Decoding the non-coding genome: Elucidating genetic risk outside the coding genome

Genes, Brain and Behavior

Volumn 15, Issue 1, 2016, Pages 187-204

  Barr, C L ^a,b   Misener, V L ^a  

^a UNIVERSITY HEALTH NETWORK   (Canada)

^b HOSPITAL FOR SICK CHILDREN   (Canada)

Author keywords

5 Hydroxymethylation; Adolescent brain; Enhancers; Epigenetics; Gene expression; Gene regulation; Methylation; Non CG methylation; Non coding RNA; Psychiatric disorders; Transcriptome

Indexed keywords

TRANSCRIPTION FACTOR; TRANSCRIPTOME; UNTRANSLATED RNA;

DNA METHYLATION; ENHANCER REGION; EPIGENETICS; GENE CONTROL; GENE EXPRESSION; GENE MAPPING; GENETIC ASSOCIATION; GENETIC RISK; GENETIC VARIABILITY; GENOME; HUMAN; MENTAL DISEASE; PRIORITY JOURNAL; QUANTITATIVE TRAIT LOCUS MAPPING; REVIEW; TRANSCRIPTION REGULATION; GENETIC PREDISPOSITION; GENETICS; HUMAN GENOME; REGULATORY SEQUENCE; TRANSCRIPTION INITIATION;

DNA METHYLATION; GENETIC PREDISPOSITION TO DISEASE; GENOME, HUMAN; HUMANS; MENTAL DISORDERS; REGULATORY SEQUENCES, NUCLEIC ACID; TRANSCRIPTIONAL ACTIVATION;

EID: 84954240290     PISSN: 16011848     EISSN: 1601183X     Source Type: Journal    
DOI: 10.1111/gbb.12269     Document Type: Review

References (269)

1. Abou El Hassan, M. & Bremner, R. (2009) A rapid simple approach to quantify chromosome conformation capture. Nucleic Acids Res 37, e35.
2. Andersson, R., Gebhard, C., Miguel-Escalada, I. et al. (2014) An atlas of active enhancers across human cell types and tissues. Nature 507, 455-461.
3. Angold, A., Costello, E.J. & Worthman, C.M. (1998) Puberty and depression: the roles of age, pubertal status and pubertal timing. Psychol Med 28, 51-61.
4. Anney, R., Klei, L., Pinto, D. et al. (2012) Individual common variants exert weak effects on the risk for autism spectrum disorderspi. Hum Mol Genet 21, 4781-4792.
5. Arnold, C.D., Gerlach, D., Stelzer, C., Boryn, L.M., Rath, M. & Stark, A. (2013) Genome-wide quantitative enhancer activity maps identified by STARR-seq. Science 339, 1074-1077.
6. Banovich, N.E., Lan, X., McVicker, G., van de Geijn, B., Degner, J.F., Blischak, J.D., Roux, J., Pritchard, J.K. & Gilad, Y. (2014) Methylation QTLs are associated with coordinated changes in transcription factor binding, histone modifications, and gene expression levels. PLoS Genet 10, e1004663.
7. Baron-Cohen, S., Lombardo, M.V., Auyeung, B., Ashwin, E., Chakrabarti, B. & Knickmeyer, R. (2011) Why are autism spectrum conditions more prevalent in males? PLoS Biol 9, e1001081.
8. Barry, G. (2014) Integrating the roles of long and small non-coding RNA in brain function and disease. Mol Psychiatry 19, 410-416.
9. Barski, A., Cuddapah, S., Cui, K., Roh, T.Y., Schones, D.E., Wang, Z., Wei, G., Chepelev, I. & Zhao, K. (2007) High-resolution profiling of histone methylations in the human genome. Cell 129, 823-837.
10. Batista, P.J. & Chang, H.Y. (2013) Long noncoding RNAs: cellular address codes in development and disease. Cell 152, 1298-1307.
11. Baubec, T. & Schubeler, D. (2014) Genomic patterns and context specific interpretation of DNA methylation. Curr Opin Genet Dev 25, 85-92.
12. Berger, M.F. & Bulyk, M.L. (2009) Universal protein-binding microarrays for the comprehensive characterization of the DNA-binding specificities of transcription factors. Nat Protoc 4, 393-411.
13. Bernstein, B.E., Kamal, M., Lindblad-Toh, K., Bekiranov, S., Bailey, D.K., Huebert, D.J., McMahon, S., Karlsson, E.K., Kulbokas, E.J. III, Gingeras, T.R., Schreiber, S.L. & Lander, E.S. (2005) Genomic maps and comparative analysis of histone modifications in human and mouse. Cell 120, 169-181.
14. Bernstein, B.E., Stamatoyannopoulos, J.A., Costello, J.F., Ren, B., Milosavljevic, A., Meissner, A., Kellis, M., Marra, M.A., Beaudet, A.L., Ecker, J.R., Farnham, P.J., Hirst, M., Lander, E.S., Mikkelsen, T.S. & Thomson, J.A. (2010) The NIH Roadmap Epigenomics Mapping Consortium. Nat Biotechnol 28, 1045-1048.
15. Bernstein, B.E., Birney, E., Dunham, I., Green, E.D., Gunter, C., Snyder, M. & The ENCODE Project Consortium (2012) An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57-74.
16. Bhattacharya, N., Sarno, A., Idler, I.S., Fuhrer, M., Zenz, T., Dohner, H., Stilgenbauer, S. & Mertens, D. (2010) High-throughput detection of nuclear factor-kappaB activity using a sensitive oligo-based chemiluminescent enzyme-linked immunosorbent assay. Int J Cancer 127, 404-411.
17. Blakemore, S.J. (2012) Imaging brain development: the adolescent brain. Neuroimage 61, 397-406.
18. Boffelli, D., Nobrega, M.A. & Rubin, E.M. (2004) Comparative genomics at the vertebrate extremes. Nat Rev Genet 5, 456-465.
19. Brennand, K.J., Simone, A., Jou, J., Gelboin-Burkhart, C., Tran, N., Sangar, S., Li, Y., Mu, Y., Chen, G., Yu, D., McCarthy, S., Sebat, J. & Gage, F.H. (2011) Modelling schizophrenia using human induced pluripotent stem cells. Nature 473, 221-225.
20. Brennand, K., Savas, J.N., Kim, Y., Tran, N., Simone, A., Hashimoto-Torii, K., Beaumont, K.G., Kim, H.J., Topol, A., Ladran, I., Abdelrahim, M., Matikainen-Ankney, B., Chao, S.H., Mrksich, M., Rakic, P., Fang, G., Zhang, B., Yates, J.R. III & Gage, F.H. (2015) Phenotypic differences in hiPSC NPCs derived from patients with schizophrenia. Mol Psychiatry 20, 361-368.
21. Butler, J.E. & Kadonaga, J.T. (2002) The RNA polymerase II core promoter: a key component in the regulation of gene expression. Genes Dev 16, 2583-2592.
22. Cabili, M.N., Trapnell, C., Goff, L., Koziol, M., Tazon-Vega, B., Regev, A. & Rinn, J.L. (2011) Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses. Genes Dev 25, 1915-1927.
23. Casey, J.P., Magalhaes, T., Conroy, J.M. et al. (2012) A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder. Hum Genet 131, 565-579.
24. Charpentier, E. & Doudna, J.A. (2013) Biotechnology: rewriting a genome. Nature 495, 50-51.
25. Chen, H.M., DeLong, C.J., Bame, M., Rajapakse, I., Herron, T.J., McInnis, M.G. & O'Shea, K.S. (2014) Transcripts involved in calcium signaling and telencephalic neuronal fate are altered in induced pluripotent stem cells from bipolar disorder patients. Transl Psychiatry 4, e375.
26. Chen, L., Chen, K., Lavery, L.A., Baker, S.A., Shaw, C.A., Li, W. & Zoghbi, H.Y. (2015) MeCP2 binds to non-CG methylated DNA as neurons mature, influencing transcription and the timing of onset for Rett syndrome. Proc Natl Acad Sci USA 112, 5509-5514.
27. Choi, J.H., Li, Y., Guo, J., Pei, L., Rauch, T.A., Kramer, R.S., Macmil, S.L., Wiley, G.B., Bennett, L.B., Schnabel, J.L., Taylor, K.H., Kim, S., Xu, D., Sreekumar, A., Pfeifer, G.P., Roe, B.A., Caldwell, C.W., Bhalla, K.N. & Shi, H. (2010) Genome-wide DNA methylation maps in follicular lymphoma cells determined by methylation-enriched bisulfite sequencing. PLoS One 5. DOI: 10.1371/journal.pone.0013020.
28. Chorley, B.N., Wang, X., Campbell, M.R., Pittman, G.S., Noureddine, M.A. & Bell, D.A. (2008) Discovery and verification of functional single nucleotide polymorphisms in regulatory genomic regions: current and developing technologies. Mutat Res 659, 147-157.
29. Clark, S.L., Aberg, K.A., Nerella, S., Kumar, G., McClay, J.L., Chen, W., Xie, L.Y., Harada, A., Shabalin, A.A., Gao, G., Bergen, S.E., Hultman, C.M., Magnusson, P.K., Sullivan, P.F. & van den Oord, E.J. (2015) Combined whole methylome and genomewide association study implicates CNTN4 in alcohol use. Alcohol Clin Exp Res 39, 1396-1405.
30. Colantuoni, C., Lipska, B.K., Ye, T., Hyde, T.M., Tao, R., Leek, J.T., Colantuoni, E.A., Elkahloun, A.G., Herman, M.M., Weinberger, D.R. & Kleinman, J.E. (2011) Temporal dynamics and genetic control of transcription in the human prefrontal cortex. Nature 478, 519-523.
31. Collaer, M.L. & Hines, M. (1995) Human behavioral sex differences: a role for gonadal hormones during early development? Psychol Bull 118, 55-107.
32. Couto, J.M., Livne-Bar, I., Huang, K., Xu, Z., Cate-Carter, T., Feng, Y., Wigg, K., Humphries, T., Tannock, R., Kerr, E.N., Lovett, M.W., Bremner, R. & Barr, C.L. (2010) Association of reading disabilities with regions marked by acetylated H3 histones in KIAA0319. Am J Med Genet 153B, 447-462.
33. Cross-Disorder Group of the Psychiatric Genomics Consortium, Smoller, J.W., Craddock, N., Kendler, K., Lee, P.H., Neale, B.M., Nurnberger, J.I., Ripke, S., Santangelo, S. & Sullivan, P.F. (2013) Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet 381, 1371-1379.
34. Dantas Machado, A.C., Zhou, T., Rao, S., Goel, P., Rastogi, C., Lazarovici, A., Bussemaker, H.J. & Rohs, R. (2015) Evolving insights on how cytosine methylation affects protein-DNA binding. Brief Funct Genomics 14, 61-73.
35. Darabi, H., McCue, K., Beesley, J. et al. (2015) Polymorphisms in a putative enhancer at the 10q21.2 breast cancer risk locus regulate NRBF2 expression. Am J Hum Genet 97, 22-34.
36. Dathe, K., Kjaer, K.W., Brehm, A., Meinecke, P., Nurnberg, P., Neto, J.C., Brunoni, D., Tommerup, N., Ott, C.E., Klopocki, E., Seemann, P. & Mundlos, S. (2009) Duplications involving a conserved regulatory element downstream of BMP2 are associated with brachydactyly type A2. Am J Hum Genet 84, 483-492.
37. Datson, N.A., van der Perk, J., de Kloet, E.R. & Vreugdenhil, E. (2001) Expression profile of 30, 000 genes in rat hippocampus using SAGE. Hippocampus 11, 430-444.
38. Davies, W., Isles, A.R., Humby, T. & Wilkinson, L.S. (2007) What are imprinted genes doing in the brain? Epigenetics 2, 201-206.
39. De Gobbi, M., Viprakasit, V., Hughes, J.R., Fisher, C., Buckle, V.J., Ayyub, H., Gibbons, R.J., Vernimmen, D., Yoshinaga, Y., de Jong, P., Cheng, J.F., Rubin, E.M., Wood, W.G., Bowden, D. & Higgs, D.R. (2006) A regulatory SNP causes a human genetic disease by creating a new transcriptional promoter. Science 312, 1215-1217.
40. De Santa, F., Barozzi, I., Mietton, F., Ghisletti, S., Polletti, S., Tusi, B.K., Muller, H., Ragoussis, J., Wei, C.L. & Natoli, G. (2010) A large fraction of extragenic RNA pol II transcription sites overlap enhancers. PLoS Biol 8, e1000384.
41. Dean, A. (2006) On a chromosome far, far away: LCRs and gene expression. Trends Genet 22, 38-45.
42. Dempster, E., Viana, J., Pidsley, R. & Mill, J. (2013) Epigenetic studies of schizophrenia: progress, predicaments, and promises for the future. Schizophr Bull 39, 11-16.
43. Deng, J., Shoemaker, R., Xie, B., Gore, A., LeProust, E.M., Antosiewicz-Bourget, J., Egli, D., Maherali, N., Park, I.H., Yu, J., Daley, G.Q., Eggan, K., Hochedlinger, K., Thomson, J., Wang, W., Gao, Y. & Zhang, K. (2009) Targeted bisulfite sequencing reveals changes in DNA methylation associated with nuclear reprogramming. Nat Biotechnol 27, 353-360.
44. Deng, X., Berletch, J.B., Nguyen, D.K. & Disteche, C.M. (2014) X chromosome regulation: diverse patterns in development, tissues and disease. Nat Rev Genet 15, 367-378.
45. Dermitzakis, E.T. & Clark, A.G. (2002) Evolution of transcription factor binding sites in mammalian gene regulatory regions: conservation and turnover. Mol Biol Evol 19, 1114-1121.
46. Derrien, T., Johnson, R., Bussotti, G. et al. (2012) The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression. Genome Res 22, 1775-1789.
47. Diep, D., Plongthongkum, N., Gore, A., Fung, H.L., Shoemaker, R. & Zhang, K. (2012) Library-free methylation sequencing with bisulfite padlock probes. Nat Methods 9, 270-272.
48. Dixon, J.R., Selvaraj, S., Yue, F., Kim, A., Li, Y., Shen, Y., Hu, M., Liu, J.S. & Ren, B. (2012) Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 485, 376-380.
49. Djebali, S., Davis, C.A., Merkel, A. et al. (2012) Landscape of transcription in human cells. Nature 489, 101-108.
50. Dostie, J., Richmond, T.A., Arnaout, R.A., Selzer, R.R., Lee, W.L., Honan, T.A., Rubio, E.D., Krumm, A., Lamb, J., Nusbaum, C., Green, R.D. & Dekker, J. (2006) Chromosome conformation capture carbon copy (5C): a massively parallel solution for mapping interactions between genomic elements. Genome Res 16, 1299-1309.
51. Driscoll, M.C., Dobkin, C.S. & Alter, B.P. (1989) Gamma delta beta-thalassemia due to a de novo mutation deleting the 5' beta-globin gene activation-region hypersensitive sites. Proc Natl Acad Sci USA 86, 7470-7474.
52. Dwyer, S., Williams, H., Holmans, P., Moskvina, V., Craddock, N., Owen, M.J. & O'Donovan, M.C. (2010) No evidence that rare coding variants in ZNF804A confer risk of schizophrenia. Am J Med Genet B Neuropsychiatr Genet 153B, 1411-1416.
53. Eberharter, A. & Becker, P.B. (2002) Histone acetylation: a switch between repressive and permissive chromatin. Second in review series on chromatin dynamics. EMBO Rep 3, 224-229.
54. van Eijk, K.R., de Jong, S., Strengman, E., Buizer-Voskamp, J.E., Kahn, R.S., Boks, M.P., Horvath, S. & Ophoff, R.A. (2015) Identification of schizophrenia-associated loci by combining DNA methylation and gene expression data from whole blood. Eur J Hum Genet 23, 1106-1110.
55. Elbert, A., Lovett, M.W., Cate-Carter, T., Pitch, A., Kerr, E.N. & Barr, C.L. (2011) Genetic variation in the KIAA0319 5' region as a possible contributor to dyslexia. Behav Genet 41, 77-89.
56. Elia, J., Glessner, J.T., Wang, K. et al. (2011) Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder. Nat Genet 44, 78-84.
57. Ellinghaus, D., Ellinghaus, E., Nair, R.P. et al. (2012) Combined analysis of genome-wide association studies for Crohn disease and psoriasis identifies seven shared susceptibility loci. Am J Hum Genet 90, 636-647.
58. Ernst, J., Kheradpour, P., Mikkelsen, T.S., Shoresh, N., Ward, L.D., Epstein, C.B., Zhang, X., Wang, L., Issner, R., Coyne, M., Ku, M., Durham, T., Kellis, M. & Bernstein, B.E. (2011) Mapping and analysis of chromatin state dynamics in nine human cell types. Nature 473, 43-49.
59. Espuny-Camacho, I., Michelsen, K.A., Gall, D., Linaro, D., Hasche, A., Bonnefont, J., Bali, C., Orduz, D., Bilheu, A., Herpoel, A., Lambert, N., Gaspard, N., Peron, S., Schiffmann, S.N., Giugliano, M., Gaillard, A. & Vanderhaeghen, P. (2013) Pyramidal neurons derived from human pluripotent stem cells integrate efficiently into mouse brain circuits in vivo. Neuron 77, 440-456.
60. Estes, A., Zwaigenbaum, L., Gu, H., St John, T., Paterson, S., Elison, J.T., Hazlett, H., Botteron, K., Dager, S.R., Schultz, R.T., Kostopoulos, P., Evans, A., Dawson, G., Eliason, J., Alvarez, S., Piven, J. & IBIS Network (2015) Behavioral, cognitive, and adaptive development in infants with autism spectrum disorder in the first 2 years of life. J Neurodev Disord 7, 24.
61. Farh, K.K., Marson, A., Zhu, J. et al. (2014) Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature 518, 337-343.
62. Ferreira, M.A., O'Donovan, M.C., Meng, Y.A. et al. (2008) Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat Genet 40, 1056-1058.
63. Forest, M.G., Sizonenko, P.C., Cathiard, A.M. & Bertrand, J. (1974) Hypophyso-gonadal function in humans during the first year of life. 1. Evidence for testicular activity in early infancy. J Clin Invest 53, 819-828.
64. Francescatto, M., Vitezic, M., Heutink, P. & Saxena, A. (2014) Brain-specific noncoding RNAs are likely to originate in repeats and may play a role in up-regulating genes in cis. Int J Biochem Cell Biol 54, 331-337.
65. Franke, B., Neale, B.M. & Faraone, S.V. (2009) Genome-wide association studies in ADHD. Hum Genet 126, 13-50.
66. Franke, A., McGovern, D.P., Barrett, J.C. et al. (2010) Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nat Genet 42, 1118-1125.
67. Fullwood, M.J., Liu, M.H., Pan, Y.F. et al. (2009) An oestrogen-receptor-alpha-bound human chromatin interactome. Nature 462, 58-64.
68. Furniss, D., Lettice, L.A., Taylor, I.B., Critchley, P.S., Giele, H., Hill, R.E. & Wilkie, A.O. (2008) A variant in the sonic hedgehog regulatory sequence (ZRS) is associated with triphalangeal thumb and deregulates expression in the developing limb. Hum Mol Genet 17, 2417-2423.
69. Gabel, H.W., Kinde, B., Stroud, H., Gilbert, C.S., Harmin, D.A., Kastan, N.R., Hemberg, M., Ebert, D.H. & Greenberg, M.E. (2015) Disruption of DNA-methylation-dependent long gene repression in Rett syndrome. Nature 522, 89-93.
70. Gabellini, D., Green, M.R. & Tupler, R. (2002) Inappropriate gene activation in FSHD: a repressor complex binds a chromosomal repeat deleted in dystrophic muscle. Cell 110, 339-348.
71. Gamazon, E.R., Badner, J.A., Cheng, L. et al. (2013) Enrichment of cis-regulatory gene expression SNPs and methylation quantitative trait loci among bipolar disorder susceptibility variants. Mol Psychiatry 18, 340-346.
72. Gao, Z. & Ruan, J. (2015) A structure-based multiple-instance learning approach to predicting in vitro transcription factor-DNA interaction. BMC Genomics 16 (Suppl 4), S3.
73. Garber, K. (2011) Psoriasis: from bed to bench and back. Nat Biotechnol 29, 563-566.
74. Gerasimova, A., Chavez, L., Li, B., Seumois, G., Greenbaum, J., Rao, A., Vijayanand, P. & Peters, B. (2013) Predicting cell types and genetic variations contributing to disease by combining GWAS and epigenetic data. PLoS One 8, e54359.
75. Gibbs, J.R., van der Brug, M.P., Hernandez, D.G., Traynor, B.J., Nalls, M.A., Lai, S.L., Arepalli, S., Dillman, A., Rafferty, I.P., Troncoso, J., Johnson, R., Zielke, H.R., Ferrucci, L., Longo, D.L., Cookson, M.R. & Singleton, A.B. (2010) Abundant quantitative trait loci exist for DNA methylation and gene expression in human brain. PLoS Genet 6, e1000952.
76. Green, E.K., Hamshere, M., Forty, L., Gordon-Smith, K., Fraser, C., Russell, E., Grozeva, D., Kirov, G., Holmans, P., Moran, J.L., Purcell, S., Sklar, P., Owen, M.J., O'Donovan, M.C., Jones, L., Jones, I.R. & Craddock, N. (2013) Replication of bipolar disorder susceptibility alleles and identification of two novel genome-wide significant associations in a new bipolar disorder case-control sample. Mol Psychiatry 18, 1302-1307.
77. GTEx Consortium (2013) The genotype-tissue expression (GTEx) project. Nat Genet 45, 580-585.
78. GTEx Consortium (2015) The genotype-tissue expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science 348, 648-660.
79. Guo, J.U., Su, Y., Shin, J.H., Shin, J., Li, H., Xie, B., Zhong, C., Hu, S., Le, T., Fan, G., Zhu, H., Chang, Q., Gao, Y., Ming, G.L. & Song, H. (2014) Distribution, recognition and regulation of non-CpG methylation in the adult mammalian brain. Nat Neurosci 17, 215-222.
80. Hahn, M.A., Qiu, R., Wu, X., Li, A.X., Zhang, H., Wang, J., Jui, J., Jin, S.G., Jiang, Y., Pfeifer, G.P. & Lu, Q. (2013) Dynamics of 5-hydroxymethylcytosine and chromatin marks in mammalian neurogenesis. Cell Rep 3, 291-300.
81. Hamshere, M.L., Walters, J.T., Smith, R. et al. (2013) Genome-wide significant associations in schizophrenia to ITIH3/4, CACNA1C and SDCCAG8, and extensive replication of associations reported by the schizophrenia PGC. Mol Psychiatry 18, 708-712.
82. Hankin, B.L., Abramson, L.Y., Moffitt, T.E., Silva, P.A., McGee, R. & Angell, K.E. (1998) Development of depression from preadolescence to young adulthood: emerging gender differences in a 10-year longitudinal study. J Abnorm Psychol 107, 128-140.
83. Harris, R.A., Wang, T., Coarfa, C. et al. (2010) Comparison of sequencing-based methods to profile DNA methylation and identification of monoallelic epigenetic modifications. Nat Biotechnol 28, 1097-1105.
84. Hatton, C.S., Wilkie, A.O., Drysdale, H.C., Wood, W.G., Vickers, M.A., Sharpe, J., Ayyub, H., Pretorius, I.M., Buckle, V.J. & Higgs, D.R. (1990) Alpha-thalassemia caused by a large (62 kb) deletion upstream of the human alpha globin gene cluster. Blood 76, 221-227.
85. Hawrylycz, M.J., Lein, E.S., Guillozet-Bongaarts, A.L. et al. (2012) An anatomically comprehensive atlas of the adult human brain transcriptome. Nature 489, 391-399.
86. He, Y. & Ecker, J.R. (2015) Non-CG methylation in the human genome. Annu Rev Genomics Hum Genet 16, 55-77.
87. He, Y.F., Li, B.Z., Li, Z., Liu, P., Wang, Y., Tang, Q., Ding, J., Jia, Y., Chen, Z., Li, L., Sun, Y., Li, X., Dai, Q., Song, C.X., Zhang, K., He, C. & Xu, G.L. (2011) Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science 333, 1303-1307.
88. Heidari, N., Phanstiel, D.H., He, C., Grubert, F., Jahanbani, F., Kasowski, M., Zhang, M.Q. & Snyder, M.P. (2014) Genome-wide map of regulatory interactions in the human genome. Genome Res 24, 1905-1917.
89. Heintzman, N.D., Stuart, R.K., Hon, G., Fu, Y., Ching, C.W., Hawkins, R.D., Barrera, L.O., Van Calcar, S., Qu, C., Ching, K.A., Wang, W., Weng, Z., Green, R.D., Crawford, G.E. & Ren, B. (2007) Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat Genet 39, 311-318.
90. Heinz, S., Romanoski, C.E., Benner, C., Allison, K.A., Kaikkonen, M.U., Orozco, L.D. & Glass, C.K. (2013) Effect of natural genetic variation on enhancer selection and function. Nature 503, 487-492.
91. Heinz, S., Romanoski, C.E., Benner, C. & Glass, C.K. (2015) The selection and function of cell type-specific enhancers. Nat Rev Mol Cell Biol 16, 144-154.
92. Higgs, D.R., Vernimen, D., Hughes, J. & Gibbons, R. (2006) Using genomics to study how chromatin influences gene expression. Annu Rev Genomics Hum Genet 14, 14.
93. Hines, M. (2008) Early androgen influences on human neural and behavioural development. Early Hum Dev 84, 805-807.
94. Hinney, A., Scherag, A., Jarick, I. et al. (2011) Genome-wide association study in German patients with attention deficit/hyperactivity disorder. Am J Med Genet B Neuropsychiatr Genet 156B, 888-897.
95. Hnisz, D., Abraham, B.J., Lee, T.I., Lau, A., Saint-Andre, V., Sigova, A.A., Hoke, H.A. & Young, R.A. (2013) Super-enhancers in the control of cell identity and disease. Cell 155, 934-947.
96. Ho, S.M., Topol, A. & Brennand, K.J. (2015) From directed differentiation to neuronal induction: modeling neuropsychiatric disease. Biomark Insights 10, 31-41.
97. Huang, Y.T. (2014) Integrative modeling of multiple genomic data from different types of genetic association studies. Biostatistics 15, 587-602.
98. Hughes, J.R., Roberts, N., McGowan, S., Hay, D., Giannoulatou, E., Lynch, M., De Gobbi, M., Taylor, S., Gibbons, R. & Higgs, D.R. (2014) Analysis of hundreds of cis-regulatory landscapes at high resolution in a single, high-throughput experiment. Nat Genet 46, 205-212.
99. Ingalhalikar, M., Smith, A., Parker, D., Satterthwaite, T.D., Elliott, M.A., Ruparel, K., Hakonarson, H., Gur, R.E., Gur, R.C. & Verma, R. (2014) Sex differences in the structural connectome of the human brain. Proc Natl Acad Sci USA 111, 823-828.
100. International Genetics of Ankylosing Spondylitis Consortium, Cortes, A., Hadler, J. et al. (2013) Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci. Nat Genet 45, 730-738.
101. Ito, S., Shen, L., Dai, Q., Wu, S.C., Collins, L.B., Swenberg, J.A., He, C. & Zhang, Y. (2011) Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science 333, 1300-1303.
102. Jaffe, A.E., Shin, J., Collado-Torres, L., Leek, J.T., Tao, R., Li, C., Gao, Y., Jia, Y., Maher, B.J., Hyde, T.M., Kleinman, J.E. & Weinberger, D.R. (2015) Developmental regulation of human cortex transcription and its clinical relevance at single base resolution. Nat Neurosci 18, 154-161.
103. Jin, F., Li, Y., Ren, B. & Natarajan, R. (2011) Enhancers: multi-dimensional signal integrators. Transcription 2, 226-230.
104. Jinek, M., Chylinski, K., Fonfara, I., Hauer, M., Doudna, J.A. & Charpentier, E. (2012) A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science 337, 816-821.
105. Johnson, D.S., Mortazavi, A., Myers, R.M. & Wold, B. (2007) Genome-wide mapping of in vivo protein-DNA interactions. Science 316, 1497-1502.
106. Kang, H.J., Kawasawa, Y.I., Cheng, F. et al. (2011) Spatio-temporal transcriptome of the human brain. Nature 478, 483-489.
107. Kessler, R.C., Berglund, P., Demler, O., Jin, R., Merikangas, K.R. & Walters, E.E. (2005) Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 62, 593-602.
108. Khor, B., Gardet, A. & Xavier, R.J. (2011) Genetics and pathogenesis of inflammatory bowel disease. Nature 474, 307-317.
109. Kigar, S.L. & Auger, A.P. (2013) Epigenetic mechanisms may underlie the aetiology of sex differences in mental health risk and resilience. J Neuroendocrinol 25, 1141-1150.
110. Kilpinen, H., Waszak, S.M., Gschwind, A.R. et al. (2013) Coordinated effects of sequence variation on DNA binding, chromatin structure, and transcription. Science 342, 744-747.
111. Kim, T.H., Abdullaev, Z.K., Smith, A.D., Ching, K.A., Loukinov, D.I., Green, R.D., Zhang, M.Q., Lobanenkov, V.V. & Ren, B. (2007) Analysis of the vertebrate insulator protein CTCF-binding sites in the human genome. Cell 128, 1231-1245.
112. Kim, T.K., Hemberg, M., Gray, J.M., Costa, A.M., Bear, D.M., Wu, J., Harmin, D.A., Laptewicz, M., Barbara-Haley, K., Kuersten, S., Markenscoff-Papadimitriou, E., Kuhl, D., Bito, H., Worley, P.F., Kreiman, G. & Greenberg, M.E. (2010) Widespread transcription at neuronal activity-regulated enhancers. Nature 465, 182-187.
113. Kinde, B., Gabel, H.W., Gilbert, C.S., Griffith, E.C. & Greenberg, M.E. (2015) Reading the unique DNA methylation landscape of the brain: non-CpG methylation, hydroxymethylation, and MeCP2. Proc Natl Acad Sci USA 112, 6800-6806.
114. King, M.C. & Wilson, A.C. (1975) Evolution at two levels in humans and chimpanzees. Science 188, 107-116.
115. Kocerha, J., Dwivedi, Y. & Brennand, K.J. (2015) Noncoding RNAs and neurobehavioral mechanisms in psychiatric disease. Mol Psychiatry 20, 677-684.
116. Koch, F., Fenouil, R., Gut, M., Cauchy, P., Albert, T.K., Zacarias-Cabeza, J., Spicuglia, S., de la Chapelle, A.L., Heidemann, M., Hintermair, C., Eick, D., Gut, I., Ferrier, P. & Andrau, J.C. (2011) Transcription initiation platforms and GTF recruitment at tissue-specific enhancers and promoters. Nat Struct Mol Biol 18, 956-963.
117. Kovacs, M., Obrosky, D.S. & Sherrill, J. (2003) Developmental changes in the phenomenology of depression in girls compared to boys from childhood onward. J Affect Disord 74, 33-48.
118. Kriaucionis, S. & Heintz, N. (2009) The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science 324, 929-930.
119. Kriukiene, E., Liutkeviciute, Z. & Klimasauskas, S. (2012) 5-Hydroxymethylcytosine-the elusive epigenetic mark in mammalian DNA. Chem Soc Rev 41, 6916-6930.
120. Kumar, G., Clark, S.L., McClay, J.L., Shabalin, A.A., Adkins, D.E., Xie, L., Chan, R., Nerella, S., Kim, Y., Sullivan, P.F., Hultman, C.M., Magnusson, P.K., Aberg, K.A. & van den Oord, E.J. (2015) Refinement of schizophrenia GWAS loci using methylome-wide association data. Hum Genet 134, 77-87.
121. Labrie, V., Pai, S. & Petronis, A. (2012) Epigenetics of major psychosis: progress, problems and perspectives. Trends Genet 28, 427-435.
122. Lai, F., Orom, U.A., Cesaroni, M., Beringer, M., Taatjes, D.J., Blobel, G.A. & Shiekhattar, R. (2013) Activating RNAs associate with mediator to enhance chromatin architecture and transcription. Nature 494, 497-501.
123. Lasky-Su, J., Neale, B.M., Franke, B. et al. (2008) Genome-wide association scan of quantitative traits for attention deficit hyperactivity disorder identifies novel associations and confirms candidate gene associations. Am J Med Genet B Neuropsychiatr Genet 147B, 1345-1354.
124. Lasky-Su, J., Won, S., Mick, E., Anney, R.J., Franke, B., Neale, B., Biederman, J., Smalley, S.L., Loo, S.K., Todorov, A., Faraone, S.V., Weiss, S.T. & Lange, C. (2010) On genome-wide association studies for family-based designs: an integrative analysis approach combining ascertained family samples with unselected controls. Am J Hum Genet 86, 573-580.
125. van de Leemput, J., Boles, N.C., Kiehl, T.R., Corneo, B., Lederman, P., Menon, V., Lee, C., Martinez, R.A., Levi, B.P., Thompson, C.L., Yao, S., Kaykas, A., Temple, S. & Fasano, C.A. (2014) CORTECON: a temporal transcriptome analysis of in vitro human cerebral cortex development from human embryonic stem cells. Neuron 83, 51-68.
126. Lesch, K.P., Timmesfeld, N., Renner, T.J., Halperin, R., Roser, C., Nguyen, T.T., Craig, D.W., Romanos, J., Heine, M., Meyer, J., Freitag, C., Warnke, A., Romanos, M., Schafer, H., Walitza, S., Reif, A., Stephan, D.A. & Jacob, C. (2008) Molecular genetics of adult ADHD: converging evidence from genome-wide association and extended pedigree linkage studies. J Neural Transm 115, 1573-1585.
127. Lettice, L.A., Heaney, S.J., Purdie, L.A., Li, L., de Beer, P., Oostra, B.A., Goode, D., Elgar, G., Hill, R.E. & de Graaff, E. (2003) A long-range Shh enhancer regulates expression in the developing limb and fin and is associated with preaxial polydactyly. Hum Mol Genet 12, 1725-1735.
128. Leveille, N., Melo, C.A. & Agami, R. (2015) Enhancer-associated RNAs as therapeutic targets. Expert Opin Biol Ther 15, 723-734.
129. Li, X., Wei, W., Zhao, Q.Y., Widagdo, J., Baker-Andresen, D., Flavell, C.R., D'Alessio, A., Zhang, Y. & Bredy, T.W. (2014) Neocortical Tet3-mediated accumulation of 5-hydroxymethylcytosine promotes rapid behavioral adaptation. Proc Natl Acad Sci USA 111, 7120-7125.
130. Lieberman-Aiden, E., van Berkum, N.L., Williams, L., Imakaev, M., Ragoczy, T., Telling, A., Amit, I., Lajoie, B.R., Sabo, P.J., Dorschner, M.O., Sandstrom, R., Bernstein, B., Bender, M.A., Groudine, M., Gnirke, A., Stamatoyannopoulos, J., Mirny, L.A., Lander, E.S. & Dekker, J. (2009) Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326, 289-293.
131. Lipovich, L., Dachet, F., Cai, J., Bagla, S., Balan, K., Jia, H. & Loeb, J.A. (2012) Activity-dependent human brain coding/noncoding gene regulatory networks. Genetics 192, 1133-1148.
132. Lister, R., Pelizzola, M., Dowen, R.H., Hawkins, R.D., Hon, G., Tonti-Filippini, J., Nery, J.R., Lee, L., Ye, Z., Ngo, Q.M., Edsall, L., Antosiewicz-Bourget, J., Stewart, R., Ruotti, V., Millar, A.H., Thomson, J.A., Ren, B. & Ecker, J.R. (2009) Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 462, 315-322.
133. Lister, R., Mukamel, E.A., Nery, J.R. et al. (2013) Global epigenomic reconfiguration during mammalian brain development. Science 341, 1237905.
134. Liu, S., Wang, J., Su, Y., Guerrero, C., Zeng, Y., Mitra, D., Brooks, P.J., Fisher, D.E., Song, H. & Wang, Y. (2013a) Quantitative assessment of Tet-induced oxidation products of 5-methylcytosine in cellular and tissue DNA. Nucleic Acids Res 41, 6421-6429.
135. Liu, Y., Ding, J., Reynolds, L.M. et al. (2013b) Methylomics of gene expression in human monocytes. Hum Mol Genet 22, 5065-5074.
136. Loke, H., Harley, V. & Lee, J. (2015) Biological factors underlying sex differences in neurological disorders. Int J Biochem Cell Biol 65, 139-150.
137. Loots, G.G., Kneissel, M., Keller, H., Baptist, M., Chang, J., Collette, N.M., Ovcharenko, D., Plajzer-Frick, I. & Rubin, E.M. (2005) Genomic deletion of a long-range bone enhancer misregulates sclerostin in Van Buchem disease. Genome Res 15, 928-935.
138. Ludwig, M.Z., Bergman, C., Patel, N.H. & Kreitman, M. (2000) Evidence for stabilizing selection in a eukaryotic enhancer element. Nature 403, 564-567.
139. Luijk, R., Goeman, J.J., Slagboom, E.P., Heijmans, B.T. & van Zwet, E.W. (2015) An alternative approach to multiple testing for methylation QTL mapping reduces the proportion of falsely identified CpGs. Bioinformatics 31, 340-345.
140. Lyst, M.J. & Bird, A. (2015) Rett syndrome: a complex disorder with simple roots. Nat Rev Genet 16, 261-275.
141. Madison, J.M., Zhou, F., Nigam, A. et al. (2015) Characterization of bipolar disorder patient-specific induced pluripotent stem cells from a family reveals neurodevelopmental and mRNA expression abnormalities. Mol Psychiatry 20, 703-717.
142. Maienschein-Cline, M., Dinner, A.R., Hlavacek, W.S. & Mu, F. (2012) Improved predictions of transcription factor binding sites using physicochemical features of DNA. Nucleic Acids Res 40, e175.
143. Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium1 (2013) A mega-analysis of genome-wide association studies for major depressive disorder. Mol Psychiatry 18, 497-511.
144. Malhotra, A.K., Correll, C.U., Chowdhury, N.I., Muller, D.J., Gregersen, P.K., Lee, A.T., Tiwari, A.K., Kane, J.M., Fleischhacker, W.W., Kahn, R.S., Ophoff, R.A., Lieberman, J.A., Meltzer, H.Y., Lencz, T. & Kennedy, J.L. (2012) Association between common variants near the melanocortin 4 receptor gene and severe antipsychotic drug-induced weight gain. Arch Gen Psychiatry 69, 904-912.
145. Matigian, N., Abrahamsen, G., Sutharsan, R. et al. (2010) Disease-specific, neurosphere-derived cells as models for brain disorders. Dis Model Mech 3, 785-798.
146. Mattheisen, M., Samuels, J.F., Wang, Y. et al. (2015) Genome-wide association study in obsessive-compulsive disorder: results from the OCGAS. Mol Psychiatry 20, 337-344.
147. Maurano, M.T., Humbert, R., Rynes, E. et al. (2012) Systematic localization of common disease-associated variation in regulatory DNA. Science 337, 1190-1195.
148. Maury, Y., Come, J., Piskorowski, R.A., Salah-Mohellibi, N., Chevaleyre, V., Peschanski, M., Martinat, C. & Nedelec, S. (2015) Combinatorial analysis of developmental cues efficiently converts human pluripotent stem cells into multiple neuronal subtypes. Nat Biotechnol 33, 89-96.
149. Meissner, A., Gnirke, A., Bell, G.W., Ramsahoye, B., Lander, E.S. & Jaenisch, R. (2005) Reduced representation bisulfite sequencing for comparative high-resolution DNA methylation analysis. Nucleic Acids Res 33, 5868-5877.
150. Mele, M., Ferreira, P.G., Reverter, F. et al. (2015) The human transcriptome across tissues and individuals. Science 348, 660-665.
151. Melnikov, A., Murugan, A., Zhang, X., Tesileanu, T., Wang, L., Rogov, P., Feizi, S., Gnirke, A., Callan, C.G. Jr., Kinney, J.B., Kellis, M., Lander, E.S. & Mikkelsen, T.S. (2012) Systematic dissection and optimization of inducible enhancers in human cells using a massively parallel reporter assay. Nat Biotechnol 30, 271-277.
152. Merkle, F.T., Maroof, A., Wataya, T., Sasai, Y., Studer, L., Eggan, K. & Schier, A.F. (2015) Generation of neuropeptidergic hypothalamic neurons from human pluripotent stem cells. Development 142, 633-643.
153. Miele, A. & Dekker, J. (2008) Mapping cis- and trans-chromatin interaction networks using chromosome conformation capture (3C). In Hancock, R. (ed), The Nucleus: Volume 2: Chromatin, Transcription, Envelope, Proteins, Dynamics, and Imaging. Humana Press, Totowa, NJ, USA, pp. 105-121.
154. Mifsud, B., Tavares-Cadete, F., Young, A.N., Sugar, R., Schoenfelder, S., Ferreira, L., Wingett, S.W., Andrews, S., Grey, W., Ewels, P.A., Herman, B., Happe, S., Higgs, A., LeProust, E., Follows, G.A., Fraser, P., Luscombe, N.M. & Osborne, C.S. (2015) Mapping long-range promoter contacts in human cells with high-resolution capture Hi-C. Nat Genet 47, 598-606.
155. Mikkelsen, T.S., Ku, M., Jaffe, D.B. et al. (2007) Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448, 553-560.
156. Miller, J.A., Ding, S.L., Sunkin, S.M. et al. (2014) Transcriptional landscape of the prenatal human brain. Nature 508, 199-206.
157. Mitchell, A.C., Bharadwaj, R., Whittle, C., Krueger, W., Mirnics, K., Hurd, Y., Rasmussen, T. & Akbarian, S. (2014) The genome in three dimensions: a new frontier in human brain research. Biol Psychiatry 75, 961-969.
158. Mo, A., Mukamel, E.A., Davis, F.P., Luo, C., Henry, G.L., Picard, S., Urich, M.A., Nery, J.R., Sejnowski, T.J., Lister, R., Eddy, S.R., Ecker, J.R. & Nathans, J. (2015) Epigenomic signatures of neuronal diversity in the mammalian brain. Neuron 86, 1369-1384.
159. Moraes, C.F., Lins, T.C., Carmargos, E.F., Naves, J.O., Pereira, R.W. & Nobrega, O.T. (2012) Lessons from genome-wide association studies findings in Alzheimer's disease. Psychogeriatrics 12, 62-73.
160. Muhleisen, T.W., Leber, M., Schulze, T.G. et al. (2014) Genome-wide association study reveals two new risk loci for bipolar disorder. Nat Commun 5, 3339.
161. Munzel, M., Globisch, D., Bruckl, T., Wagner, M., Welzmiller, V., Michalakis, S., Muller, M., Biel, M. & Carell, T. (2010) Quantification of the sixth DNA base hydroxymethylcytosine in the brain. Angew Chem 49, 5375-5377.
162. Naranjo, S., Voesenek, K., de la Calle-Mustienes, E., Robert-Moreno, A., Kokotas, H., Grigoriadou, M., Economides, J., Van Camp, G., Hilgert, N., Moreno, F., Alsina, B., Petersen, M.B., Kremer, H. & Gomez-Skarmeta, J.L. (2010) Multiple enhancers located in a 1-Mb region upstream of POU3F4 promote expression during inner ear development and may be required for hearing. Hum Genet 128, 411-419.
163. Neale, B.M., Lasky-Su, J., Anney, R. et al. (2008) Genome-wide association scan of attention deficit hyperactivity disorder. Am J Med Genet B Neuropsychiatr Genet 147B, 1337-1344.
164. Neale, B.M., Medland, S., Ripke, S. et al. (2010a) Case-control genome-wide association study of attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 49, 906-920.
165. Neale, B.M., Medland, S.E., Ripke, S. et al. (2010b) Meta-analysis of genome-wide association studies of attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 49, 884-897.
166. Nestor, C.E., Ottaviano, R., Reddington, J., Sproul, D., Reinhardt, D., Dunican, D., Katz, E., Dixon, J.M., Harrison, D.J. & Meehan, R.R. (2012) Tissue type is a major modifier of the 5-hydroxymethylcytosine content of human genes. Genome Res 22, 467-477.
167. Ngun, T.C., Ghahramani, N., Sanchez, F.J., Bocklandt, S. & Vilain, E. (2011) The genetics of sex differences in brain and behavior. Front Neuroendocrinol 32, 227-246.
168. Ni, Z., Abou El Hassan, M., Xu, Z., Yu, T. & Bremner, R. (2008) The chromatin-remodeling enzyme BRG1 coordinates CIITA induction through many interdependent distal enhancers. Nat Immunol 9, 785-793.
169. Nicholas, C.R., Chen, J., Tang, Y., Southwell, D.G., Chalmers, N., Vogt, D., Arnold, C.M., Chen, Y.J., Stanley, E.G., Elefanty, A.G., Sasai, Y., Alvarez-Buylla, A., Rubenstein, J.L. & Kriegstein, A.R. (2013) Functional maturation of hPSC-derived forebrain interneurons requires an extended timeline and mimics human neural development. Cell Stem Cell 12, 573-586.
170. Nicolae, D.L., Gamazon, E., Zhang, W., Duan, S., Dolan, M.E. & Cox, N.J. (2010) Trait-associated SNPs are more likely to be eQTLs: annotation to enhance discovery from GWAS. PLoS Genet 6, e1000888.
171. Nityanandam, A. & Baldwin, K.K. (2015) Advances in reprogramming-based study of neurologic disorders. Stem Cells Dev 24, 1265-1283.
172. Nobrega, M.A., Ovcharenko, I., Afzal, V. & Rubin, E.M. (2003) Scanning human gene deserts for long-range enhancers. Science 302, 413.
173. Nugent, B.M., Tobet, S.A., Lara, H.E., Lucion, A.B., Wilson, M.E., Recabarren, S.E. & Paredes, A.H. (2012) Hormonal programming across the lifespan. Horm Metab Res 44, 577-586.
174. O'Donovan, M.C., Craddock, N., Norton, N. et al. (2008) Identification of loci associated with schizophrenia by genome-wide association and follow-up. Nat Genet 40, 1053-1055.
175. O'Donovan, M.C., Craddock, N.J. & Owen, M.J. (2009) Genetics of psychosis; insights from views across the genome. Hum Genet 126, 3-12.
176. Orom, U.A. & Shiekhattar, R. (2013) Long noncoding RNAs usher in a new era in the biology of enhancers. Cell 154, 1190-1193.
177. Orom, U.A., Derrien, T., Beringer, M., Gumireddy, K., Gardini, A., Bussotti, G., Lai, F., Zytnicki, M., Notredame, C., Huang, Q., Guigo, R. & Shiekhattar, R. (2010) Long noncoding RNAs with enhancer-like function in human cells. Cell 143, 46-58.
178. Owen, M.J., O'Donovan, M.C., Thapar, A. & Craddock, N. (2011) Neurodevelopmental hypothesis of schizophrenia. Br J Psychiatry 198, 173-175.
179. Parker, S.C., Stitzel, M.L., Taylor, D.L., Orozco, J.M., Erdos, M.R., Akiyama, J.A., van Bueren, K.L., Chines, P.S., Narisu, N., Program, N.C.S., Black, B.L., Visel, A., Pennacchio, L.A., Collins, F.S., National Institutes of Health Intramural Sequencing Center Comparative Sequencing Program Authors & NISC Comparative Sequencing Program Authors (2013) Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variants. Proc Natl Acad Sci USA 110, 17921-17926.
180. Patwardhan, R.P., Hiatt, J.B., Witten, D.M., Kim, M.J., Smith, R.P., May, D., Lee, C., Andrie, J.M., Lee, S.I., Cooper, G.M., Ahituv, N., Pennacchio, L.A. & Shendure, J. (2012) Massively parallel functional dissection of mammalian enhancers in vivo. Nat Biotechnol 30, 265-270.
181. Pedrosa, E., Sandler, V., Shah, A., Carroll, R., Chang, C., Rockowitz, S., Guo, X., Zheng, D. & Lachman, H.M. (2011) Development of patient-specific neurons in schizophrenia using induced pluripotent stem cells. J Neurogenet 25, 88-103.
182. Pennacchio, L.A., Ahituv, N., Moses, A.M., Prabhakar, S., Nobrega, M.A., Shoukry, M., Minovitsky, S., Dubchak, I., Holt, A., Lewis, K.D., Plajzer-Frick, I., Akiyama, J., De Val, S., Afzal, V., Black, B.L., Couronne, O., Eisen, M.B., Visel, A. & Rubin, E.M. (2006) In vivo enhancer analysis of human conserved non-coding sequences. Nature 444, 499-502.
183. Peters, A.H. & Schubeler, D. (2005) Methylation of histones: playing memory with DNA. Curr Opin Cell Biol 17, 230-238.
184. Pineda, S., Gomez-Rubio, P., Picornell, A., Bessonov, K., Marquez, M., Kogevinas, M., Real, F.X., Van Steen, K. & Malats, N. (2015) Framework for the integration of genomics, epigenomics and transcriptomics in complex diseases. Hum Hered 79, 124-136.
185. Plongthongkum, N., Diep, D.H. & Zhang, K. (2014) Advances in the profiling of DNA modifications: cytosine methylation and beyond. Nat Rev Genet 15, 647-661.
186. Prabhakar, S., Noonan, J.P., Paabo, S. & Rubin, E.M. (2006) Accelerated evolution of conserved noncoding sequences in humans. Science 314, 786.
187. Prokunina, L., Castillejo-Lopez, C., Oberg, F. et al. (2002) A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nat Genet 32, 666-669.
188. Psychiatric GWAS Consortium Bipolar Disorder Working Group (2011) Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. Nat Genet 43, 977-983.
189. Ramasamy, A., Trabzuni, D., Guelfi, S., Varghese, V., Smith, C., Walker, R., De, T., UK Brain Expression Consortium, North American Brain Expression Consortium, Coin, L., de Silva, R., Cookson, M.R., Singleton, A.B., Hardy, J., Ryten, M. & Weale, M.E. (2014) Genetic variability in the regulation of gene expression in ten regions of the human brain. Nat Neurosci 17, 1418-1428.
190. Ran, F.A., Hsu, P.D., Wright, J., Agarwala, V., Scott, D.A. & Zhang, F. (2013) Genome engineering using the CRISPR-Cas9 system. Nat Protoc 8, 2281-2308.
191. Rao, S.S., Huntley, M.H., Durand, N.C., Stamenova, E.K., Bochkov, I.D., Robinson, J.T., Sanborn, A.L., Machol, I., Omer, A.D., Lander, E.S. & Aiden, E.L. (2014) A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell 159, 1665-1680.
192. Ren, B., Robert, F., Wyrick, J.J., Aparicio, O., Jennings, E.G., Simon, I., Zeitlinger, J., Schreiber, J., Hannett, N., Kanin, E., Volkert, T.L., Wilson, C.J., Bell, S.P. & Young, R.A. (2000) Genome-wide location and function of DNA binding proteins. Science 290, 2306-2309.
193. Ricano-Ponce, I. & Wijmenga, C. (2013) Mapping of immune-mediated disease genes. Annu Rev Genomics Hum Genet 14, 325-353.
194. Roadmap Epigenomics Consortium, Kundaje, A., Meuleman, W. et al. (2015) Integrative analysis of 111 reference human epigenomes. Nature 518, 317-330.
195. Robertson, G., Hirst, M., Bainbridge, M., Bilenky, M., Zhao, Y., Zeng, T., Euskirchen, G., Bernier, B., Varhol, R., Delaney, A., Thiessen, N., Griffith, O.L., He, A., Marra, M., Snyder, M. & Jones, S. (2007) Genome-wide profiles of STAT1 DNA association using chromatin immunoprecipitation and massively parallel sequencing. Nat Methods 4, 651-657.
196. Robicsek, O., Karry, R., Petit, I., Salman-Kesner, N., Muller, F.J., Klein, E., Aberdam, D. & Ben-Shachar, D. (2013) Abnormal neuronal differentiation and mitochondrial dysfunction in hair follicle-derived induced pluripotent stem cells of schizophrenia patients. Mol Psychiatry 18, 1067-1076.
197. Rockman, M.V., Hahn, M.W., Soranzo, N., Goldstein, D.B. & Wray, G.A. (2003) Positive selection on a human-specific transcription factor binding site regulating IL4 expression. Curr Biol 13, 2118-2123.
198. Sajan, S.A. & Hawkins, R.D. (2012) Methods for identifying higher-order chromatin structure. Annu Rev Genomics Hum Genet 13, 59-82.
199. Sandborn, W.J., Ghosh, S., Panes, J., Vranic, I., Su, C., Rousell, S., Niezychowski, W. & Study A3921063 Investigators (2012) Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. N Engl J Med 367, 616-624.
200. Sandoe, J. & Eggan, K. (2013) Opportunities and challenges of pluripotent stem cell neurodegenerative disease models. Nat Neurosci 16, 780-789.
201. Santiago, M., Antunes, C., Guedes, M., Sousa, N. & Marques, C.J. (2014) TET enzymes and DNA hydroxymethylation in neural development and function-how critical are they? Genomics 104, 334-340.
202. Sanyal, A., Lajoie, B.R., Jain, G. & Dekker, J. (2012) The long-range interaction landscape of gene promoters. Nature 489, 109-113.
203. Scharf, J.M., Yu, D., Mathews, C.A. et al. (2013) Genome-wide association study of Tourette's syndrome. Mol Psychiatry 18, 721-728.
204. Schaub, M.A., Boyle, A.P., Kundaje, A., Batzoglou, S. & Snyder, M. (2012) Linking disease associations with regulatory information in the human genome. Genome Res 22, 1748-1759.
205. Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium (2011) Genome-wide association study identifies five new schizophrenia loci. Nat Genet 43, 969-976.
206. Schizophrenia Working Group of the Psychiatric Genomics Consortium (2014) Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421-427.
207. Schubeler, D., MacAlpine, D.M., Scalzo, D., Wirbelauer, C., Kooperberg, C., van Leeuwen, F., Gottschling, D.E., O'Neill, L.P., Turner, B.M., Delrow, J., Bell, S.P. & Groudine, M. (2004) The histone modification pattern of active genes revealed through genome-wide chromatin analysis of a higher eukaryote. Genes Dev 18, 1263-1271.
208. Schug, J. (2008) Using TESS to predict transcription factor binding sites in DNA sequence. Curr Protoc Bioinformatics Chapter 2, Unit 2.6.
209. Schultz, M.D., He, Y., Whitaker, J.W., Hariharan, M., Mukamel, E.A., Leung, D., Rajagopal, N., Nery, J.R., Urich, M.A., Chen, H., Lin, S., Lin, Y., Jung, I., Schmitt, A.D., Selvaraj, S., Ren, B., Sejnowski, T.J., Wang, W. & Ecker, J.R. (2015) Human body epigenome maps reveal noncanonical DNA methylation variation. Nature 523, 212-216.
210. Sexton, T., Kurukuti, S., Mitchell, J.A., Umlauf, D., Nagano, T. & Fraser, P. (2012) Sensitive detection of chromatin coassociations using enhanced chromosome conformation capture on chip. Nat Protoc 7, 1335-1350.
211. Sharpe, J.A., Chan-Thomas, P.S., Lida, J., Ayyub, H., Wood, W.G. & Higgs, D.R. (1992) Analysis of the human alpha globin upstream regulatory element (HS-40) in transgenic mice. EMBO J 11, 4565-4572.
212. Shen, Y., Yue, F., McCleary, D.F., Ye, Z., Edsall, L., Kuan, S., Wagner, U., Dixon, J., Lee, L., Lobanenkov, V.V. & Ren, B. (2012) A map of the cis-regulatory sequences in the mouse genome. Nature 488, 116-120.
213. Shin, J., Ming, G.L. & Song, H. (2014) DNA modifications in the mammalian brain. Philos Trans R Soc Lond B Biol Sci 369, 20130512.
214. Shull, A.Y., Noonepalle, S.K., Lee, E.J., Choi, J.H. & Shi, H. (2015) Sequencing the cancer methylome. Methods Mol Biol 1238, 627-651.
215. Simonis, M., Klous, P., Splinter, E., Moshkin, Y., Willemsen, R., de Wit, E., van Steensel, B. & de Laat, W. (2006) Nuclear organization of active and inactive chromatin domains uncovered by chromosome conformation capture-on-chip (4C). Nat Genet 38, 1348-1354.
216. Sisk, C.L. & Zehr, J.L. (2005) Pubertal hormones organize the adolescent brain and behavior. Front Neuroendocrinol 26, 163-174.
217. Song, C.X., Szulwach, K.E., Fu, Y., Dai, Q., Yi, C., Li, X., Li, Y., Chen, C.H., Zhang, W., Jian, X., Wang, J., Zhang, L., Looney, T.J., Zhang, B., Godley, L.A., Hicks, L.M., Lahn, B.T., Jin, P. & He, C. (2011) Selective chemical labeling reveals the genome-wide distribution of 5-hydroxymethylcytosine. Nat Biotechnol 29, 68-72.
218. Song, C.X., Szulwach, K.E., Dai, Q., Fu, Y., Mao, S.Q., Lin, L., Street, C., Li, Y., Poidevin, M., Wu, H., Gao, J., Liu, P., Li, L., Xu, G.L., Jin, P. & He, C. (2013) Genome-wide profiling of 5-formylcytosine reveals its roles in epigenetic priming. Cell 153, 678-691.
219. Spiers, H., Hannon, E., Schalkwyk, L.C., Smith, R., Wong, C.C., O'Donovan, M.C., Bray, N.J. & Mill, J. (2015) Methylomic trajectories across human fetal brain development. Genome Res 25, 338-352.
220. Spilianakis, C.G. & Flavell, R.A. (2004) Long-range intrachromosomal interactions in the T helper type 2 cytokine locus. Nat Immunol 5, 1017-1027.
221. Splinter, E., de Wit, E., van de Werken, H.J., Klous, P. & de Laat, W. (2012) Determining long-range chromatin interactions for selected genomic sites using 4C-seq technology: from fixation to computation. Methods 58, 221-230.
222. Steidl, U., Steidl, C., Ebralidze, A. et al. (2007) A distal single nucleotide polymorphism alters long-range regulation of the PU.1 gene in acute myeloid leukemia. J Clin Invest 117, 2611-2620.
223. Stergiakouli, E., Hamshere, M., Holmans, P., Langley, K., Zaharieva, I., Hawi, Z., Kent, L., Gill, M., Williams, N., Owen, M.J., O'Donovan, M. & Thapar, A. (2012) Investigating the contribution of common genetic variants to the risk and pathogenesis of ADHD. Am J Psychiatry 169, 186-194.
224. Stewart, S.E., Yu, D., Scharf, J.M. et al. (2013) Genome-wide association study of obsessive-compulsive disorder. Mol Psychiatry 18, 788-798.
225. Sun, Y.V. (2014) The influences of genetic and environmental factors on methylome-wide association studies for human diseases. Curr Genet Med Rep 2, 261-270.
226. Sun, M., Ma, F., Zeng, X., Liu, Q., Zhao, X.L., Wu, F.X., Wu, G.P., Zhang, Z.F., Gu, B., Zhao, Y.F., Tian, S.H., Lin, B., Kong, X.Y., Zhang, X.L., Yang, W., Lo, W.H. & Zhang, X. (2008) Triphalangeal thumb-polysyndactyly syndrome and syndactyly type IV are caused by genomic duplications involving the long range, limb-specific SHH enhancer. J Med Genet 45, 589-595.
227. Sun, W., Zang, L., Shu, Q. & Li, X. (2014) From development to diseases: the role of 5hmC in brain. Genomics 104, 347-351.
228. Szulwach, K.E., Li, X., Li, Y., Song, C.X., Wu, H., Dai, Q., Irier, H., Upadhyay, A.K., Gearing, M., Levey, A.I., Vasanthakumar, A., Godley, L.A., Chang, Q., Cheng, X., He, C. & Jin, P. (2011) 5-hmC-mediated epigenetic dynamics during postnatal neurodevelopment and aging. Nat Neurosci 14, 1607-1616.
229. Tahiliani, M., Koh, K.P., Shen, Y., Pastor, W.A., Bandukwala, H., Brudno, Y., Agarwal, S., Iyer, L.M., Liu, D.R., Aravind, L. & Rao, A. (2009) Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324, 930-935.
230. Tanaka, Y., Maeshima, K. & Yamaoka, K. (2012) In vitro and in vivo analysis of a JAK inhibitor in rheumatoid arthritis. Ann Rheum Dis 71 (Suppl 2), i70-i74.
231. The Psychiatric GWAS Consortium Steering Committee (2009) A framework for interpreting genome-wide association studies of psychiatric disorders. Mol Psychiatry 14, 10-17.
232. Tokuhiro, S., Yamada, R., Chang, X., Suzuki, A., Kochi, Y., Sawada, T., Suzuki, M., Nagasaki, M., Ohtsuki, M., Ono, M., Furukawa, H., Nagashima, M., Yoshino, S., Mabuchi, A., Sekine, A., Saito, S., Takahashi, A., Tsunoda, T., Nakamura, Y. & Yamamoto, K. (2003) An intronic SNP in a RUNX1 binding site of SLC22A4, encoding an organic cation transporter, is associated with rheumatoid arthritis. Nat Genet 35, 341-348.
233. Tomizawa, S., Kobayashi, H., Watanabe, T., Andrews, S., Hata, K., Kelsey, G. & Sasaki, H. (2011) Dynamic stage-specific changes in imprinted differentially methylated regions during early mammalian development and prevalence of non-CpG methylation in oocytes. Development 138, 811-820.
234. Trabzuni, D., Ramasamy, A., Imran, S., Walker, R., Smith, C., Weale, M.E., Hardy, J., Ryten, M. & North American Brain Expression Consortium (2013) Widespread sex differences in gene expression and splicing in the adult human brain. Nat Commun 4, 2771.
235. Ulahannan, N. & Greally, J.M. (2015) Genome-wide assays that identify and quantify modified cytosines in human disease studies. Epigenetics Chromatin 8, 5.
236. Vanhille, L., Griffon, A., Maqbool, M.A., Zacarias-Cabeza, J., Dao, L.T., Fernandez, N., Ballester, B., Andrau, J.C. & Spicuglia, S. (2015) High-throughput and quantitative assessment of enhancer activity in mammals by CapStarr-seq. Nat Commun 6, 6905.
237. Vawter, M.P., Evans, S., Choudary, P., Tomita, H., Meador-Woodruff, J., Molnar, M., Li, J., Lopez, J.F., Myers, R., Cox, D., Watson, S.J., Akil, H., Jones, E.G. & Bunney, W.E. (2004) Gender-specific gene expression in post-mortem human brain: localization to sex chromosomes. Neuropsychopharmacology 29, 373-384.
238. Verlaan, D.J., Berlivet, S., Hunninghake, G.M. et al. (2009) Allele-specific chromatin remodeling in the ZPBP2/GSDMB/ORMDL3 locus associated with the risk of asthma and autoimmune disease. Am J Hum Genet 85, 377-393.
239. Visser, M., Kayser, M. & Palstra, R.J. (2012) HERC2 rs12913832 modulates human pigmentation by attenuating chromatin-loop formation between a long-range enhancer and the OCA2 promoter. Genome Res 22, 446-455.
240. Wagner, M., Steinbacher, J., Kraus, T.F., Michalakis, S., Hackner, B., Pfaffeneder, T., Perera, A., Muller, M., Giese, A., Kretzschmar, H.A. & Carell, T. (2015) Age-dependent levels of 5-methyl-, 5-hydroxymethyl-, and 5-formylcytosine in human and mouse brain tissues. Angew Chem 54, 12511-12514.
241. Wang, K.S., Liu, X.F. & Aragam, N. (2010) A genome-wide meta-analysis identifies novel loci associated with schizophrenia and bipolar disorder. Schizophr Res 124, 192-199.
242. Wang, T., Pan, Q., Lin, L., Szulwach, K.E., Song, C.X., He, C., Wu, H., Warren, S.T., Jin, P., Duan, R. & Li, X. (2012) Genome-wide DNA hydroxymethylation changes are associated with neurodevelopmental genes in the developing human cerebellum. Hum Mol Genet 21, 5500-5510.
243. Wang, J.L., Shamah, S.M., Sun, A.X., Waldman, I.D., Haggarty, S.J. & Perlis, R.H. (2014) Label-free, live optical imaging of reprogrammed bipolar disorder patient-derived cells reveals a functional correlate of lithium responsiveness. Transl Psychiatry 4, e428.
244. Ward, L.D. & Kellis, M. (2012) HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res 40, D930-D934.
245. Weickert, C.S., Elashoff, M., Richards, A.B., Sinclair, D., Bahn, S., Paabo, S., Khaitovich, P. & Webster, M.J. (2009) Transcriptome analysis of male-female differences in prefrontal cortical development. Mol Psychiatry 14, 558-561.
246. Weinberger, D.R. (1987) Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 44, 660-669.
247. Weirauch, M.T., Cote, A., Norel, R., Annala, M., Zhao, Y., Riley, T.R., Saez-Rodriguez, J., Cokelaer, T., Vedenko, A., Talukder, S., DREAM5 Consortium, Bussemaker, H.J., Morris, Q.D., Bulyk, M.L., Stolovitzky, G. & Hughes, T.R. (2013) Evaluation of methods for modeling transcription factor sequence specificity. Nat Biotechnol 31, 126-134.
248. Wen, L. & Tang, F. (2014) Genomic distribution and possible functions of DNA hydroxymethylation in the brain. Genomics 104, 341-346.
249. Wen, L., Li, X., Yan, L. et al. (2014a) Whole-genome analysis of 5-hydroxymethylcytosine and 5-methylcytosine at base resolution in the human brain. Genome Biol 15, R49.
250. Wen, Z., Nguyen, H.N., Guo, Z. et al. (2014b) Synaptic dysregulation in a human iPS cell model of mental disorders. Nature 515, 414-418.
251. van de Werken, H.J., de Vree, P.J., Splinter, E., Holwerda, S.J., Klous, P., de Wit, E. & de Laat, W. (2012a) 4C technology: protocols and data analysis. Methods Enzymol 513, 89-112.
252. van de Werken, H.J., Landan, G., Holwerda, S.J., Hoichman, M., Klous, P., Chachik, R., Splinter, E., Valdes-Quezada, C., Oz, Y., Bouwman, B.A., Verstegen, M.J., de Wit, E., Tanay, A. & de Laat, W. (2012b) Robust 4C-seq data analysis to screen for regulatory DNA interactions. Nat Methods 9, 969-972.
253. Whitaker, J.W., Chen, Z. & Wang, W. (2015) Predicting the human epigenome from DNA motifs. Nat Methods 12, 265-272, 267 p following 272.
254. Whyte, W.A., Orlando, D.A., Hnisz, D., Abraham, B.J., Lin, C.Y., Kagey, M.H., Rahl, P.B., Lee, T.I. & Young, R.A. (2013) Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell 153, 307-319.
255. Wockner, L.F., Noble, E.P., Lawford, B.R., Young, R.M., Morris, C.P., Whitehall, V.L. & Voisey, J. (2014) Genome-wide DNA methylation analysis of human brain tissue from schizophrenia patients. Transl Psychiatry 4, e339.
256. Wright, R., Rethelyi, J.M. & Gage, F.H. (2014) Enhancing induced pluripotent stem cell models of schizophrenia. JAMA Psychiatry 71, 334-335.
257. Xie, W., Barr, C.L., Kim, A., Yue, F., Lee, A.Y., Eubanks, J., Dempster, E.L. & Ren, B. (2012) Base-resolution analyses of sequence and parent-of-origin dependent DNA methylation in the mouse genome. Cell 148, 816-831.
258. Yoon, K.J., Nguyen, H.N., Ursini, G. et al. (2014) Modeling a genetic risk for schizophrenia in iPSCs and mice reveals neural stem cell deficits associated with adherens junctions and polarity. Cell Stem Cell 15, 79-91.
259. Yu, M., Hon, G.C., Szulwach, K.E., Song, C.X., Zhang, L., Kim, A., Li, X., Dai, Q., Shen, Y., Park, B., Min, J.H., Jin, P., Ren, B. & He, C. (2012) Base-resolution analysis of 5-hydroxymethylcytosine in the mammalian genome. Cell 149, 1368-1380.
260. Zahn-Waxler, C., Shirtcliff, E.A. & Marceau, K. (2008) Disorders of childhood and adolescence: gender and psychopathology. Annu Rev Clin Psychol 4, 275-303.
261. Zandi, P.P., Avramopoulos, D., Willour, V.L., Huo, Y., Miao, K., Mackinnon, D.F., McInnis, M.G., Potash, J.B. & Depaulo, J.R. (2007) SNP fine mapping of chromosome 8q24 in bipolar disorder. Am J Med Genet B Neuropsychiatr Genet 144B, 625-630.
262. Zhao, Z., Tavoosidana, G., Sjolinder, M., Gondor, A., Mariano, P., Wang, S., Kanduri, C., Lezcano, M., Sandhu, K.S., Singh, U., Pant, V., Tiwari, V., Kurukuti, S. & Ohlsson, R. (2006) Circular chromosome conformation capture (4C) uncovers extensive networks of epigenetically regulated intra- and interchromosomal interactions. Nat Genet 38, 1341-1347.
263. Zhao, Z., Li, Y., Chen, H., Lu, J., Thompson, P.M., Chen, J., Wang, Z., Xu, J., Xu, C. & Li, X. (2014) PD_NGSAtlas: a reference database combining next-generation sequencing epigenomic and transcriptomic data for psychiatric disorders. BMC Med Genomics 7, 71.
264. Zhi, D., Aslibekyan, S., Irvin, M.R., Claas, S.A., Borecki, I.B., Ordovas, J.M., Absher, D.M. & Arnett, D.K. (2013) SNPs located at CpG sites modulate genome-epigenome interaction. Epigenetics 8, 802-806.
265. Zhong, H., Beaulaurier, J., Lum, P.Y. et al. (2010) Liver and adipose expression associated SNPs are enriched for association to type 2 diabetes. PLoS Genet 6, e1000932.
266. Zhou, T., Shen, N., Yang, L., Abe, N., Horton, J., Mann, R.S., Bussemaker, H.J., Gordan, R. & Rohs, R. (2015) Quantitative modeling of transcription factor binding specificities using DNA shape. Proc Natl Acad Sci USA 112, 4654-4659.
267. Zou, F., Chai, H.S., Younkin, C.S. et al. (2012) Brain expression genome-wide association study (eGWAS) identifies human disease-associated variants. PLoS Genet 8, e1002707.
268. Zuin, J., Dixon, J.R., van der Reijden, M.I., Ye, Z., Kolovos, P., Brouwer, R.W., van de Corput, M.P., van de Werken, H.J., Knoch, T.A., van Ijcken, W.F., Grosveld, F.G., Ren, B. & Wendt, K.S. (2014) Cohesin and CTCF differentially affect chromatin architecture and gene expression in human cells. Proc Natl Acad Sci USA 111, 996-1001.
269. Zwaigenbaum, L., Bryson, S., Rogers, T., Roberts, W., Brian, J. & Szatmari, P. (2005) Behavioral manifestations of autism in the first year of life. Int J Dev Neurosci 23, 143-152.