal.pgen.1001273. View

Horvath S, Zhang Y, Langfelder P, Kahn R, Boks M, van Eijk K . Aging effects on DNA methylation modules in human brain and blood tissue. Genome Biol. 2012; 13(10):R97. PMC: 4053733. DOI: 10.1186/gb-2012-13-10-r97. View

Zou F, Chai H, Younkin C, Allen M, Crook J, Pankratz V . Brain expression genome-wide association study (eGWAS) identifies human disease-associated variants. PLoS Genet. 2012; 8(6):e1002707. PMC: 3369937. DOI: 10.1371/journal.pgen.1002707. View

Numata S, Ye T, Hyde T, Guitart-Navarro X, Tao R, Wininger M . DNA methylation signatures in development and aging of the human prefrontal cortex. Am J Hum Genet. 2012; 90(2):260-72. PMC: 3276664. DOI: 10.1016/j.ajhg.2011.12.020. View

Bock C . Analysing and interpreting DNA methylation data. Nat Rev Genet. 2012; 13(10):705-19. DOI: 10.1038/nrg3273. View

Naj A, Jun G, Beecham G, Wang L, Vardarajan B, Buros J . Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease. Nat Genet. 2011; 43(5):436-41. PMC: 3090745. DOI: 10.1038/ng.801. View

10.

Lambert J, Ibrahim-Verbaas C, Harold D, Naj A, Sims R, Bellenguez C . Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet. 2013; 45(12):1452-8. PMC: 3896259. DOI: 10.1038/ng.2802. View

11.

Bennett D, Wilson R, Boyle P, Buchman A, Schneider J . Relation of neuropathology to cognition in persons without cognitive impairment. Ann Neurol. 2012; 72(4):599-609. PMC: 3490232. DOI: 10.1002/ana.23654. View

12.

Lunnon K, Smith R, Hannon E, De Jager P, Srivastava G, Volta M . Methylomic profiling implicates cortical deregulation of ANK1 in Alzheimer's disease. Nat Neurosci. 2014; 17(9):1164-70. PMC: 4410018. DOI: 10.1038/nn.3782. View

13.

Ziller M, Gu H, Muller F, Donaghey J, Tsai L, Kohlbacher O . Charting a dynamic DNA methylation landscape of the human genome. Nature. 2013; 500(7463):477-81. PMC: 3821869. DOI: 10.1038/nature12433. View

14.

Bakulski K, Dolinoy D, Sartor M, Paulson H, Konen J, Lieberman A . Genome-wide DNA methylation differences between late-onset Alzheimer's disease and cognitively normal controls in human frontal cortex. J Alzheimers Dis. 2012; 29(3):571-88. PMC: 3652332. DOI: 10.3233/JAD-2012-111223. View

15.

Xi Y, Li W . BSMAP: whole genome bisulfite sequence MAPping program. BMC Bioinformatics. 2009; 10:232. PMC: 2724425. DOI: 10.1186/1471-2105-10-232. View

16.

Guintivano J, Aryee M, Kaminsky Z . A cell epigenotype specific model for the correction of brain cellular heterogeneity bias and its application to age, brain region and major depression. Epigenetics. 2013; 8(3):290-302. PMC: 3669121. DOI: 10.4161/epi.23924. View

17.

Gifford C, Ziller M, Gu H, Trapnell C, Donaghey J, Tsankov A . Transcriptional and epigenetic dynamics during specification of human embryonic stem cells. Cell. 2013; 153(5):1149-63. PMC: 3709577. DOI: 10.1016/j.cell.2013.04.037. View

18.

Adrain C, Zettl M, Christova Y, Taylor N, Freeman M . Tumor necrosis factor signaling requires iRhom2 to promote trafficking and activation of TACE. Science. 2012; 335(6065):225-8. PMC: 3272371. DOI: 10.1126/science.1214400. View

19.

Johnson W, Li C, Rabinovic A . Adjusting batch effects in microarray expression data using empirical Bayes methods. Biostatistics. 2006; 8(1):118-27. DOI: 10.1093/biostatistics/kxj037. View

20.

Hollingworth P, Harold D, Sims R, Gerrish A, Lambert J, Carrasquillo M . Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nat Genet. 2011; 43(5):429-35. PMC: 3084173. DOI: 10.1038/ng.803. View