Prevention Science

, Volume 19, Issue 1, pp 49–57 | Cite as

Informing Prevention and Intervention Policy Using Genetic Studies of Resistance

  • Brion S. MaherEmail author
  • Shawn Latendresse
  • Michael M. Vanyukov


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.


Genetic resistance Resilience Prevention High-risk design 


Compliance with Ethical Standards


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.

Conflict of Interest

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

Ethical Approval

For this type of study ethical approval is not required.

Formal Consent

For this type of study, formal consent is not required.


  1. 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.Google Scholar
  2. 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.CrossRefGoogle Scholar
  3. Bierut, L. J. (2011). Genetic vulnerability and susceptibility to substance dependence. Neuron, 69, 618–627. doi: 10.1016/j.neuron.2011.02.015.CrossRefPubMedPubMedCentralGoogle Scholar
  4. Cicchetti, D. (2010). Resilience under conditions of extreme stress: A multilevel perspective. World Psychiatry, 9, 145–154.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 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.
  6. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 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.CrossRefPubMedGoogle Scholar
  8. 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.Google Scholar
  9. Falconer, D. S. (1965). The inheritance of liability to certain diseases, estimated from the incidence among relatives. Annals of Human Genetics, 29, 51–76.CrossRefGoogle Scholar
  10. Feder, A., Nestler, E. J., & Charney, D. S. (2009). Psychobiology and molecular genetics of resilience. Nature Reviews Neuroscience, 10, 446–457.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 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.Google Scholar
  12. 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.Google Scholar
  13. 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.PubMedGoogle Scholar
  14. 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.Google Scholar
  15. Harada, S., Agarwal, D., & Goedde, H. (1981). Aldehyde dehydrogenase deficiency as cause of facial flushing reaction to alcohol in japanese. The Lancet, 318, 982.CrossRefGoogle Scholar
  16. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 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.CrossRefPubMedGoogle Scholar
  18. Hsu, T. H., & Spindler K. R. (2012). Identifying host factors that regulate viral infection. PLoS Pathogens8.7, e1002772.Google Scholar
  19. 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.Google Scholar
  20. 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.Google Scholar
  21. 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.Google Scholar
  22. 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.CrossRefPubMedGoogle Scholar
  23. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 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
  25. Maher, B. S. (2015). Polygenic scores in epidemiology: Risk prediction, etiology, and clinical utility. Current Epidemiology Reports, 2, 239–244.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 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.
  27. Masten, A. S. (2001). Ordinary magic: Resilience processes in development. American Psychologist, 56, 227.CrossRefPubMedGoogle Scholar
  28. 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.Google Scholar
  29. 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.CrossRefGoogle Scholar
  30. Paterson, A. D. (1997). Case-control association studies in complex traits--the end of an era? Molecular Psychiatry, 2, 277–278.Google Scholar
  31. 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.CrossRefPubMedGoogle Scholar
  32. Risch, N., & Zhang, H. (1995). Extreme discordant sib pairs for mapping quantitative trait loci in humans. Science, 268, 1584.CrossRefPubMedGoogle Scholar
  33. 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.PubMedPubMedCentralGoogle Scholar
  34. 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.Google Scholar
  35. 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.
  36. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 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.Google Scholar
  38. 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.Google Scholar
  39. 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.Google Scholar
  40. 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.
  41. 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.CrossRefGoogle Scholar
  42. 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.CrossRefPubMedGoogle Scholar
  43. 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.CrossRefGoogle Scholar
  44. 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.CrossRefGoogle Scholar
  45. 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.Google Scholar
  46. 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.Google Scholar
  47. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 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.Google Scholar
  49. Wolff, P. H. (1972). Ethnic differences in alcohol sensitivity. Science (New York, N.Y.), 175, 449–450.CrossRefGoogle Scholar
  50. Wolff, P. H. (1973). Vasomotor sensitivity to alcohol in diverse mongoloid populations. American Journal of Human Genetics, 25, 193–199.PubMedPubMedCentralGoogle Scholar
  51. 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.
  52. Zaykin, D. V., & Zhivotovsky, L. A. (2005). Ranks of genuine associations in whole-genome scans. Genetics, 171, 813–823.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Society for Prevention Research 2016

Authors and Affiliations

  • Brion S. Maher
    • 1
    Email author
  • Shawn Latendresse
    • 2
  • Michael M. Vanyukov
    • 3
  1. 1.Department of Mental HealthJohns Hopkins Bloomberg School of Public HealthBaltimoreUSA
  2. 2.Department of Psychology and NeuroscienceBaylor UniversityWacoUSA
  3. 3.Departments of Pharmaceutical Sciences, Psychiatry, and Human GeneticsUniversity of PittsburghPittsburghUSA

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