Buccals are likely to be a more informative surrogate tissue than blood for epigenome-wide association studies
Open accessAbstract
There is increasing evidence that interindividual epigenetic variation is an etiological factor in common human diseases. Such epigenetic variation could be genetic or non-genetic in origin, and epigenome-wide association studies (EWASs) are underway for a wide variety of diseases/phenotypes. However, performing an EWAS is associated with a range of issues not typically encountered in genome-wide association studies (GWASs), such as the tissue to be analyzed. In many EWASs, it is not possible to analyze the target tissue in large numbers of live humans, and consequently surrogate tissues are employed, most commonly blood. But there is as yet no evidence demonstrating that blood is more informative than buccal cells, the other easily accessible tissue. To assess the potential of buccal cells for use in EWASs, we performed a comprehensive analysis of a buccal cell methylome using whole-genome bisulfite sequencing. Strikingly, a buccal vs. blood comparison reveals>6X as many hypomethylated regions in buccal. These tissue-specific differentially methylated regions (tDMRs) are strongly enriched for DNaseI hotspots. Almost 75% of these tDMRs are not captured by commonly used DNA methylome profiling platforms such as Reduced Representational Bisulfite Sequencing and the Illumina Infinium HumanMethylation450 BeadChip, and they also display distinct genomic properties. Buccal hypo-tDMRs show a statistically significant enrichment near SNPs associated to disease identified through GWASs. Finally, we find that, compared with blood, buccal hypo-tDMRs show significantly greater overlap with hypomethylated regions in other tissues. We propose that for non-blood based diseases/phenotypes, buccal will be a more informative tissue for EWASs.
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DNA methylation patterns in saliva may be closer to that of brain tissue than DNA methylation in blood or buccal cells.
“it has been suggested that DNA methylation patterns in saliva may be closer to that of brain tissue than DNA methylation in blood or buccal cells (Braun et al., 2019;Lowe et al., 2013;Smith et al., 2015).”
From The applied implications of epigenetics in anxiety, affective and stress-related disorders - A review and synthesis on psychosocial stress, psychotherapy and prevention (2020) · cites this paper as Lowe et al., 2013
In “Generation of a human buccal cell DNA methylome” (page not available), the paper reports that buccal methylation profiles are closer than blood profiles to other non-blood tissues, including brain. It explicitly says it profiled brushed buccal cells, not saliva, and provides no comparison showing saliva is closer to brain than either blood or buccal cells. (LLM, conf=0.84)
Experimental — accuracy not yet measuredOverlap in DNA methylation levels measured in saliva, buccal cells and blood is limited.
“overlap in DNA methylation levels measured in saliva, buccal cells and blood is limited”
From The applied implications of epigenetics in anxiety, affective and stress-related disorders - A review and synthesis on psychosocial stress, psychotherapy and prevention (2020) · cites this paper as Lowe et al., 2013
The 'Generation of a human buccal cell DNA methylome' section reports substantial methylation differences between buccal cells and blood. It explicitly says the researchers profiled brushed buccal cells, not saliva, so it does not establish limited overlap across all three sample types. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measured
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Cites
Ultrafast and memory-efficient alignment of short DNA sequences to the human genome.
Langmead, B., Trapnell, C., Pop, M., & Salzberg, S. L. (2009) · Genome Biology · doi:10.1186/gb-2009-10-3-r25 · Cited by 21,849 · see citing works
An integrated encyclopedia of DNA elements in the human genome
The ENCODE Project Consortium (2012) · Nature · doi:10.1038/nature11247 · Cited by 18,072 · see citing works
Bismark: a flexible aligner and methylation caller for Bisulfite-Seq applications
Krueger, F., & Andrews, S. (2011) · Bioinformatics · doi:10.1093/bioinformatics/btr167 · Cited by 5,161 · see citing works
Human DNA methylomes at base resolution show widespread epigenomic differences
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., et al. (2009) · Nature · doi:10.1038/nature08514 · Cited by 4,673 · see citing works
Genome-wide methylation profiles reveal quantitative views of human aging rates
Hannum, G., Guinney, J., Zhao, L., Zhang, L., Hughes, G., Sadda, S., Klotzle, B., Bibikova, M., Fan, J.-B., Gao, Y., et al. (2013) · Molecular Cell · doi:10.1016/j.molcel.2012.10.016 · Cited by 4,270 · see citing works
Systematic Localization of Common Disease-Associated Variation in Regulatory DNA
Maurano, M. T., Humbert, R., Rynes, E., Thurman, R. E., Haugen, E., Wang, H., Reynolds, A. P., Sandstrom, R., Qu, H., Brody, J., et al. (2012) · Science · doi:10.1126/science.1222794 · Cited by 3,716 · see citing works
Mapping and analysis of chromatin state dynamics in nine human cell types
Ernst, J., Kheradpour, P., Mikkelsen, T. S., Shoresh, N., Ward, L. D., Epstein, C. B., Zhang, X., Wang, L., Issner, R., Coyne, M., et al. (2011) · Nature · doi:10.1038/nature09906 · Cited by 2,898 · see citing works
Genome-scale DNA methylation maps of pluripotent and differentiated cells
Meissner, A., Mikkelsen, T. S., Gu, H., Wernig, M., Hanna, J., Sivachenko, A., Zhang, X., Bernstein, B. E., Nusbaum, C., Jaffe, D. B., et al. (2008) · Nature · doi:10.1038/nature07107 · Cited by 2,536 · see citing works
Weber, M., Hellmann, I., Stadler, M. B., Ramos, L., Pääbo, S., Rebhan, M., & Schübeler, D. (2007) · Nature Genetics · doi:10.1038/ng1990 · Cited by 2,267 · see citing works
Genome-Wide Evolutionary Analysis of Eukaryotic DNA Methylation
Zemach, A., McDaniel, I. E., Silva, P., & Zilberman, D. (2010) · Science · doi:10.1126/science.1186366 · Cited by 1,796 · see citing works
Genetics of gene expression and its effect on disease
Emilsson, V., Thorleifsson, G., Zhang, B., Leonardson, A. S., Zink, F., Zhu, J., Carlson, S., Helgason, A., Walters, G. B., Gunnarsdottir, S., et al. (2008) · Nature · doi:10.1038/nature06758 · Cited by 1,296 · see citing works
Conservation and divergence of methylation patterning in plants and animals
Feng, S., Cokus, S. J., Zhang, X., Chen, P.-Y., Bostick, M., Goll, M. G., Hetzel, J., Jain, J., Strauss, S. H., Halpern, M. E., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1002720107 · Cited by 1,285 · see citing works
Epigenome-wide association studies for common human diseases
Rakyan, V. K., Down, T. A., Balding, D. J., & Beck, S. (2011) · Nature Reviews Genetics · doi:10.1038/nrg3000 · Cited by 1,272 · see citing works
Self-citationValidation of a DNA methylation microarray for 450,000 CpG sites in the human genome
Sandoval, J., Heyn, H., Moran, S., Serra-Musach, J., Pujana, M. A., Bibikova, M., & Esteller, M. (2011) · Epigenetics · doi:10.4161/epi.6.6.16196 · Cited by 990 · see citing works
Human aging-associated DNA hypermethylation occurs preferentially at bivalent chromatin domainsPreprint
Rakyan, V. K., Down, T. A., Maslau, S., Andrew, T., Yang, T.-P., Beyan, H., Whittaker, P., McCann, O. T., Finer, S., Valdes, A. M., et al. (2010) · Genome Research · doi:10.1101/gr.103101.109 · Cited by 750 · see citing works
Self-citationBell, J., Tsai, P.-C., Yang, T.-P., Pidsley, R., Nisbet, J. P., Glass, D., Mangino, M., Zhai, G., Zhang, F., Valdes, A., et al. (2012) · PLoS Genetics · doi:10.1371/journal.pgen.1002629 · Cited by 722 · see citing works
Joubert, B. R., Håberg, S. E., Nilsen, R. M., Wang, X., Vollset, S. E., Murphy, S. K., Huang, Z., Hoyo, C., Midttun, Ø., Cupul-Uicab, L. A., et al. (2012) · Environmental Health Perspectives · doi:10.1289/ehp.1205412 · Cited by 716 · see citing works
Harris, R. A., Wang, T., Coarfa, C., Nagarajan, R. P., Hong, C., Downey, S. L., Johnson, B., Fouse, S. D., Delaney, A. D., Zhao, Y., et al. (2010) · Nature Biotechnology · doi:10.1038/nbt.1682 · Cited by 713 · see citing works
Epigenetics as a unifying principle in the aetiology of complex traits and diseases
Petronis, A. (2010) · Nature · doi:10.1038/nature09230 · Cited by 682 · see citing works
Javierre, B. M., Fernández, A. F., Richter, J., Al‐Shahrour, F., Martín-Subero, J. I., Rodríguez‐Ubreva, J., Berdasco, M., Fraga, M. F., OʼHanlon, T. P., Rider, L. G., et al. (2009) · Genome Research · doi:10.1101/gr.100289.109 · Cited by 669 · see citing works
Tobacco-smoking-related differential DNA methylation: 27K discovery and replication
Breitling, L. P., Yang, R., Korn, B., Burwinkel, B., & Brenner, H. (2011) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2011.03.003 · Cited by 640 · see citing works
Quantitative comparison of genome-wide DNA methylation mapping technologies
Bock, C., Tomazou, E. M., Brinkman, A. B., Müller, F., Simmer, F., Gu, H., Jäger, N., Gnirke, A., Stunnenberg, H. G., & Meissner, A. (2010) · Nature Biotechnology · doi:10.1038/nbt.1681 · Cited by 587 · see citing works
Feinberg, A. P., & Irizarry, R. A. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0906183107 · Cited by 524 · see citing works
Dempster, E. L., Pidsley, R., Schalkwyk, L. C., Owens, S., Georgiades, A., Kane, F., Kalidindi, S., Picchioni, M., Kravariti, E., Toulopoulou, T., et al. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr416 · Cited by 460 · see citing works
Season of Conception in Rural Gambia Affects DNA Methylation at Putative Human Metastable Epialleles
Waterland, R. A., Kellermayer, R., Laritsky, E., Rayco‐Solon, P., Harris, R. A., Travisano, M., Zhang, W., Torskaya, M. S., Zhang, J., Shen, L., et al. (2010) · PLoS Genetics · doi:10.1371/journal.pgen.1001252 · Cited by 454 · see citing works
Sperm Methylation Profiles Reveal Features of Epigenetic Inheritance and Evolution in Primates
Molaro, A., Hodges, E. C., Fang, F., Song, Q., McCombie, W. R., Hannon, G. J., & Smith, A. D. (2011) · Cell · doi:10.1016/j.cell.2011.08.016 · Cited by 418 · see citing works
The Architecture of Gene Regulatory Variation across Multiple Human Tissues: The MuTHER Study
Nica, A. C., Parts, L., Glass, D., Nisbet, J. P., Barrett, A., Sekowska, M., Travers, M. E., Potter, S., Grundberg, E., Small, K. S., et al. (2011) · PLoS Genetics · doi:10.1371/journal.pgen.1002003 · Cited by 395 · see citing works
Rakyan, V. K., Down, T. A., Thorne, N., Flicek, P., Kulesha, E., Gräf, S., Tomazou, E. M., Bäckdahl, L., Johnson, N., Herberth, M., et al. (2008) · Genome Research · doi:10.1101/gr.077479.108 · Cited by 379 · see citing works
Self-citationA twin approach to unraveling epigenetics
Bell, J. T., & Spector, T. D. (2011) · Trends in Genetics · doi:10.1016/j.tig.2010.12.005 · Cited by 353 · see citing works
Toperoff, G., Aran, D., Kark, J. D., Rosenberg, M. H., Dubnikov, T., Nissan, B., Wainstein, J., Friedlander, Y., Levy‐Lahad, E., Gläser, B., et al. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr472 · Cited by 349 · see citing works
Rakyan, V. K., Beyan, H., Down, T. A., Hawa, M. I., Maslau, S., Aden, D., Daunay, A., Busato, F., Mein, C. A., Manfras, B. J., et al. (2011) · PLoS Genetics · doi:10.1371/journal.pgen.1002300 · Cited by 343 · see citing works
Self-citationThe DNA Methylome of Human Peripheral Blood Mononuclear Cells
Li, Y., Zhu, J., Tian, G., Li, N., Li, Q., Ye, M., Zheng, H., Yu, J., Wu, H., Sun, J., et al. (2010) · PLoS Biology · doi:10.1371/journal.pbio.1000533 · Cited by 318 · see citing works
Akalin, A., Garrett-Bakelman, F. E., Kormaksson, M., Busuttil, J., Zhang, L., Khrebtukova, I., Milne, T. A., Huang, Y., Biswas, D., Hess, J. L., et al. (2012) · PLoS Genetics · doi:10.1371/journal.pgen.1002781 · Cited by 296 · see citing works
Relton, C. L., & Davey Smith, G. (2010) · PLoS Medicine · doi:10.1371/journal.pmed.1000356 · Cited by 254 · see citing works
Commentary: The seven plagues of epigenetic epidemiology
Heijmans, B. T., & Mill, J. (2012) · International Journal of Epidemiology · doi:10.1093/ije/dyr225 · Cited by 208 · see citing works
A functional methylome map of ulcerative colitisPreprint
Häsler, R., Feng, Z., Bäckdahl, L., Spehlmann, M. E., Franke, A., Teschendorff, A. E., Rakyan, V. K., Down, T. A., Wilson, G. A., Feber, A., et al. (2012) · Genome Research · doi:10.1101/gr.138347.112 · Cited by 150 · see citing works
Self-citationEpigenomics reveals a functional genome anatomy and a new approach to common disease
Feinberg, A. P. (2010) · Nature Biotechnology · doi:10.1038/nbt1010-1049 · Cited by 113 · see citing works
Nanty, L., Carbajosa, G., Heap, G., Ratnieks, F. L. W., van Heel, D. A., Down, T. A., & Rakyan, V. K. (2011) · Genome Research · doi:10.1101/gr.121640.111 · Cited by 65 · see citing works
Self-citationGuthrie card methylomics identifies temporally stable epialleles that are present at birth in humansPreprint
Beyan, H., Down, T. A., Ramagopalan, S. V., Uvebrant, K., Nilsson, A., Holland, M. L., Gemma, C., Giovannoni, G., Boehm, B. O., Ebers, G. C., et al. (2012) · Genome Research · doi:10.1101/gr.134304.111 · Cited by 64 · see citing works
Self-citationEllis, J. A., Munro, J. E., Chavez, R. A., Gordon, L., Joo, J. E., Akikusa, J. D., Allen, R. C., Ponsonby, A., Craig, J. M., & Saffery, R. (2012) · Clinical Epigenetics · doi:10.1186/1868-7083-4-20 · Cited by 48 · see citing works
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Smith, A. K., Kilaru, V., Klengel, T., Mercer, K. B., Bradley, B., Conneely, K. N., Ressler, K. J., & Binder, E. B. (2015) · American Journal of Medical Genetics Part B: Neuropsychiatric Genetics · doi:10.1002/ajmg.b.32278 · Cited by 355 · see citing works
The Role of Epigenetic Change in Autism Spectrum Disorders
Loke, Y. J., Hannan, A. J., & Craig, J. M. (2015) · Frontiers in Neurology · doi:10.3389/fneur.2015.00107 · Cited by 250 · see citing works
Houtepen, L. C., Vinkers, C. H., Carrillo-Roa, T., Hiemstra, M., van Lier, P. A., Meeus, W., Branje, S., Heim, C. M., Nemeroff, C. B., Mill, J., et al. (2016) · Nature Communications · doi:10.1038/ncomms10967 · Cited by 242 · see citing works
Maternal intake of methyl-group donors affects DNA methylation of metabolic genes in infants
Pauwels, S., Ghosh, M., Duca, R. C., Bekaert, B., Freson, K., Huybrechts, I., Langie, S. A. S., Koppen, G., Devlieger, R., & Godderis, L. (2017) · Clinical Epigenetics · doi:10.1186/s13148-017-0321-y · Cited by 195 · see citing works
Zheng, S., Webster, A. P., Dong, D., Feber, A., Graham, D. G., Sullivan, R., Jevons, S., Lovat, L. B., Beck, S., Widschwendter, M., et al. (2018) · Epigenomics · doi:10.2217/epi-2018-0037 · Cited by 189 · see citing works
DNA methylation signature of human fetal alcohol spectrum disorder
Portales-Casamar, É., Lussier, A. A., Jones, M. J., MacIsaac, J. L., Edgar, R. D., Mah, S. M., Barhdadi, A., Provost, S., Perreault, L. L., Cynader, M. S., et al. (2016) · Epigenetics & Chromatin · doi:10.1186/s13072-016-0074-4 · Cited by 167 · see citing works
Schiele, M. A., Gottschalk, M. G., & Domschke, K. (2020) · Clinical Psychology Review · doi:10.1016/j.cpr.2020.101830 · Cited by 156 · see citing works
Differential methylation of the TRPA1 promoter in pain sensitivity
Bell, J. T., Loomis, A. K., Butcher, L. M., Gao, F., Zhang, B., Hyde, C. L., Sun, J., Wu, H., Ward, K. J., Harris, J. M., et al. (2014) · Nature Communications · doi:10.1038/ncomms3978 · Cited by 155 · see citing works
Concordant and discordant DNA methylation signatures of aging in human blood and brain
Farré, P., Jones, M. J., Meaney, M. J., Emberly, E. G., Turecki, G., & Kobor, M. S. (2015) · Epigenetics & Chromatin · doi:10.1186/s13072-015-0011-y · Cited by 145 · see citing works
Development and the epigenome: the ‘synapse’ of gene–environment interplay
Boyce, W. T., & Kobor, M. S. (2014) · Developmental Science · doi:10.1111/desc.12282 · Cited by 152 · see citing works
Maud, C., Ryan, J., McIntosh, J. E., & Olsson, C. A. (2018) · BMC Psychiatry · doi:10.1186/s12888-018-1740-9 · Cited by 151 · see citing works
Epigenome-Wide Association Studies (EWAS): Past, Present, and Future
Flanagan, J. M. (2014) · Methods in molecular biology · doi:10.1007/978-1-4939-1804-1_3 · Cited by 139 · see citing works
Epigenetic Research in Neuropsychiatric Disorders: the “Tissue Issue”
Bakulski, K. M., Halladay, A., Hu, V. W., Mill, J., & Fallin, M. D. (2016) · Current Behavioral Neuroscience Reports · doi:10.1007/s40473-016-0083-4 · Cited by 127 · see citing works
Genome-wide Methylomic Analysis of Monozygotic Twins Discordant for Adolescent Depression
Dempster, E. L., Wong, C. C. Y., Lester, K. J., Burrage, J., Gregory, A. M., Mill, J. S., & Eley, T. C. (2014) · Biological Psychiatry · doi:10.1016/j.biopsych.2014.04.013 · Cited by 132 · see citing works
Thurner, M., van de Bunt, M., Torres, J., Mahajan, A., Nylander, V., Bennett, A. J., Gaulton, K. J., Barrett, A., Burrows, C., Bell, C. G., et al. (2018) · eLife · doi:10.7554/elife.31977 · Cited by 124 · see citing works
Self-citationBush, N. R., Edgar, R. D., Park, M., MacIsaac, J. L., McEwen, L. M., Adler, N. E., Essex, M. J., Kobor, M. S., & Boyce, W. T. (2018) · Epigenomics · doi:10.2217/epi-2018-0042 · Cited by 120 · see citing works
Non, A. L., Hollister, B. M., Humphreys, K. L., Childebayeva, A., Esteves, K. C., Zeanah, C. H., Fox, N. A., Nelson, C. A., & Drury, S. S. (2016) · American Journal of Physical Anthropology · doi:10.1002/ajpa.23010 · Cited by 107 · see citing works
Childhood adversity and DNA methylation in two population-based cohorts
Houtepen, L. C., Hardy, R., Maddock, J., Kuh, D. J., Anderson, E. L., Relton, C. L., Suderman, M. J., & Howe, L. D. (2018) · Translational Psychiatry · doi:10.1038/s41398-018-0307-3 · Cited by 110 · see citing works
Hpa axis related genes and response to psychological therapies: Genetics and epigenetics
Roberts, S., Keers, R., Lester, K. J., Coleman, J. R. I., Breen, G., Arendt, K., Blatter‐Meunier, J., Cooper, P., Creswell, C., Fjermestad, K., et al. (2015) · Depression and Anxiety · doi:10.1002/da.22430 · Cited by 107 · see citing works
DNA methylation as a predictor of fetal alcohol spectrum disorder
Lussier, A. A., Morin, A. M., MacIsaac, J. L., Salmon, J., Weinberg, J., Reynolds, J. N., Pavlidis, P., Chudley, A. E., & Kobor, M. S. (2018) · Clinical Epigenetics · doi:10.1186/s13148-018-0439-6 · Cited by 105 · see citing works
Epigenetic programming—The important first 1000 days
Linnér, A., & Almgren, M. (2019) · Acta Paediatrica · doi:10.1111/apa.15050 · Cited by 101 · see citing works
Roberts, S., Lester, K. J., Hudson, J. L., Rapee, R. M., Creswell, C., Cooper, P. J., Thirlwall, K. J., Coleman, J. R. I., Breen, G., Wong, C. C. Y., et al. (2014) · Translational Psychiatry · doi:10.1038/tp.2014.83 · Cited by 118 · see citing works
Epigenetics and depressive disorders: a review of current progress and future directions
Januar, V., Saffery, R., & Ryan, J. (2015) · International Journal of Epidemiology · doi:10.1093/ije/dyu273 · Cited by 99 · see citing works
Epigenetic correlates of neonatal contact in humans
Moore, S. R., McEwen, L. M., Quirt, J., Morin, A. M., Mah, S. M., Barr, R. G., Boyce, W. T., & Kobor, M. S. (2017) · Development and Psychopathology · doi:10.1017/s0954579417001213 · Cited by 91 · see citing works
Distinct DNA methylation patterns of cognitive impairment and trisomy 21 in down syndrome
Jones, M. J., Farré, P., McEwen, L. M., MacIsaac, J. L., Watt, K., Neumann, S., Emberly, E. G., Cynader, M. S., Virji‐Babul, N., & Kobor, M. S. (2013) · BMC Medical Genomics · doi:10.1186/1755-8794-6-58 · Cited by 87 · see citing works
Sparrow, S. A., Manning, J. R., Cartier, J., Anblagan, D., Bastin, M. E., Piyasena, C., Pataky, R., Moore, E. J., Semple, S. I., Wilkinson, A. G., et al. (2016) · Translational Psychiatry · doi:10.1038/tp.2015.210 · Cited by 85 · see citing works
Ovenden, E. S., McGregor, N. W., Emsley, R. A., & Warnich, L. (2017) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2017.10.004 · Cited by 85 · see citing works
Salivary DNA Methylation Profiling: Aspects to Consider for Biomarker Identification
Langie, S. A. S., Moisse, M., Declerck, K., Koppen, G., Godderis, L., Berghe, W. V., Drury, S. S., & Boever, P. D. (2016) · Basic & Clinical Pharmacology & Toxicology · doi:10.1111/bcpt.12721 · Cited by 84 · see citing works
Principles and Challenges of Applying Epigenetic Epidemiology to Psychology
Jones, M. J., Moore, S. R., & Kobor, M. S. (2017) · Annual Review of Psychology · doi:10.1146/annurev-psych-122414-033653 · Cited by 88 · see citing works
DNA methylation and brain structure and function across the life course: A systematic review
Wheater, E., Stoye, D. Q., Cox, S. R., Wardlaw, J. M., Drake, A. J., Bastin, M. E., & Boardman, J. P. (2020) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2020.03.007 · Cited by 82 · see citing works
The early care environment and DNA methylome variation in childhood
Garg, E., Chen, L., Nguyen, T. T. T., Pokhvisneva, I., Chen, L. M., Unternaehrer, E., MacIsaac, J. L., McEwen, L. M., Mah, S. M., Gaudreau, H., et al. (2018) · Development and Psychopathology · doi:10.1017/s0954579418000627 · Cited by 82 · see citing works
Everson, T. M., Marsit, C. J., Michael O’Shea, T., Burt, A., Hermetz, K., Carter, B. S., Helderman, J., Hofheimer, J. A., McGowan, E. C., Neal, C. R., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-42654-4 · Cited by 82 · see citing works
Schechter, D. S., Moser, D. A., Paoloni‐Giacobino, A., Stenz, L., Gex‐Fabry, M., Aue, T., Adouan, W., Cordero, M. I., Suardi, F., Manini, A., et al. (2015) · Frontiers in Psychology · doi:10.3389/fpsyg.2015.00690 · Cited by 81 · see citing works
Ali, O., Cerjak, D., Kent, J. W., James, R. G., Blangero, J., Carless, M. A., & Zhang, Y. (2016) · Epigenetics · doi:10.1080/15592294.2016.1216284 · Cited by 75 · see citing works
Development of precision medicine approaches based on inter-individual variability of BCRP/ABCG2
Chen, L., Manautou, J. E., Rasmussen, T. P., & Zhong, X. (2019) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2019.01.007 · Cited by 73 · see citing works
Islam, S. A., Goodman, S. J., MacIsaac, J. L., Obradović, J., Barr, R. G., Boyce, W. T., & Kobor, M. S. (2019) · Epigenetics & Chromatin · doi:10.1186/s13072-018-0245-6 · Cited by 73 · see citing works
Discordance of DNA Methylation Variance Between two Accessible Human Tissues
Jiang, R., Jones, M. J., Chen, E., Neumann, S., Fraser, H. B., Miller, G. E., & Kobor, M. S. (2015) · Scientific Reports · doi:10.1038/srep08257 · Cited by 71 · see citing works
Kumsta, R., Marzi, S. J., Viana, J. F., Dempster, E. L., Crawford, B., Rutter, M. L., Mill, J. S., & Sonuga-Barke, E. J. S. (2016) · Translational Psychiatry · doi:10.1038/tp.2016.95 · Cited by 69 · see citing works
Teh, A. L., Pan, H., Lin, X., Lim, I. Y., Patro, C. P. K., Cheong, C. Y., Gong, M., MacIsaac, J. L., Kwoh, C.-K., Meaney, M. J., et al. (2016) · Epigenetics · doi:10.1080/15592294.2015.1132136 · Cited by 67 · see citing works
Lisoway, A. J., Zai, C. C. H., Tiwari, A. K., & Kennedy, J. L. (2017) · Neuroscience Letters · doi:10.1016/j.neulet.2016.12.071 · Cited by 66 · see citing works
Humphreys, K. L., Moore, S. R., Davis, E., MacIsaac, J. L., Lin, D. T. S., Kobor, M. S., & Gotlib, I. H. (2019) · Translational Psychiatry · doi:10.1038/s41398-019-0582-7 · Cited by 67 · see citing works
Epigenetics and ADHD: Toward an Integrative Approach of the Disorder Pathogenesis
Hamza, M., Halayem, S., Bourgou, S., Daoud, M., Charfi, F., & Belhadj, A. (2017) · Journal of Attention Disorders · doi:10.1177/1087054717696769 · Cited by 67 · see citing works
Toward personalized medicine in schizophrenia: Genetics and epigenetics of antipsychotic treatment
Lisoway, A. J., Chen, C. C., Zai, C. C. H., Tiwari, A. K., & Kennedy, J. L. (2021) · Schizophrenia Research · doi:10.1016/j.schres.2021.05.010 · Cited by 63 · see citing works
Agreement in DNA methylation levels from the Illumina 450K array across batches, tissues, and time
Forest, M., O’Donnell, K. J., Voisin, G., Gaudreau, H., MacIsaac, J. L., McEwen, L. M., Silveira, P. P., Steiner, M. S., Kobor, M. S., Meaney, M. J., et al. (2018) · Epigenetics · doi:10.1080/15592294.2017.1411443 · Cited by 59 · see citing works
Smoking-Associated Site-Specific Differential Methylation in Buccal Mucosa in the COPDGene Study
Wan, E. S., Qiu, W., Carey, V. J., Morrow, J. D., Bacherman, H., Foreman, M. G., Hokanson, J. E., Bowler, R. P., Crapo, J. D., & DeMeo, D. L. (2014) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2014-0103oc · Cited by 58 · see citing works
Whole-Genome Saliva and Blood DNA Methylation Profiling in Individuals with a Respiratory Allergy
Langie, S. A. S., Szic, K. S. V., Declerck, K., Traen, S., Koppen, G., Camp, G. V., Schoeters, G. E. R., Berghe, W. V., & Boever, P. D. (2016) · PLoS ONE · doi:10.1371/journal.pone.0151109 · Cited by 58 · see citing works
Kraaijenvanger, E. J., He, Y., Spencer, H., Smith, A. K., Bos, P. A., & Boks, M. P. (2018) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2018.11.016 · Cited by 57 · see citing works
Zhou, J., Li, M., Wang, X., He, Y., Xia, Y., Sweeney, J. A., Kopp, R. F., Liu, C., & Chen, C. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.674273 · Cited by 56 · see citing works
Lowe, R., Slodkowicz, G., Goldman, N., & Rakyan, V. K. (2015) · Epigenetics · doi:10.1080/15592294.2014.1003744 · Cited by 56 · see citing works
Self-citationBelsky, J., & Shalev, I. (2016) · Development and Psychopathology · doi:10.1017/s0954579416000900 · Cited by 56 · see citing works
DNA methylation in relation to gestational age and brain dysmaturation in preterm infants
Wheater, E., Galdi, P., McCartney, D. L., Blesa, M., Sullivan, G., Stoye, D. Q., Lamb, G. J., Sparrow, S. A., Murphy, L., Wrobel, N., et al. (2022) · Brain Communications · doi:10.1093/braincomms/fcac056 · Cited by 52 · see citing works
The Influence of the Duration of Breastfeeding on the Infant’s Metabolic Epigenome
Pauwels, S., Symons, L., Vanautgaerden, E.-L., Ghosh, M., Duca, R. C., Bekaert, B., Freson, K., Huybrechts, I., Langie, S. A. S., Koppen, G., et al. (2019) · Nutrients · doi:10.3390/nu11061408 · Cited by 49 · see citing works
Everson, T. M., O’Shea, T. M., Burt, A., Hermetz, K. E., Carter, B. S., Helderman, J., Hofheimer, J. A., McGowan, E. C., Neal, C. R., Pastyrnak, S. L., et al. (2020) · Clinical Epigenetics · doi:10.1186/s13148-020-00942-1 · Cited by 49 · see citing works
Robakis, T. K., Zhang, S., Rasgon, N., Li, T., Wang, T., Roth, M. C., Humphreys, K., Gotlib, I., Ho, M., Khechaduri, A., et al. (2020) · Translational Psychiatry · doi:10.1038/s41398-020-0703-3 · Cited by 44 · see citing works
Goodman, S. J., Burton, C. L., Butcher, D. T., Siu, M. T., Lemire, M., Chater‐Diehl, E., Turinsky, A. L., Brudno, M., Soreni, N., Rosenberg, D., et al. (2020) · Journal of Neurodevelopmental Disorders · doi:10.1186/s11689-020-09324-3 · Cited by 46 · see citing works
Methylomic analysis of monozygotic twins discordant for childhood psychotic symptoms
Fisher, H. L., Murphy, T. M., Arseneault, L., Caspi, A., Moffitt, T. E., Viana, J. F., Hannon, E. J., Pidsley, R., Burrage, J., Dempster, E. L., et al. (2015) · Epigenetics · doi:10.1080/15592294.2015.1099797 · Cited by 46 · see citing works
Stathopoulos, S., Gaujoux, R., Lindeque, J. Z., Mahony, C., Colff, R. V. D., van der Westhuizen, F. H., & O’Ryan, C. (2020) · Autism Research · doi:10.1002/aur.2310 · Cited by 45 · see citing works
Fitzgerald, E., Boardman, J. P., & Drake, A. J. (2018) · Current Genomics · doi:10.2174/1389202919666171229144807 · Cited by 44 · see citing works
Lewis, C. R., Breitenstein, R. S., Henderson-Smith, A., Sowards, H., Piras, I. S., Huentelman, M. J., Doane, L. D., & Lemery‐Chalfant, K. (2020) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-020-00885-4 · Cited by 44 · see citing works
Edematous severe acute malnutrition is characterized by hypomethylation of DNA
Schulze, K., Swaminathan, S., Howell, S., Jajoo, A., Lie, N. C., Brown, O., Sadat, R., Hall, N. J., Zhao, L., Marshall, K., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-13433-6 · Cited by 44 · see citing works
Epigenetics for anthropologists: An introduction to methods
Non, A. L., & Thayer, Z. M. (2015) · American Journal of Human Biology · doi:10.1002/ajhb.22679 · Cited by 39 · see citing works
Growing Up or Growing Old? Cellular Aging Linked With Testosterone Reactivity to Stress in Youth
Drury, S. S., Shachet, A., Brett, Z. H., Wren, M. E., Esteves, K. C., Shirtcliff, E. A., Phan, J., Mabile, E., & Theall, K. P. (2014) · The American Journal of the Medical Sciences · doi:10.1097/maj.0000000000000299 · Cited by 39 · see citing works
Bam, S., Buchanan, E., Mahony, C., & O’Ryan, C. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.696428 · Cited by 39 · see citing works
Choice of surrogate tissue influences neonatal EWAS findings
Lin, X., Teh, A. L., Chen, L., Lim, I. Y., Tan, P. F., MacIsaac, J. L., Morin, A. M., Yap, F. K. P., Tan, K. H., Saw, S., et al. (2017) · BMC Medicine · doi:10.1186/s12916-017-0970-x · Cited by 37 · see citing works
Bauer, M. (2018) · International Journal of Epidemiology · doi:10.1093/ije/dyy029 · Cited by 36 · see citing works
Wrigglesworth, J., Ryan, J., Vijayakumar, N., & Whittle, S. (2019) · Psychiatry Research: Neuroimaging · doi:10.1016/j.pscychresns.2018.12.012 · Cited by 34 · see citing works
Mulligan, C. J., Quinn, E. B., Hamadmad, D., Dutton, C. L., Nevell, L., Binder, A. M., Panter-Brick, C., & Dajani, R. (2025) · Scientific Reports · doi:10.1038/s41598-025-89818-z · Cited by 36 · see citing works
DNA methylation profiles between airway epithelium and proxy tissues in children
Brugha, R. E., Lowe, R., Henderson, A. J., Holloway, J. W., Rakyan, V. K., Woźniak, E. L., Mahmud, N., Seymour, K., Grigg, J., & Shaheen, S. O. (2017) · Acta Paediatrica · doi:10.1111/apa.14027 · Cited by 35 · see citing works
Self-citationLussier, A. A., Bodnar, T. S., Mingay, M., Morin, A., Hirst, M., Kobor, M. S., & Weinberg, J. (2018) · Frontiers in Genetics · doi:10.3389/fgene.2018.00610 · Cited by 36 · see citing works
Moving pharmacoepigenetics tools for depression toward clinical use
Hack, L. M., Fries, G. R., Eyre, H. A., Bousman, C. A., Singh, A. B., Quevedo, J., John, V. P., Baune, B. T., & Dunlop, B. W. (2019) · Journal of Affective Disorders · doi:10.1016/j.jad.2019.02.009 · Cited by 33 · see citing works
Yeung, E. H., Guan, W., Zeng, X., Salas, L. A., Mumford, S. L., de Prado-Bert, P., van Meel, E. R., Malmberg, A., Sunyer, J., Duijts, L., et al. (2020) · Clinical Epigenetics · doi:10.1186/s13148-020-00852-2 · Cited by 32 · see citing works
Implication de l’épigénétique dans les troubles du spectre autistique : revue de la littérature
Hamza, M., Halayem, S., M’rad, R., Bourgou, S., Charfi, F., & Belhadj, A. (2016) · L Encéphale · doi:10.1016/j.encep.2016.07.007 · Cited by 32 · see citing works
England-Mason, G., Merrill, S. M., Gladish, N., Moore, S. R., Giesbrecht, G. F., Letourneau, N. L., MacIsaac, J. L., MacDonald, A. M., Kinniburgh, D. W., Ponsonby, A., et al. (2022) · Environment International · doi:10.1016/j.envint.2022.107183 · Cited by 32 · see citing works
Sante, J. D., Ismaylova, E., Nemoda, Z., Gouin, J., Yu, W.-J., Caldwell, W., Vitaro, F., Szyf, M., Tremblay, R., & Booij, L. (2018) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2018.07.019 · Cited by 27 · see citing works
Genome-Wide Association Studies and Epigenome-Wide Association Studies Go Together in Cancer Control
Verma, M. (2016) · Future Oncology · doi:10.2217/fon-2015-0035 · Cited by 30 · see citing works
Musci, R. J., Raghunathan, R. S., Johnson, S. B., Klein, L., Ladd-Acosta, C., Ansah, R., Hassoun, R., & Voegtline, K. M. (2023) · Prevention Science · doi:10.1007/s11121-023-01576-4 · Cited by 27 · see citing works
Nys, S. D., Duca, R. C., Nawrot, T. S., Hoet, P., MEERBEEK, B. V., LANDUYT, K. L. V., & Godderis, L. (2017) · Environment International · doi:10.1016/j.envint.2017.11.002 · Cited by 27 · see citing works
DNA methylation in candidate genes for handedness predicts handedness direction
Schmitz, J., Kumsta, R., Moser, D., Güntürkün, O., & Ocklenburg, S. (2017) · Laterality Asymmetries of Body Brain and Cognition · doi:10.1080/1357650x.2017.1377726 · Cited by 26 · see citing works
Conole, E. L. S., Vaher, K., Blesa, M., Sullivan, G., Stevenson, A. J., Hall, J., Murphy, L., Thrippleton, M. J., Quigley, A. J., Bastin, M. E., et al. (2023) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2023.03.011 · Cited by 25 · see citing works
Epigenetic and Neural Circuitry Landscape of Psychotherapeutic Interventions
Miller, C. W. T. (2017) · Psychiatry Journal · doi:10.1155/2017/5491812 · Cited by 24 · see citing works
Mendonça, M. S., Mangiavacchi, P. M., Mendes, A. V., Loureiro, S. R., Martín-Santos, R., Glória, L. S., Marques, W., De Marco, S. P. G., Kanashiro, M. M., Hallak, J. E. C., et al. (2023) · Journal of Affective Disorders · doi:10.1016/j.jad.2023.03.031 · Cited by 24 · see citing works
Saliva Gene Promoter Hypermethylation as a Biomarker in Oral Cancer
Rapado‐González, Ó., López-Cedrún, J. L., López‐López, R., Rodríguez‐Ces, A. M., & Suárez‐Cunqueiro, M. M. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10091931 · Cited by 24 · see citing works
Young, J. I., Slifer, S., Hecht, J. T., & Blanton, S. H. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.656865 · Cited by 23 · see citing works
Ismaylova, E., Sante, J. D., Szyf, M., Nemoda, Z., Yu, W.-J., Pomares, F. B., Turecki, G., Gobbi, G., Vitaro, F., Tremblay, R. E., et al. (2017) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2017.07.005 · Cited by 22 · see citing works
Lewis, C. R., Henderson-Smith, A., Breitenstein, R. S., Sowards, H., Piras, I. S., Huentelman, M. J., Doane, L. D., & Lemery‐Chalfant, K. (2019) · Epigenetics · doi:10.1080/15592294.2019.1583032 · Cited by 22 · see citing works
Perinatal stress and methylation of the <i>NR3C1</i> gene in newborns: systematic review
Chalfun, G., Reis, M. M., de Oliveira, M. B. G., de Araújo Brasil, A., dos Santos Salú, M., da Cunha, A. J. L. A., Prata-Barbosa, A., & de Magalhães-Barbosa, M. C. (2022) · Epigenetics · doi:10.1080/15592294.2021.1980691 · Cited by 22 · see citing works
Robakis, T. K., Roth, M. C., King, L. S., Humphreys, K. L., Ho, M., Zhang, X., Chen, Y., Li, T., Rasgon, N., Watson, K. T., et al. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01592-w · Cited by 20 · see citing works
Schmitz, J., Kumsta, R., Moser, D., Güntürkün, O., & Ocklenburg, S. (2017) · Behavioural Brain Research · doi:10.1016/j.bbr.2017.09.035 · Cited by 19 · see citing works
Taylor, R., Smith, R., Collins, C. E., Mossman, D., Wong‐Brown, M. W., Chan, E., Evans, T., Attia, J., Smith, T. A., Butler, T. A. J., et al. (2018) · Nutrients · doi:10.3390/nu10030273 · Cited by 19 · see citing works
Arpone, M., Baker, E. K., Bretherton, L., Bui, M., Li, X., Whitaker, S., Dissanayake, C., Cohen, J., Hickerton, C. L., Rogers, C., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-21990-x · Cited by 19 · see citing works
Saliva DNA Methylation Detects Nascent Smoking in Adolescents
Dawes, K., Andersen, A. M., Vercande, K., Papworth, E., Philibert, W., Beach, S. R. H., Gibbons, F. X., Gerrard, M., & Philibert, R. A. (2019) · Journal of Child and Adolescent Psychopharmacology · doi:10.1089/cap.2018.0176 · Cited by 18 · see citing works
Social Epigenomics: Conceptualizations and Considerations for Oral Health
Gomaa, N. A. (2022) · Journal of Dental Research · doi:10.1177/00220345221110196 · Cited by 17 · see citing works
Herzog, E. M., Eggink, A. J., Willemsen, S. P., Slieker, R. C., Felix, J. F., Stubbs, A., van der Spek, P. J., van Meurs, J. B. J., Heijmans, B. T., & Steegers‐Theunissen, R. P. M. (2020) · Journal of Developmental Origins of Health and Disease · doi:10.1017/s2040174420000136 · Cited by 17 · see citing works
DNA methylation in adolescents with anxiety disorder: A longitudinal study
Bortoluzzi, A., Salum, G. A., da Rosa, E. D., Chagas, V. D. S., Castro, M. A. A., & Manfro, G. G. (2018) · Scientific Reports · doi:10.1038/s41598-018-32090-1 · Cited by 16 · see citing works
A set of common buccal CpGs that predict epigenetic age and associate with lifespan-regulating genes
Johnson, A. A., Torosin, N. S., Shokhirev, M. N., & Cuellar, T. L. (2022) · iScience · doi:10.1016/j.isci.2022.105304 · Cited by 16 · see citing works
Infant DNA methylation: an early indicator of intergenerational trauma?
Moore, S. R., Merrill, S. M., Sekhon, B., MacIsaac, J. L., Kobor, M. S., Giesbrecht, G. F., & Letourneau, N. L. (2021) · Early Human Development · doi:10.1016/j.earlhumdev.2021.105519 · Cited by 16 · see citing works
Sommerer, Y., Ohlei, O., Dobričić, V., Oakley, D. H., Wesse, T., Sabet, S. S., Demuth, I., Franke, A., Hyman, B. T., Lill, C. M., et al. (2022) · Clinical Epigenetics · doi:10.1186/s13148-022-01357-w · Cited by 15 · see citing works
San-Cristóbal, R., Navas‐Carretero, S., Milagro, F. I., Riezu‐Boj, J. I., Guruceaga, E., Celis-Morales, C. A., Livingstone, K. M., Brennan, L., Lovegrove, J. A., Daniel, H., et al. (2016) · Journal of Physiology and Biochemistry · doi:10.1007/s13105-017-0560-6 · Cited by 15 · see citing works
Ho, N. F., Tng, J. X. J., Wang, M., Chen, G., Subbaraju, V., Shukor, S., Ng, D., Tan, B., Puang, S. J., Kho, S.-H., et al. (2020) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2020.03.013 · Cited by 15 · see citing works
DNA Methylation: A Mediator Between Parenting Stress and Adverse Child Development?
Mulder, R. H., Rijlaarsdam, J., & van IJzendoorn, M. H. (2017) · Springer eBooks · doi:10.1007/978-3-319-55376-4_7 · Cited by 15 · see citing works
- Authors
- Lowe, R., Gemma, C., Beyan, H., Hawa, M. I., Bazeos, A., Leslie, R. D., Montpetit, A., Rakyan, V. K., & Ramagopalan, S. V.
- Affiliations
- Queen Mary University of London (GB)
- McGill University and Génome Québec Innovation Centre (CA)
- Corresponding author
- Lowe, Robert
- Rakyan, Vardhman K.
- Ramagopalan, Sreeram V.
- Venue
- Epigenetics
- Publisher
- Informa UK Limited
- Published
- 2013-04
- Volume
- 8
- Issue
- 4
- Pages
- 445-454
- ISSN
- 1559-2294 (ISSN-L)
- 1559-2308
- PMC
- PMC3674053
- OpenAlex
- W2118382560
- Cited by
- 160
- References
- 40
- Citations by year
- 2026: 9 · 2025: 7 · 2024: 5 · 2023: 7 · 2022: 10 · 2021: 12 · 2020: 19 · 2019: 13 · 2018: 18 · 2017: 17 · 2016: 17 · 2015: 13 · 2014: 10 · 2013: 1 · 2012: 1
- FWCI
- 6.13
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Epigenetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Juvenile Diabetes Research Foundation International
- Diabetes UK (10/0004107)
- Multiple Sclerosis Society
- European Foundation for the Study of Diabetes
- Novo Nordisk
- Medical Research Council (G0801976)
- Biotechnology and Biological Sciences Research Council (BB/H012494/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- buccal epithelial cells, blood, DNA methylation, epigenome-wide association study, hypomethylated regions, surrogate tissue
- MeSH terms
- Adult, Aged, DNA, Humans, Middle Aged, Mouth Mucosa, Genome, Human, Sequence Analysis, DNA, DNA Methylation, Polymorphism, Single Nucleotide, Epigenesis, Genetic, Genome-Wide Association Study, Young Adult
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