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Prevention of Early Substance Use Mediates, and Variation at SLC6A4 Moderates, SAAF Intervention Effects on OXTR Methylation

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Abstract

The Strong African American Family (SAAF) program has been shown to have a variety of short and long-term benefits for participating youth and families. However, biological mechanisms potentially influencing long-term effects on resilience in young adulthood have not been examined. In the current investigation, we examine the effects of SAAF on methylation of the OXTR gene in young adulthood, focusing on a regulatory region previously identified to be both responsive to stress and implicated in resilience. Using the subsample of participants from the original study for whom methylation data was available (N = 388), we replicated the previously reported G × E effect on prevention of early substance use and then examined whether there would also be a moderated effect on OXTR methylation in early adulthood, with “s” allele carriers, but not “LL” participants, showing a significant indirect effect of SAAF on OXTR methylation. Results suggest that for susceptible youth (i.e., “s” allele carriers), preventive intervention may “get under the skin,” in a manner potentially beneficial for long-term outcomes. Implications for examination of OXTR methylation in future prevention research are discussed.

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References

  • Baumgartner, T., Heinrichs, M., Vonlanthen, A., Fischbacker, U., & Fehr, E. (2008). Oxytocin shapes the neural circuitry of trust and trust adaptations in humans. Neuron, 58, 639–650. doi:10.1016/j.neuron.2008.04.009.

    Article  CAS  PubMed  Google Scholar 

  • Beach, S. R. H., Brody, G. H., Lei, M. K., Kim, S., Cui, J., & Philibert, R. A. (2014). Is serotonin transporter genotype associated with epigenetic susceptibility or vulnerability? Examination of the impact of socioeconomic status risk on African American youth. Development and Psychopathology, 26, 289–304. doi:10.1017/S0954579413000990.

    Article  PubMed  PubMed Central  Google Scholar 

  • Beach, S. R. H., Lei, M. K., Brody, G. H., Dogan, M. V., & Philibert, R. A. (2015). Higher levels of protective parenting are associated with better young adult health: exploration of mediation through epigenetic influences on pro-inflammatory processes. Frontiers in Psychology, 6, 676. doi:10.3389/fpsyg.2015.00676.

    Article  PubMed  PubMed Central  Google Scholar 

  • Beach, S. R. H., Brody, G. H., Barton, A.W., Philibert, R. A. (2016). Exploring genetic moderators and epigenetic mediators of contextual and family effects: From G × E to epigenetics. Development and Psychopathology. doi:10.1017/S0954579416000882.

  • Belsky, J., & Pluess, M. (2009). Beyond diathesis stress: Differential susceptibility to environmental influences. Psychological Bulletin, 135, 885–908. doi:10.1037/a0017376.

    Article  PubMed  Google Scholar 

  • Bradley, S. L., Dodelzon, K., Sandhu, H. K., & Philibert, R. A. (2005). Relationship of serotonin transporter gene polymorphisms and haplotypes to mRNA transcription. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 136B, 58–61. doi:10.1002/ajmg.b.30185.

    Article  Google Scholar 

  • Brenet, F., Moh, M., Funk, P., Feierstein, E., Viale, A. J., Socci, N. D., & Scandura, J. M. (2011). DNA methylation of the first exon is tightly linked to transcriptional silencing. PLoS ONE, 6, e14524. doi:10.1371/journal.pone.0014524.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brody, G. H., Murry, V. M., Kogan, S. M., Gerrard, M., Gibbons, F. X., Molgaard, V., & Wills, T. A. (2006). The strong African American families program: a cluster-randomized prevention trial of long-term effects and a mediational model. Journal of Consulting and Clinical Psychology, 74, 356–366. doi:10.1037/0022-006X.74.2.356.

    Article  PubMed  Google Scholar 

  • Brody, G. H., Beach, S. R. H., Philibert, R. A., Chen, Y.-F., & Murry, V. M. (2009). Prevention effects moderate the association of 5-HTTLPR and youth risk behavior initiation: Gene × environment hypotheses tested via a randomized prevention design. Child Development, 80, 645–661. doi:10.1111/j.1467-8624.2009.01288.x.

    Article  PubMed  Google Scholar 

  • Brook, J. S., & Newcomb, M. D. (1995). Childhood aggression and unconventionality: Impact on later academic achievement, drug use, and workforce involvement. Journal of Genetic Psychology, 156, 393–410. doi:10.1080/00221325.1995.9914832.

    Article  CAS  PubMed  Google Scholar 

  • Caspi, A., Hariri, A. R., Holmes, A., Uher, R., & Moffit, T. E. (2010). Genetic sensitivity to the environment: The case of the serotonin transporter gene (5-HTT) and its implications for studying complex diseases and traits. American Journal of Psychiatry, 167, 509–527. doi:10.1176/appi.ajp.2010.09101452.

    Article  PubMed  PubMed Central  Google Scholar 

  • Cecil, C. A. M., Lysenko, L. J., Jaffee, S. R., Pingault, J. B., Smith, R. G., Relton, C. L., & Barker, E. D. (2014). Environmental risk, oxytocin receptor gene (OXTR) methylation and youth callous-unemotional traits: A 13-year longitudinal study. Molecular Psychiatry, 19, 1071–1077. doi:10.1038/mp.2014.95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Choi, W. S., Gilpin, E. A., Farkas, A. J., & Pierce, J. P. (2001). Determining the probability of future smoking among adolescents. Addiction, 96, 313–323. doi:10.1046/j.1360-0443.2001.96231315.x.

    Article  CAS  PubMed  Google Scholar 

  • Dadds, M. R., Moul, C., Cauchi, A., Dobson-Stone, C., Hawes, D. J., Brennanm, J., & Ebstein, R. E. (2014). Methylation of the oxytocin receptor gene and oxytocin blood levels in the development of psychopathy. Development and Psychopathology, 26, 33–40. doi:10.1017/S09545794130000497.

    Article  PubMed  Google Scholar 

  • Dogan, M. V., Shields, B., Cutrona, C., Gao, L., Gibbons, F. X., Simons, R., Monick, M., Brody, G. H., Tan, K., Beach, S. R. H., & Philibert, R. A. (2014). The effect of smoking on DNA methylation of peripheral blood mononuclear cells from African American women. BMC Genomics, 15, 151. doi:10.1186/1471-2164-15-151.

    Article  PubMed  PubMed Central  Google Scholar 

  • Falush, D., Stephens, M., & Pritchard, J. K. (2007). Inference of population structure using multilocus genotype data: Dominant markers and null alleles. Molecular Ecology Notes, 155, 945–959. doi:10.1111/j.1471-8286.2007.01758.x.

    Google Scholar 

  • Galfi, M., Radacs, M., Juhasz, A., Molner, A., & Laszlo, F. A. (2005). Serotonin-induced enhancement of vasopressin and oxytocin secretion in neurohypophyseal tissue culture. Regulatory Peptides, 127, 225–231. doi:10.1016/j.regpep.2004.12.009.

    Article  CAS  PubMed  Google Scholar 

  • Gamer, M., Zurowski, B., & Burchel, C. (2010). Different amygdala subregions mediate valence related and attentional effects of oxytocin in humans. Proceedings of the National Academy of Science, 107, 9400–9405. doi:10.1073/pnas.1000985107.

    Article  CAS  Google Scholar 

  • Halder, I., Yang, B.-Z., Kranzler, H. R., Stein, M. B., Shriver, M. D., & Gelernter, J. (2009). Measurement of admixture proportions and description of admixture structure in different U.S. populations. Human Mutation, 30, 1299–1309. doi:10.1002/humu.21045.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Houseman, E. A., Accomando, W. P., Koestler, D. C., Christensen, B. C., Marsit, C. J., Nelson, H. H., Wiencke, J. K., & Kelsey, K. T. (2012). DNA methylation arrays as surrogate measures of cell mixture distribution. BMC Bioinformatics, 13, 86–101. doi:10.1186/1471-2105-13-86.

    Article  PubMed  PubMed Central  Google Scholar 

  • Kaufman, J., Ying, B., Douglas-Palumberi, H., Cruse-Artus, M., Lipshitz, D., Krystal, J. H., & Gelernter, J. (2007). Genetic and environmental predictors of early alcohol use. Biological Psychiatry, 61, 1228–1234. doi:10.1086/j.biopsych.2006.06.039.

    Article  CAS  PubMed  Google Scholar 

  • Kim, Y.-R., Kim, J.-H., Kim, M. J., & Treasure, J. (2014). Differential methylation of the oxytocin receptor gene in patients with anorexia nervosa: A pilot study. PLoS ONE, 9, 1–4. doi:10.1371/journal.pone.0088673.

    Google Scholar 

  • Kogan, S. M., Brody, G. H., Beach, S. R. H., & Philibert, R. A. (2010). 5-HTTLPR status moderates the effect of early adolescent substance use on risky sexual behavior. Health Psychology, 29, 471–476. doi:10.1037/a0020594.

    Article  PubMed  PubMed Central  Google Scholar 

  • Kosfeld, M., Heinrichs, M., Zak, P. J., Fischbacker, U., & Fehr, E. (2005). Oxytocin increases trust in humans. Nature, 435, 673–676. doi:10.1038/nature03701.

    Article  CAS  PubMed  Google Scholar 

  • Kovacs, G. L., Zoltan, S., & Szabo, G. (1998). Oxytocin and addiction: A review. Psychoneuroendocrinology, 23, 945–962. doi:10.1016/s0306-4530(98)00064-x.

    Article  CAS  PubMed  Google Scholar 

  • Kumsta, R., Hummel, E., Chen, F. S., & Heinrichs, M. (2013). Epigenetic regulation of the oxytocin receptor gene: Implications fr behavioral neuroscience. Frontiers in Neuroscience, 7, 1–6. doi:10.3389/fnins.2013.00083.

    Article  Google Scholar 

  • Kusui, C., Kimura, T., Ogita, K., Nakamura, H., Matsumara, Y., Koyama, M., Azuma, C., & Murata, Y. (2001). DNA methylation of the human oxytocin receptor gene promoter regulates tissue-specific gene suppression. Biochemical and Biophysical Research Communications, 289, 681–686. doi:10.1006/bbrc.2001.6024.

    Article  CAS  PubMed  Google Scholar 

  • Landecker, H., & Panofsky, A. (2013). From social structure to gene regulation, and back: A critical introduction to environmental epigenetics for sociology. Annual Review of Sociology, 39, 333–357. doi:10.1146/annureview-soc.071312-145707.

    Article  Google Scholar 

  • MacDonald, K., & MacDonald, T. M. (2010). The peptide that binds: A systematic review of oxytocin and its prosocial effects in humans. Harvard Review of Psychiatry, 18, 1–21. doi:10.3109/10673220903523615.

    Article  PubMed  Google Scholar 

  • MacPhee, D., Lunkenheimer, E., & Riggs, N. R. (2015). Resilience as regulation of developmental and family processes. Family Relations, 64, 153–175. doi:10.1111/fare.12100.

    Article  PubMed  PubMed Central  Google Scholar 

  • McGregor, J. S., & Bowen, M. T. (2012). Breaking the loop: Oxytocin as a potential treatment for drug addiction. Hormones and Behavior, 61, 331–339. doi:10.1016/j.yhbeh.2011.12.001.

    Article  CAS  PubMed  Google Scholar 

  • Meloni, M. (2014). The social brain meets the reactive genome: Neuroscience, epigenetics and the new social biology. Frontiers in Human Neuroscience, 8, 1–12. doi:10.3389/fnhum.2014.00309.

    Article  Google Scholar 

  • Mottolese, R., Redoute, J., Costes, N., Le Bars, D., & Sirigu, A. (2014). Switching brain serotonin with oxytocin. Proceedings of the National Academy of Science, 111, 8637–8642. doi:10.1073/pnas.1319810111.

    Article  CAS  Google Scholar 

  • Nakamura, M., Ueno, S., Sano, A., & Tanabe, H. (2000). The human serotonin transporter gene linked polymorphism (5-HTTLPR) shows ten novel allelic variants. Molecular Psychiatry, 5, 32–38. doi:10.1038/sj.mp.4000698.

    Article  CAS  PubMed  Google Scholar 

  • Olff, M., Frijing, J. L., Kubzansky, L. D., Bradley, B., Ellenbogen, M. A., Cardoso, C., Bartz, J. A., Yee, J. R., & van Zuiden, M. (2013). The role of oxytocin in social bonding, stress regulation and mental health: An update on the moderating effects of context and interindividual differences. Psychoneuroendocrinology, 38, 1883–1894. doi:10.1016/j.psyneuen.2013.06.019.

    Article  CAS  PubMed  Google Scholar 

  • Philibert, R. A., Sandhu, H., Hollenbeck, N., Gunter, T., Adams, W., & Madan, A. (2008). The relationship of 5HTT (SLC6A4) methylation and genotype on mRNA expression and liability to major depression and alcohol dependence in subjects from the Iowa Adoption Studies. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 147B, 543–9. doi:10.1002/ajmg.b.30657.

    Article  CAS  Google Scholar 

  • Pidsley, R., Wong, C. C. Y., Volta, M., Lunnon, K., Mill, J., & Schalkwyk, L. C. (2013). A data-driven approach to preprocessing Illumina 450K methylation array data. BMC Genomics, 14, 293–302. doi:10.1186/1471-2164-14-293.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Preacher, K. J., Rucker, D. D., & Hayes, A. F. (2007). Addressing moderated mediation hypotheses: Theory, methods, and prescriptions. Multivariate Behavioral Research, 42, 185–227. doi:10.1080/00273170701341316.

    Article  PubMed  Google Scholar 

  • Proctor, B. D., & Dalaker, J. (2003). Poverty in the United States: 2002. U.S. Census Bureau, Current Population Reports, P60-222, U.S. Government Printing Office, Washington, DC.

  • Puglia, M. H., Lillard, T. S., Morris, J. P., & Connelly, J. J. (2015). Epigenetic modification of the oxytocin receptor gene influences the perception of anger and fear in the human brain. Proceedings of the National Academy of Science, 112, 3308–3313. doi:10.1073/pnas.1422096112.

    Article  CAS  Google Scholar 

  • Raleigh, M. J., McGuire, M. T., Brammer, G. L., & Yuwiler, A. (1984). Social and environmental influences on blood serotonin concentrations in monkeys. Archives of General Psychiatry, 41, 405–410. doi:10.1001/archpsyc.1984.01790150095013.

    Article  CAS  PubMed  Google Scholar 

  • Reinius, L. E., Acevedo, N., Joerink, M., Pershagen, G., Dahlén, S. E., Greco, D., Söderhäll, C., Scheynius, A., & Kere, J. (2012). Differential DNA methylation in purified human blood cells: Implications for cell lineage and studies on disease susceptibility. PLoS ONE, 7, e41361. doi:10.1371/journal.pone.0041361.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sarnyai, Z. (2011). Oxytocin as a potential mediator and modulator of drug addiction. Addiction Biology, 16, 199–201. doi:10.1111/j.1369-1600.2011.00332.x.

    Article  CAS  PubMed  Google Scholar 

  • Simons, R. L., & Klopack, E. T. (2015). Invited address: “The Times They Are A-Changin” gene expression, neuroplasticity, and developmental research. Journal of Youth and Adolescence, 44, 573–580. doi:10.1007/s10964-014-0245-1.

    Article  PubMed  Google Scholar 

  • Simons, R. L., Lei, M K., Beach, S. S. H., Cutrona, C. E., & Philibert, R. A. (2016). Methylation of the oxytocin receptor gene mediates the effect of adversity on negative schemas and depression. Development and Psychopathology. doi:10.1017/S0954579416000420.

  • Tops, M., Van Peer, J. M., Korf, J., Wijers, A. A., & Tucker, D. M. (2007). Anxiety, Cortisol and attachment predict plasma oxytocin levels in healthy females. Psychophysiology, 44, 444–449. doi:10.1111/j.1469-8986.2007.00510.x.

    Article  PubMed  Google Scholar 

  • van IJzendoorn, M. H., Belsky, J., & Bakermans-Kranenburg, M. J. (2012). Serotonin transporter genotype 5HTTLPR as a marker of differential susceptibility? A meta-analysis of child and adolescent gene-by-environment studies. Translational Psychiatry, 2, 1–6. doi:10.1038/tp.2012.73.

    Google Scholar 

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Acknowledgments

This article was supported in part by grant 5R01HD030588-16A1 and grant P30 DA027827 awarded to Gene H. Brody and by grant R01HD069439 awarded to Steven R. H. Beach. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Correspondence to Steven R. H. Beach.

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This article was supported in part by grants 5R01HD030588-16A1 and P30 DA027827 awarded to Gene H. Brody.

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Beach, S.R.H., Lei, M.K., Brody, G.H. et al. Prevention of Early Substance Use Mediates, and Variation at SLC6A4 Moderates, SAAF Intervention Effects on OXTR Methylation. Prev Sci 19, 90–100 (2018). https://doi.org/10.1007/s11121-016-0709-5

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