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Informing Prevention and Intervention Policy Using Genetic Studies of Resistance

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Abstract

The common paradigm for conceptualizing the influence of genetic and environmental factors on a particular disease relies on the concept of risk. Consequently, the bulk of etiologic, including genetic, work focuses on “risk” factors. These factors are aggregated at the high end of the distribution of liability to disease, the latent variable underlying the distribution of probability and severity of a disorder. However, liability has a symmetric but distinct aspect to risk, resistance to disorder. Resistance factors, aggregated at the low end of the liability distribution and supporting health and recovery, appear to be more promising for effective prevention and intervention. Herein, we discuss existing work on resistance factors, highlighting those with known genetic influences. We examine the utility of incorporating resistance genetics in prevention and intervention trials and compare the statistical power of a series of ascertainment schemes to develop a general framework for examining resistance outcomes in genetically informative designs. We find that an approach that samples individuals discordant on measured liability, a low-risk design, is the most feasible design and yields power equivalent to or higher than commonly used designs for detecting resistance genetic and environmental effects.

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References

  • Asante, E. A., Smidak, M., Grimshaw, A., Houghton, R., Tomlinson, A., Jeelani, A., . . . Brandner, S. (2015). A naturally occurring variant of the human prion protein completely prevents prion disease. Nature, 522, 478–481.

  • Barzilai, N., & Gabriely, I. (2010). Genetic studies reveal the role of the endocrine and metabolic systems in aging. The Journal of Clinical Endocrinology & Metabolism, 95, 4493–4500.

    Article  CAS  Google Scholar 

  • Bierut, L. J. (2011). Genetic vulnerability and susceptibility to substance dependence. Neuron, 69, 618–627. doi:10.1016/j.neuron.2011.02.015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cicchetti, D. (2010). Resilience under conditions of extreme stress: A multilevel perspective. World Psychiatry, 9, 145–154.

    Article  PubMed  PubMed Central  Google Scholar 

  • Cornelis, M. C., Monda, K. L., Yu, K., Paynter, N., Azzato, E. M., Bennett, S. N., . . . Caporaso, N. E. (2011). Genome-wide meta-analysis identifies regions on 7p21 (AHR) and 15q24 (CYP1A2) as determinants of habitual caffeine consumption. PLoS Genetics, 7, e1002033. doi:10.1371/journal.pgen.1002033.

  • Crabb, D. W., Edenberg, H. J., Bosron, W. F., & Li, T. K. (1989). Genotypes for aldehyde dehydrogenase deficiency and alcohol sensitivity. The inactive ALDH2(2) allele is dominant. The Journal of Clinical Investigation, 83, 314–316. doi:10.1172/JCI113875.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dean, M., Carrington, M., Winkler, C., & Huttley, G. A. (1996). Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structual gene. Science, 273, 1856.

    Article  CAS  PubMed  Google Scholar 

  • Erikson, G. A., Bodian, D. L., Rueda, M., Molparia, B., Scott, E. R., Scott-Van Zeeland, A. A., . . . Topol, E. J. (2016). Whole-genome sequencing of a healthy aging cohort. Cell, 165, 1002–1011.

  • Falconer, D. S. (1965). The inheritance of liability to certain diseases, estimated from the incidence among relatives. Annals of Human Genetics, 29, 51–76.

    Article  Google Scholar 

  • Feder, A., Nestler, E. J., & Charney, D. S. (2009). Psychobiology and molecular genetics of resilience. Nature Reviews Neuroscience, 10, 446–457.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Flannick, J., Thorleifsson, G., Beer, N. L., Jacobs, S. B., Grarup, N., Burtt, N. P., . . . Benediktsson, R. (2014). Loss-of-function mutations in SLC30A8 protect against type 2 diabetes. Nature Genetics, 46, 357–363.

  • Freudenberg-Hua, Y., Freudenberg, J., Vacic, V., Abhyankar, A., Emde, A., Ben-Avraham, D., . . . Koppel, J. (2014). Disease variants in genomes of 44 centenarians. Molecular Genetics & Genomic Medicine, 2, 438–450.

  • Goedde, H. W., Agarwal, D. P., & Harada, S. (1983). The role of alcohol dehydrogenase and aldehyde dehydrogenase isozymes in alcohol metabolism, alcohol sensitivity, and alcoholism. Isozymes, 8, 175–193.

    CAS  PubMed  Google Scholar 

  • Grucza, R. A., Wang, J. C., Stitzel, J. A., Hinrichs, A. L., Saccone, S. F., Saccone, N. L., . . . Budde, J. P. (2008). A risk allele for nicotine dependence in CHRNA5 is a protective allele for cocaine dependence. Biological Psychiatry, 64, 922–929.

  • Harada, S., Agarwal, D., & Goedde, H. (1981). Aldehyde dehydrogenase deficiency as cause of facial flushing reaction to alcohol in japanese. The Lancet, 318, 982.

    Article  Google Scholar 

  • Hartz, S. M., & Bierut, L. J. (2010). Genetics of addictions. The Psychiatric Clinics of North America, 33, 107–124. doi:10.1016/j.psc.2009.10.003.

    Article  PubMed  PubMed Central  Google Scholar 

  • Hawkins, J. D., Catalano, R. F., & Miller, J. Y. (1992). Risk and protective factors for alcohol and other drug problems in adolescence and early adulthood: Implications for substance abuse prevention. Psychological Bulletin, 112, 64.

    Article  CAS  PubMed  Google Scholar 

  • Hsu, T. H., & Spindler K. R. (2012). Identifying host factors that regulate viral infection. PLoS Pathogens, 8.7, e1002772.

  • Janes, A. C., Smoller, J. W., David, S. P., Haddad, S., Basu, A., Fava, M., . . . Kaufman, M. J. (2012). Association between CHRNA5 genetic variation at rs16969968 and brain reactivity to smoking images in nicotine dependent women. Drug and Alcohol Dependence, 120, 7–13.

  • Johnston, J. J., Lewis, K. L., Ng, D., Singh, L. N., Wynter, J., Brewer, C., . . . Gonsalves, S. G. (2015). Individualized iterative phenotyping for genome-wide analysis of loss-of-function mutations. The American Journal of Human Genetics, 96, 913–925.

  • Liu, R., Paxton, W. A., Choe, S., Ceradini, D., Martin, S. R., Horuk, R., . . . Landau, N. R. (1996). Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell, 86, 367–377.

  • Luczak, S. E., Glatt, S. J., & Wall, T. J. (2006). Meta-analyses of ALDH2 and ADH1B with alcohol dependence in asians. Psychological Bulletin, 132, 607.

    Article  PubMed  Google Scholar 

  • Luthar, S. S., Cicchetti, D., & Becker, B. (2000). The construct of resilience: A critical evaluation and guidelines for future work. Child Development, 71, 543–562.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Macgregor, S., Lind, P. A., Bucholz, K. K., Hansell, N. K., Madden, P. A., Richter, M. M., . . . Whitfield, J. B. (2009). Associations of ADH and ALDH2 gene variation with self report alcohol reactions, consumption and dependence: An integrated analysis. Human Molecular Genetics, 18, 580–593. doi:10.1093/hmg/ddn372

  • Maher, B. S. (2015). Polygenic scores in epidemiology: Risk prediction, etiology, and clinical utility. Current Epidemiology Reports, 2, 239–244.

    Article  PubMed  PubMed Central  Google Scholar 

  • Maher, B. S., Vladimirov, V. I., Latendresse, S. J., Thiselton, D. L., McNamee, R., Kang, M., . . . Vanyukov, M. M. (2011). The AVPR1A gene and substance use disorders: Association, replication, and functional evidence. Biological Psychiatry, 70, 519–527. doi:10.1016/j.biopsych.2011.02.023.

  • Masten, A. S. (2001). Ordinary magic: Resilience processes in development. American Psychologist, 56, 227.

    Article  CAS  PubMed  Google Scholar 

  • Mead, S., Whitfield, J., Poulter, M., Shah, P., Uphill, J., Campbell, T., . . . Mein, C. A. (2009). A novel protective prion protein variant that colocalizes with kuru exposure. New England Journal of Medicine, 361, 2056–2065.

  • Peng, G., & Yin, S. (2009). Effect of the allelic variants of aldehyde dehydrogenase ALDH2* 2 and alcohol dehydrogenase ADH1B* 2 on blood acetaldehyde concentrations. Human Genomics, 3, 1.

    Article  Google Scholar 

  • Paterson, A. D. (1997). Case-control association studies in complex traits--the end of an era? Molecular Psychiatry, 2, 277–278.

  • REICH, T., James, J., & Morris, C. (1972). The use of multiple thresholds in determining the mode of transmission of semi-continuous traits*. Annals of Human Genetics, 36, 163–184.

    Article  CAS  PubMed  Google Scholar 

  • Risch, N., & Zhang, H. (1995). Extreme discordant sib pairs for mapping quantitative trait loci in humans. Science, 268, 1584.

    Article  CAS  PubMed  Google Scholar 

  • Risch, N. J., & Zhang, H. (1996). Mapping quantitative trait loci with extreme discordant sib pairs: Sampling considerations. American Journal of Human Genetics, 58, 836–843.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Saccone, S. F., Hinrichs, A. L., Saccone, N. L., Chase, G. A., Konvicka, K., Madden, P. A., . . . Bierut, L. J. (2007). Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs. Human Molecular Genetics, 16, 36–49.

  • Saccone, N. L., Culverhouse, R. C., Schwantes-An, T. H., Cannon, D. S., Chen, X., Cichon, S., . . . Bierut, L. J. (2010). Multiple independent loci at chromosome 15q25.1 affect smoking quantity: A meta-analysis and comparison with lung cancer and COPD. PLoS Genetics, 6. doi:10.1371/journal.pgen.1001053.

  • Schechter, C. B., Barzilai, N., Crandall, J. P., & Atzmon, G. (2010). Cholesteryl ester transfer protein (CETP) genotype and reduced CETP levels associated with decreased prevalence of hypertension. Mayo Clinic Proceedings, 85, 522–526.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schwantes-An, T., Zhang, J., Chen, L., Hartz, S. M., Culverhouse, R. C., Chen, X., . . . Konte, B. (2015). Association of the OPRM1 variant rs1799971 (A118G) with non-specific liability to substance dependence in a collaborative de novo meta-analysis of european-ancestry cohorts. Behavior Genetics, 1–19.

  • Shelton, J. M., Corran, P., Risley, P., Silva, N., Hubbart, C., Jeffreys, A., . . . Hensmann, M. (2015). Genetic determinants of anti-malarial acquired immunity in a large multi-centre study. Malaria Journal, 14, 1–18.

  • Sobota, R. S., Stein, C. M., Kodaman, N., Scheinfeldt, L. B., Maro, I., Wieland-Alter, W., . . . Chervenak, K. (2016). A locus at 5q33. 3 confers resistance to tuberculosis in highly susceptible individuals. The American Journal of Human Genetics, 98, 514–524.

  • Sulem, P., Gudbjartsson, D. F., Geller, F., Prokopenko, I., Feenstra, B., Aben, K. K., . . . Stefansson, K. (2011). Sequence variants at CYP1A1-CYP1A2 and AHR associate with coffee consumption. Human Molecular Genetics, 20, 2071–2077. doi:10.1093/hmg/ddr086.

  • Tobacco and Genetics Consortium. (2010). Genome-wide meta-analyses identify multiple loci associated with smoking behavior. Nature Genetics, 42, 441–447. doi:10.1038/ng.571.

    Article  Google Scholar 

  • Treutlein, J., & Rietschel, M. (2011). Genome-wide association studies of alcohol dependence and substance use disorders. Current Psychiatry Reports, 13, 147–155. doi:10.1007/s11920-011-0176-4.

    Article  PubMed  Google Scholar 

  • Vanyukov, M. M., Kirisci, L., Tarter, R. E., Simkevitz, H. F., Kirillova, G. P., Maher, B. S., & Clark, D. B. (2003a). Liability to substance use disorders: 2. A measurement approach. Neuroscience & Biobehavioral Reviews, 27, 517–526.

    Article  Google Scholar 

  • Vanyukov, M. M., Tarter, R. E., Kirisci, L., Kirillova, G. P., Maher, B. S., & Clark, D. B. (2003b). Liability to substance use disorders: 1. common mechanisms and manifestations. Neuroscience & Biobehavioral Reviews, 27, 507–515.

    Article  Google Scholar 

  • Vanyukov, M. M., Kirisci, L., Moss, L., Tarter, R. E., Reynolds, M. D., Maher, B. S., . . . Clark, D. B. (2009). Measurement of the risk for substance use disorders: Phenotypic and genetic analysis of an index of common liability. Behavior Genetics, 39, 233–244.

  • Vanyukov, M. M., Tarter, R. E., Conway, K. P., Kirillova, G. P., Chandler, R. K., & Daley, D. C. (2016). Risk and resistance perspectives in translation-oriented etiology research. Translational Behavioral Medicine, 1–11.

  • Williams, S. C. (2016). News feature: Genetic mutations you want. Proceedings of the National Academy of Sciences of the United States of America, 113, 2554–2557. doi:10.1073/pnas.1601663113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Windle, M. (2002). Critical conceptual and measurement issues in the study of resilience. In M. D. Glantz & J. L. Johnson (Eds.), Resilience and deveLopment: Positive, life adaptations. New York: Kluwer Academic/Plenum Publishers.

  • Wolff, P. H. (1972). Ethnic differences in alcohol sensitivity. Science (New York, N.Y.), 175, 449–450.

    Article  CAS  Google Scholar 

  • Wolff, P. H. (1973). Vasomotor sensitivity to alcohol in diverse mongoloid populations. American Journal of Human Genetics, 25, 193–199.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Xie, P., Kranzler, H. R., Krauthammer, M., Cosgrove, K. P., Oslin, D., Anton, R. F., . . . Gelernter, J. (2011). Rare nonsynonymous variants in alpha-4 nicotinic acetylcholine receptor gene protect against nicotine dependence. Biological Psychiatry, 70, 528–536. doi:10.1016/j.biopsych.2011.04.017.

  • Zaykin, D. V., & Zhivotovsky, L. A. (2005). Ranks of genuine associations in whole-genome scans. Genetics, 171, 813–823.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, 624 N. Broadway Ave., Baltimore, MD, 21205, USA

    Brion S. Maher

  2. Department of Psychology and Neuroscience, Baylor University, Waco, TX, USA

    Shawn Latendresse

  3. Departments of Pharmaceutical Sciences, Psychiatry, and Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA

    Michael M. Vanyukov

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  1. Brion S. Maher
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  2. Shawn Latendresse
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Correspondence to Brion S. Maher.

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This work was supported by the National Institute on Drug Abuse (NIDA) Grants R01DA036525 and R01DA039408 and the National Institute on Alcoholism and Alcohol Abuse Grant K01AA020333.

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Drs. Latendresse, Vanyukov, and Maher have no potential conflicts of interest to report.

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Maher, B.S., Latendresse, S. & Vanyukov, M.M. Informing Prevention and Intervention Policy Using Genetic Studies of Resistance. Prev Sci 19, 49–57 (2018). https://doi.org/10.1007/s11121-016-0730-8

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