Genome-wide12 DNA methylation profiling in the superior temporal gyrus reveals epigenetic signatures associated with Alzheimer's disease

Genome Medicine

Volumn 8, Issue 1, 2016, Pages

  Watson, Corey T ^a   Roussos, Panos ^a,b   Garg, Paras ^a   Ho, Daniel J ^a   Azam, Nidha ^a   Katsel, Pavel L ^a   Haroutunian, Vahram ^a,b   Sharp, Andrew J ^a  

^a MOUNT SINAI SCHOOL OF MEDICINE   (United States)

^b VETERANS AFFAIRS MEDICAL CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

HISTONE H3;

AGED; AGING; ALZHEIMER DISEASE; ARTICLE; CLINICAL ARTICLE; CONTROLLED STUDY; DIFFERENTIALLY METHYLATED REGION; DNA METHYLATION; FEMALE; FUNCTIONAL GENOMICS; GENE ONTOLOGY; GENETIC ASSOCIATION; HUMAN; HUMAN TISSUE; MALE; PRIORITY JOURNAL; PROMOTER REGION; QUANTITATIVE TRAIT LOCUS; SINGLE NUCLEOTIDE POLYMORPHISM; SUPERIOR TEMPORAL GYRUS; GENE REGULATORY NETWORK; GENETIC EPIGENESIS; GENETICS; GENOME-WIDE ASSOCIATION STUDY; METABOLISM; PROCEDURES; TEMPORAL LOBE; VERY ELDERLY;

AGED; AGED, 80 AND OVER; ALZHEIMER DISEASE; DNA METHYLATION; EPIGENESIS, GENETIC; GENE ONTOLOGY; GENE REGULATORY NETWORKS; GENOME-WIDE ASSOCIATION STUDY; HUMANS; TEMPORAL LOBE;

EID: 84955310556     PISSN: None     EISSN: 1756994X     Source Type: Journal    
DOI: 10.1186/s13073-015-0258-8     Document Type: Article

References (106)

1. Alzheimer's Association. Alzheimer's disease facts and figures. Alzheimers Dement. 2012;2012(8):131-68.
2. Braak H, Braak E. Diagnostic criteria for neuropathologic assessment of Alzheimer's disease. Neurobiol Aging. 1997;18:S85-8.
3. Bird TD. Genetic aspects of Alzheimer disease. Genet Med. 2008;10:231-9.
4. Bertram L, Lill CM, Tanzi RE. The genetics of Alzheimer disease: back to the future. Neuron. 2010;68:270-81.
5. Migliore L, Coppedè F. Genetics, environmental factors and the emerging role of epigenetics in neurodegenerative diseases. Mutat Res. 2009;667:82-97.
6. Gatz M, Reynolds CA, Fratiglioni L, Johansson B, Mortimer JA, Berg S, et al. Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry. 2006;63:168-74.
7. Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML, et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat Genet. 2009;41:1088-93.
8. Bertram L, Tanzi RE. Genome-wide association studies in Alzheimer's disease. Hum Mol Genet. 2009;18:R137-45.
9. Chapman J, Rees E, Harold D, Ivanov D, Gerrish A, Sims R, et al. A genome-wide study shows a limited contribution of rare copy number variants to Alzheimer's disease risk. Hum Mol Genet. 2013;22:816-24.
10. Lambert J-C, Grenier-Boley B, Harold D, Zelenika D, Chouraki V, Kamatani Y, et al. Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer's disease. Mol Psychiatry. 2013;18:461-70.
11. Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet. 2013;45:1452-8.
12. Lee SH, Harold D, Nyholt DR, Goddard ME, Zondervan KT, Williams J, et al. Estimation and partitioning of polygenic variation captured by common SNPs for Alzheimer's disease, multiple sclerosis and endometriosis. Hum Mol Genet. 2013;22:832-41.
13. Portela A, Esteller M. Epigenetic modifications and human disease. Nat Biotechnol. 2010;28:1057-68.
14. Handel AE, Ebers GC, Ramagopalan SV. Epigenetics: molecular mechanisms and implications for disease. Trends Mol Med. 2010;16:7-16.
15. Mastroeni D, Grover A, Delvaux E, Whiteside C, Coleman PD, Rogers J. Epigenetic mechanisms in Alzheimer's disease. Neurobiol Aging. 2011;32:1161-80.
16. Lunnon K, Mill J. Epigenetic studies in Alzheimer's disease: current findings, caveats, and considerations for future studies. Am J Med Genet B Neuropsychiatr Genet. 2013;162B(8):789-99.
17. Probst AV, Dunleavy E, Almouzni G. Epigenetic inheritance during the cell cycle. Nat Rev Mol Cell Biol. 2009;10:192-206.
18. Guilmatre A, Sharp AJ. Parent of origin effects. Clin Genet. 2012;81:201-9.
19. Ziller MJ, Gu H, Müller F, Donaghey J, Tsai LT-Y, Kohlbacher O, et al. Charting a dynamic DNA methylation landscape of the human genome. Nature. 2013;500:477-81.
20. Bell JT, Pai AA, Pickrell JK, Gaffney DJ, Pique-Regi R, Degner JF, et al. DNA methylation patterns associate with genetic and gene expression variation in HapMap cell lines. Genome Biol. 2011;12:R10.
21. Sharp AJ, Stathaki E, Migliavacca E, Brahmachary M, Montgomery SB, Dupre Y, et al. DNA methylation profiles of human active and inactive X chromosomes. Genome Res. 2011;21:1592-600.
22. Bala Tannan N, Brahmachary M, Garg P, Borel C, Alnefaie R, Watson CT, et al. DNA methylation profiling in X;autosome translocations supports a role for L1 repeats in the spread of X chromosome inactivation. Hum Mol Genet. 2014;23:1224-36.
23. Edwards CA, Ferguson-Smith AC. Mechanisms regulating imprinted genes in clusters. Curr Opin Cell Biol. 2007;19:281-9.
24. Hernando-Herraez I, Prado-Martinez J, Garg P, Fernandez-Callejo M, Heyn H, Hvilsom C, et al. Dynamics of DNA methylation in recent human and great ape evolution. PLoS Genet. 2013;9:e1003763.
25. Numata S, Ye T, Hyde TM, Guitart-Navarro X, Tao R, Wininger M, et al. DNA methylation signatures in development and aging of the human prefrontal cortex. Am J Hum Genet. 2012;90:260-72.
26. Rakyan VK, Down TA, Maslau S, Andrew T, Yang T-P, Beyan H, et al. Human aging-associated DNA hypermethylation occurs preferentially at bivalent chromatin domains. Genome Res. 2010;20:434-9.
27. Hannum G, Guinney J, Zhao L, Zhang L, Hughes G, Sadda S, et al. resource genome-wide methylation profiles reveal quantitative views of human aging rates. Mol Cell. 2013;49:1-9.
28. Hernandez DG, Nalls MA, Gibbs JR, Arepalli S, van der Brug M, Chong S, et al. Distinct DNA methylation changes highly correlated with chronological age in the human brain. Hum Mol Genet. 2011;20:1164-72.
29. Teschendorff AE, Menon U, Gentry-Maharaj A, Ramus SJ, Weisenberger DJ, Shen H, et al. Age-dependent DNA methylation of genes that are suppressed in stem cells is a hallmark of cancer. Genome Res. 2010;20:440-6.
30. Heyn H, Sayols S, Moutinho C, Vidal E, Sanchez-Mut JV, Stefansson OA, et al. Linkage of DNA methylation quantitative trait loci to human cancer risk. Cell Rep. 2014;7:331-8.
31. Stefansson OA, Moran S, Gomez A, Sayols S, Arribas-Jorba C, Sandoval J, et al. A DNA methylation-based definition of biologically distinct breast cancer subtypes. Mol Oncol. 2014;9:1-14.
32. Huynh JL, Garg P, Thin TH, Yoo S, Dutta R, Trapp BD, et al. Epigenome-wide differences in pathology-free regions of multiple sclerosis-affected brains. Nat Neurosci. 2014;17:121-30.
33. Pidsley R, Viana J, Hannon E, Spiers H, Troakes C, Al-Saraj S, et al. Methylomic profiling of human brain tissue supports a neurodevelopmental origin for schizophrenia. Genome Biol. 2014;15:483.
34. Van Eijk KR, de Jong S, Strengman E, Buizer-Voskamp JE, Kahn RS, Boks MP, et al. Identification of schizophrenia-associated loci by combining DNA methylation and gene expression data from whole blood. Eur J Hum Genet. 2014;2013:1-5.
35. Liu Y, Aryee MJ, Padyukov L, Fallin MD, Hesselberg E, Runarsson A, et al. Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis. Nat Biotechnol. 2013;31:142-7.
36. Mastroeni D, McKee A, Grover A, Rogers J, Coleman PD. Epigenetic differences in cortical neurons from a pair of monozygotic twins discordant for Alzheimer's disease. PLoS One. 2009;4:e6617.
37. Chouliaras L, Mastroeni D, Delvaux E, Grover A, Kenis G, Hof PR, et al. Consistent decrease in global DNA methylation and hydroxymethylation in the hippocampus of Alzheimer's disease patients. Neurobiol Aging. 2013;34:2091-9.
38. Pietrzak M, Rempala G, Nelson PT, Zheng J-J, Hetman M. Epigenetic silencing of nucleolar rRNA genes in Alzheimer's disease. PLoS One. 2011;6:e22585.
39. Bollati V, Galimberti D, Pergoli L, Dalla Valle E, Barretta F, Cortini F, et al. DNA methylation in repetitive elements and Alzheimer disease. Brain Behav Immun. 2011;25:1078-83.
40. Yu L, Chibnik LB, Srivastava GP, Pochet N, Yang J, Xu J, et al. Association of brain DNA methylation in SORL1, ABCA7, HLA-DRB5, SLC24A4, and BIN1 with pathological diagnosis of Alzheimer disease. JAMA Neurol. 2014;60612:15-24.
41. Bakulski KM, Dolinoy DC, Sartor MA, Paulson HL, Konen JR, Lieberman AP, et al. Genome-wide DNA methylation differences between late-onset Alzheimer's disease and cognitively normal controls in human frontal cortex. J Alzheimers Dis. 2012;29:571-88.
42. Lunnon K, Smith R, Hannon E, De Jager PL, Srivastava G, Volta M, et al. Methylomic profiling implicates cortical deregulation of ANK1 in Alzheimer's disease. Nat Neurosci. 2014;17:1164-70.
43. De Jager PL, Srivastava G, Lunnon K, Burgess J, Schalkwyk LC, Yu L, et al. Alzheimer's disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci. Nat Neurosci. 2014;17:1156-63.
44. Haroutunian V, Katsel P, Schmeidler J. Transcriptional vulnerability of brain regions in Alzheimer's disease and dementia. Neurobiol Aging. 2009;30:561-73.
45. Haroutunian V, Perl D. Regional distribution of neuritic plaques in the nondemented elderly and subjects with very mild Alzheimer disease. Arch Neurol. 1998;55:1185-91.
46. Haroutunian V, Purohit D. Neurofibrillary tangles in nondemented elderly subjects and mild Alzheimer disease. Arch Neurol. 1999;56(June 1999):713-8.
47. Haroutunian V, Davies P, Vianna C, Buxbaum JD, Purohit DP. Tau protein abnormalities associated with the progression of Alzheimer disease type dementia. Neurobiol Aging. 2007;28:1-7.
48. Xi Y, Li W. BSMAP: whole genome bisulfite sequence MAPping program. BMC Bioinformatics. 2009;10:232.
49. Abecasis GR, Altshuler D, Auton A, Brooks LD, Durbin RM, Gibbs RA, et al. A map of human genome variation from population-scale sequencing. Nature. 2010;467:1061-73.
50. Abecasis GR, Auton A, Brooks LD, DePristo MA, Durbin RM, Handsaker RE, et al. An integrated map of genetic variation from 1,092 human genomes. Nature. 2012;491:56-65.
51. Du P, Kibbe WA, Lin SM. lumi: a pipeline for processing Illumina microarray. Bioinformatics. 2008;24:1547-8.
52. Du P, Zhang X, Huang C-C, Jafari N, Kibbe WA, Hou L, et al. Comparison of Beta-value and M-value methods for quantifying methylation levels by microarray analysis. BMC Bioinformatics. 2010;11:587.
53. Teschendorff AE, Marabita F, Lechner M, Bartlett T, Tegner J, Gomez-Cabrero D, et al. A beta-mixture quantile normalization method for correcting probe design bias in Illumina Infinium 450k DNA methylation data. Bioinformatics. 2013;29:189-96.
54. Guintivano J, Aryee MJ, Kaminsky ZA. 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;8:290-302.
55. Bock C. Analysing and interpreting DNA methylation data. Nat Rev Genet. 2012;13:705-19.
56. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B. 1995;57:289-300.
57. Quinlan AR, Hall IM. BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics. 2010;26:841-2.
58. Maurano MT, Humbert R, Rynes E, Thurman RE, Haugen E, Wang H, et al. Systematic localization of common disease-associated variation in regulatory DNA. Science. 2012;337:1190-6.
59. Zhu J, Adli M, Zou JY, Verstappen G, Coyne M, Zhang X, et al. Genome-wide chromatin state transitions associated with developmental and environmental cues. Cell. 2013;152:642-54.
60. Lee PH, O'Dushlaine C, Thomas B, Purcell SM. INRICH: interval-based enrichment analysis for genome-wide association studies. Bioinformatics. 2012;28:1797-9.
61. Pique-Regi R, Degner JF, Pai AA, Gaffney DJ, Gilad Y, Pritchard JK. Accurate inference of transcription factor binding from DNA sequence and chromatin accessibility data. Genome Res. 2011;21:447-55.
62. Good PJ, Guyer MS, Kamholz S, Liefer L, Wetterstrand K, Kampa D, et al. The ENCODE ( ENCyclopedia Of DNA Elements ) Project. Science. 2004;306(5696):636-40.
63. Eden E, Navon R, Steinfeld I, Lipson D, Yakhini Z. GOrilla: a tool for discovery and visualization of enriched GO terms in ranked gene lists. BMC Bioinformatics. 2009;10:48.
64. Welter D, MacArthur J, Morales J, Burdett T, Hall P, Junkins H, et al. The NHGRI GWAS Catalog, a curated resource of SNP-trait associations. Nucleic Acids Res. 2014;42(Database issue):D1001-6.
65. Colantuoni C, Lipska BK, Ye T, Hyde TM, Tao R, Leek JT, et al. Temporal dynamics and genetic control of transcription in the human prefrontal cortex. Nature. 2011;478:519-23.
66. Gibbs JR, van der Brug MP, Hernandez DG, Traynor BJ, Nalls MA, Lai S-L, et al. Abundant quantitative trait loci exist for DNA methylation and gene expression in human brain. PLoS Genet. 2010;6:e1000952.
67. Zhang B, Gaiteri C, Bodea L-G, Wang Z, McElwee J, Podtelezhnikov AA, et al. Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer's disease. Cell. 2013;153:707-20.
68. Ramasamy A, Trabzuni D, Guelfi S, Varghese V, Smith C, Walker R, et al. Genetic variability in the regulation of gene expression in ten regions of the human brain. Nat Neurosci. 2014;17:1418-28.
69. Roussos P, Mitchell AC, Voloudakis G, Fullard JF, Pothula VM, Tsang J, et al. A role for noncoding variation in schizophrenia. Cell Rep. 2014;9:1417-29.
70. Nica AC, Montgomery SB, Dimas AS, Stranger BE, Beazley C, Barroso I, et al. Candidate causal regulatory effects by integration of expression QTLs with complex trait genetic associations. PLoS Genet. 2010;6:e1000895.
71. Grundberg E, Small KS, Hedman ÅK, Nica AC, Buil A, Keildson S, et al. Mapping cis- and trans-regulatory effects across multiple tissues in twins. Nat Genet. 2012;44:1084-9.
72. Boks MP, Derks EM, Weisenberger DJ, Strengman E, Janson E, Sommer IE, et al. The relationship of DNA methylation with age, gender and genotype in twins and healthy controls. PLoS One. 2009;4:e6767.
73. Heyn H, Moran S, Hernando-Herraez I, Sayols S, Gomez A, Sandoval J, et al. DNA methylation contributes to natural human variation. Genome Res. 2013;23:1363-72.
74. Koestler DC, Christensen B, Karagas MR, Marsit CJ, Langevin SM, Kelsey KT, et al. Blood-based profiles of DNA methylation predict the underlying distribution of cell types: a validation analysis. Epigenetics. 2013;8:816-26.
75. Kozlenkov A, Roussos P, Timashpolsky A, Barbu M, Rudchenko S, Bibikova M, et al. Differences in DNA methylation between human neuronal and glial cells are concentrated in enhancers and non-CpG sites. Nucleic Acids Res. 2014;42:109-27.
76. Gómez-Isla T, Hollister R, West H, Mui S, Growdon JH, Petersen RC, et al. Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer's disease. Ann Neurol. 1997;41:17-24.
77. Robinson MD, Kahraman A, Law CW, Lindsay H, Nowicka M, Weber LM, et al. Statistical methods for detecting differentially methylated loci and regions. Front Genet. 2014;5:324.
78. Shropshire TD, Reifert J, Rajagopalan S, Baker D, Feinstein SC, Daugherty PS. Amyloid β peptide cleavage by kallikrein 7 attenuates fibril growth and rescues neurons from Aβ-mediated toxicity in vitro. Biol Chem. 2014;395:109-18.
79. Bossers K, Wirz KTS, Meerhoff GF, Essing AHW, van Dongen JW, Houba P, et al. Concerted changes in transcripts in the prefrontal cortex precede neuropathology in Alzheimer's disease. Brain. 2010;133(Pt 12):3699-723.
80. Banzhaf-Strathmann J, Benito E, May S, Arzberger T, Tahirovic S, Kretzschmar H, et al. MicroRNA-125b induces tau hyperphosphorylation and cognitive deficits in Alzheimer's disease. EMBO J. 2014;33:1667-80.
81. Ohno Y, Suto S, Yamanaka M, Mizutani Y, Mitsutake S, Igarashi Y, et al. ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingolipid synthesis. Proc Natl Acad Sci USA. 2010;107:18439-44.
82. Demirkan A, van Duijn CM, Ugocsai P, Isaacs A, Pramstaller PP, Liebisch G, et al. Genome-wide association study identifies novel loci associated with circulating phospho- and sphingolipid concentrations. PLoS Genet. 2012;8:e1002490.
83. Jones L, Holmans PA, Hamshere ML, Harold D, Moskvina V, Ivanov D, et al. Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease. PLoS One. 2010;5:e13950.
84. Katsel P, Li C, Haroutunian V. Gene Expression alterations in the sphingolipid metabolism pathways during progression of dementia and Alzheimer's Disease: a shift toward ceramide accumulation at the earliest recognizable stages of Alzheimer's disease? Neurochem Res. 2007;32:845-56.
85. Akram A, Schmeidler J, Katsel P, Hof PR, Haroutunian V. Increased expression of RXR a in dementia: an early harbinger for the cholesterol dyshomeostasis. Mol Neurodegener. 2010;5:1-14.
86. Akram A, Schmeidler J, Katsel P, Hof PR, Haroutunian V. Association of ApoE and LRP mRNA levels with dementia and AD neuropathology. Neurobiol Aging. 2012;33:628.e1-628.e14.
87. Cutler RG, Kelly J, Storie K, Pedersen WA, Tammara A, Hatanpaa K, et al. Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer's disease. Proc Natl Acad Sci USA. 2004;101(Track I):1-6.
88. He X, Huang Y, Li B, Gong C-X, Schuchman EH. Deregulation of sphingolipid metabolism in Alzheimer's disease. Neurobiol Aging. 2010;31:398-408.
89. Mielke MM, Haughey NJ, Bandaru VVR, Zetterberg H, Blennow K, Andreasson U, et al. Cerebrospinal fluid sphingolipids, β-amyloid, and tau in adults at risk for Alzheimer's disease. Neurobiol Aging. 2014;35:2486-94.
90. Foley P. Lipids in Alzheimer's disease: a century-old story. Biochim Biophys Acta. 2010;1801:750-3.
91. Di Paolo G, Kim T-W. Linking lipids to Alzheimer's disease: cholesterol and beyond. Nat Rev Neurosci. 2011;12:284-96.
92. Cedar H, Bergman Y. Linking DNA methylation and histone modification: patterns and paradigms. Nat Rev Genet. 2009;10:295-304.
93. Bernstein BE, Mikkelsen TS, Xie X, Kamal M, Huebert DJ, Cuff J, et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell. 2006;125:315-26.
94. Watson CT, Disanto G, Sandve GK, Breden F, Giovannoni G, Ramagopalan SV. Age-associated hyper-methylated regions in the human brain overlap with bivalent chromatin domains. PLoS One. 2012;7:e43840.
95. Meissner A, Mikkelsen TS, Gu H, Wernig M, Hanna J, Sivachenko A, et al. Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature. 2008;454:766-70.
96. Ohm JE, Baylin SB. Stem cell chromatin patterns: an instructive mechanism for DNA hypermethylation? Cell Cycle. 2014;6:1040-3.
97. Hu S, Wan J, Su Y, Song Q, Zeng Y, Nguyen HN, et al. DNA methylation presents distinct binding sites for human transcription factors. Elife. 2013;2:e00726.
98. Hudry E, Wu HY, Arbel-Ornath M, Hashimoto T, Matsouaka R, Fan Z, et al. Inhibition of the NFAT pathway alleviates amyloid β neurotoxicity in a mouse model of Alzheimer's disease. J Neurosci. 2012;32:3176-92.
99. Abdul HM, Sama MA, Furman JL, Mathis DM, Beckett TL, Weidner AM, et al. Cognitive decline in Alzheimer's disease is associated with selective changes in calcineurin/NFAT signaling. J Neurosci. 2012;29:12957-69.
100. Ramanan VK, Kim S, Holohan K, Shen L, Nho K, Risacher SL, et al. Genome-wide pathway analysis of memory impairment in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort implicates gene candidates, canonical pathways, and networks. Brain Imaging Behav. 2012;6:634-48.
101. Bullido MJ, Martínez-García A, Artiga MJ, Aldudo J, Sastre I, Gil P, et al. A TAP2 genotype associated with Alzheimer's disease in APOE4 carriers. Neurobiol Aging. 2007;28:519-23.
102. Cong W, Cai H, Wang R, Daimon CM, Maudsley S, Raber K, et al. Altered hypothalamic protein expression in a rat model of Huntington's disease. PLoS One. 2012;7:e47240.
103. Yu J-T, Tan L. The Role of clusterin in Alzheimer's disease: pathways, pathogenesis, and therapy. Mol Neurobiol. 2012;45:314-26.
104. Szymanski M, Wang R, Bassett SS, Avramopoulos D. Alzheimer's risk variants in the clusterin gene are associated with alternative splicing. Transl Psychiatry. 2011;1:e18-7.
105. Schürmann B, Wiese B, Bickel H, Weyerer S, Riedel-Heller SG, Pentzek M, et al. Association of the Alzheimer's disease clusterin risk allele with plasma clusterin concentration. J Alzheimers Dis. 2011;25:421-4.
106. Miller JA, Woltjer RL, Goodenbour JM, Horvath S, Geschwind DH. Genes and pathways underlying regional and cell type changes in Alzheimer's disease. Genome Med. 2013;5:48.