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1. Genes by environment * This document was initially prepared as a factsheet for journalists who contacted Terrie Moffitt and Avshalom Caspi about their study in August…
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  • 1. Genes by environment * This document was initially prepared as a factsheet for journalists who contacted Terrie Moffitt and Avshalom Caspi about their study in August 2002. A research team lead by Terrie Moffitt and Avshalom Caspi reports new evidence of a "gene by environment" interaction, in which a functional genetic polymorphism is associated with different antisocial outcomes among maltreated children. This document contains a brief summary of the report. Publication source Caspi, A., McClay, J, Moffitt, T., Mill, J., Martin, J., Craig, I, Taylor, A., & Poulton, R. (2002). Evidence that the cycle of violence in maltreated children depends on genotype. Science, 297, 851-854. The finding We studied a representative birth cohort of 442 male children to determine why some children who are maltreated grow up to develop antisocial behaviors whereas others do not. The children were studied for 26 years, from birth to adulthood. A functional polymorphism in the gene encoding the neurotransmitter-metabolizing enzyme monoamine oxidase A (MAOA) was found to moderate the effect of maltreatment. As adults 85% of the severely maltreated children with a genotype conferring low levels of MAOA expression developed antisocial outcomes (e.g., conviction for violent crimes, antisocial personality traits). In contrast, despite being maltreated, children with a genotype conferring high levels of MAOA expression were unlikely to develop antisocial problems. The findings provide initial evidence that genotypes can moderate children's sensitivity to environmental insults. These findings may partly explain why not all victims of maltreatment grow up to victimize others; some genotypes may promote resistance to stress and trauma. Copyright 2006 Terrie Moffitt and Avshalom Caspi Reproduced with permission for Ethical Emporium, 2006.
  • 2. Implications (a) The paper provides initial evidence for a genotype associated with risk for antisocial behaviour in the human general population, specifically under stress conditions. The genotype is in the same system as the MAOA genotype first associated with aggression in a genetic linkage study of a Dutch family, published by Prof H. Brunner, in Science, 18 June 1993. (b) The paper demonstrates how molecular genetics researchers can take account of the environmental-risk status of research participants to make quicker progress toward discovering associations between genes and other disorders or diseases. The genotype was unrelated to antisocial behaviour in the full sample. This could explain why initial reports of associations between genes and disorders have not been replicated. We found an association between MAOA and violence only when we took into account the study members' maltreatment history, and looked closer at those children. We recommend that researchers should measure stressful life events in genetic studies. Further, if the interaction between MAOA and maltreatment is replicated by other scientists, the finding suggests that (c) The combination of low-activity MAOA genotype and maltreatment predicts antisocial behaviors about as well as high cholesterol predicts heart disease. Moreover, although individuals having the combination of low-activity MAOA genotype and maltreatment were only 12% of the cohort of all boys born in 1972 in one city, they accounted for 44% of the cohort's convictions for violent crimes. (d) The genotype seems to have a "protective effect" against stress or trauma. This is very different from the more usual report of genes associated with increased risk for disease. Examples of protective genes are some individuals of African descent have a genotype that protects them against malaria, and some individuals of Asian descent have a genotype that protects them against alcoholism. (e) The MAOA low-activity genotype is too common in the population to use as a screen for violence risk, about one third of males have it. Moreover, the genotype could not predict violence in the full sample of boys we studied. Its increased risk for violence was only "activated" by child maltreatment. This suggests that the best strategy for preventing violence is to prevent child abuse. (f) The MAOA gene is found on the X chromosome. Males have one X chromosome while females have two. Some females having the at-risk low-activity MAOA gene on one X chromosome may have a protective high-activity MAOA gene on their other X chromosome. This raises the interesting possibility that further research into X-linked genotypes may help to explain one of the least understood facts about violence: the sex difference. Supporting Details Maltreatment before age 11. Of the 442 children studied, 154 had been maltreated, 33 severely. Maltreatment in the first ten years of life included rejection by the child's mother, frequent changes of primary caregiver, physical abuse resulting in injury, and sexual abuse. Many of the children had more than one of these forms of maltreatment. The four antisocial outcomes. (1) the psychiatric diagnosis of adolescent conduct disorder (persistent fighting, bullying, lying, stealing, cruelty to people or animals, vandalism, and disobeying rules), (2) official court records of conviction for violent offenses (assault, robbery, rape, domestic violence, homicide), (3) aggressive personality traits (willingness to harm others Copyright 2006 Terrie Moffitt and Avshalom Caspi Reproduced with permission for Ethical Emporium, 2006.
  • 3. for own advantage, interest in and enjoyment of violent material), and (4) symptoms of adult antisocial personality disorder (a long-term history of repeated law violations, deceitfulness, conning, impulsivity, physical aggression, and irresponsibility with respect to jobs, spouse, or children, plus lack of remorse). The MAOA gene. This candidate gene has been well characterised in other research. It is known to be expressed functionally in the brain, where MAOA acts to maintain the healthy balance of several different neurotransmitters, including serotonin and dopamine. MAOA breaks down and recycles excess neurotransmitters. Brunner et al. showed that null MAOA activity has profound effects on neurotransmitter metabolism, and on this basis our research team assumed that a low level of MAOA activity affected neurotransmitter metabolism among the males in our study.The low-MAOA-activity genotype characterised 163 study participants and the high-activity genotype characterised 279. Definition of Terms. A "birth cohort" is all the children born in one city in one year. A "polymorphism" is a naturally occurring variation in the genetic sequence that partially explains why people are different from each other. "Functional" means that the gene in our study was one that has already been shown in other research to have a meaningful impact on biological processes in the brain. Controls. Socioeconomic status and intelligence test scores were statistically controlled in the research. Limitations of the study (a) The birth cohort of children were from one country, New Zealand, but the research ruled out ethnic group confounds on genotype. The study members were caucasians of mainly British, Scots or Irish descent. (b) The groups of children compared were small. However, both maltreatment and antisocial behaviour were ascertained in the general population, avoiding the referral bias that is a flaw of studies done in prisons and clinics. (c) More laboratory research is needed to understand the biological effects of stress on the neurotransmitter systems of individuals having the low-activity versus high-activity MAOA genotype. (d) Replication studies of the interaction between MAOA genotype and maltreatment are needed. What happened after publication? This paper was named a “Fast-Breaking Paper” as the most cited paper in the field of Psychiatry/Psychology from the month of August 2002 by Essential Science Indicators, http://esi_topics.com/. The paper was covered in articles and programs by The Economist, CNN, BBC World News Television, National Public Radio, Science, Science News, Wall Street Journal, NY Times Magazine, Chemistry & Industry, Chemical & Engineering News and the major newspaper and radio media in the US, UK, New Zealand, Australia, Canada, Argentina, Brazil, Hungary, France, Italy, Pakistan, Japan, and the Netherlands, during the first two weeks of August, 2002. Copyright 2006 Terrie Moffitt and Avshalom Caspi Reproduced with permission for Ethical Emporium, 2006.
  • 4. The finding was replicated by: Foley DL, Eaves LJ, Wormley B, Silberg JL, Maes HH, Kuhn J, Riley B. Childhood adversity, monoamine oxidase A genotype, and risk for conduct disorder. Arch. Gen. Psychiatry. 2004;61: 738-744. Authors Avshalom Caspi, Joseph McClay, Terrie E. Moffitt, Jonathan Mill, Judy Martin, Ian W. Craig, Alan Taylor, Richie Poulton *To whom correspondence should be addressed. E-mailt.moffitt@iop.kcl.ac.uk Members of the research team also available to answer questions i.craig@iop.kcl.ac.uk, London mobile phone 07711 617 405 RICHIEP@gandalf.otago.ac.nz Universities involved MRC Social, Genetic, and Developmental Psychiatry Research Centre, Institute of Psychiatry, King's College, London SE5 8AF, UK. Dunedin Multidisciplinary Health and Development Research Unit, Dunedin School of Medicine, Box 913, University of Otago, Dunedin, New Zealand. Department of Psychology, University of Wisconsin, Madison WI 53706, USA. The study protocol was approved by the institutional ethics review boards of the participating universities. Study participants gave informed consent for the research. Funding Sources The University of Wisconsin Graduate School. The U.K. Medical Research Council. The U.S. National Institute of Mental Health (MH49414, MH45070). The Health Research Council of New Zealand. A Royal Society-Wolfson Research Merit Award to Terrie Moffitt. Related Readings To learn more about this research team's investigations of antisocial behaviour Moffitt, TE, Caspi, A, Rutter, M & Silva, PA (2001). Sex Differences in Antisocial Behavior: Conduct Disorder, Delinquency, and Violence in the Dunedin Longitudinal Study. Cambridge, UK: Cambridge University Press. http//uk.cambridge.org/psychology/catalogue/0521010667 Experts conducting related work On the interplay between nature and nurture: Professor Peter McGuffin, Institute of Psychiatry, Kings College London, p.mcguffin@iop.kcl.ac.uk On bio-social interactions as causes of violence: Prof Adrian Raine, Dept. of Psychology, University of Southern California, <raine@almaak.usc.edu>, phone in Mauritius 230 424 5517 On MAOA genotypes: Prof Ian Craig, Oxford University and Institute of Psychiatry, Kings College London, i.craig@iop.kcl.ac.uk, mobile phone 07711 617 405 Copyright 2006 Terrie Moffitt and Avshalom Caspi Reproduced with permission for Ethical Emporium, 2006.
  • 5. On MAOA genotypes: Prof Han Brunner, University Medical Center Dept. Human Genetics, Nijmegen, Netherlands, H.Brunner@antrg.azn.nl On child maltreatment: Prof Ken Dodge, Director Center for Child and Family Policy, Duke University, NC, DODGE@pps.pubpol.duke.edu On child maltreatment: Prof Dante Cicchetti, Mt. Hope Family Center, Univ of Rochester, NY, <tlevee@netacc.net> On causes of violence: Prof. Alfred Blumstein, Director of the National Science Foundation National Consortium on Violence Research, Carnegie Mellon University, PA, <ab0q+@andrew.cmu.edu> On animal studies of genes, stressful rearing, and aggression: Prof. Steve Suomi, US National Institute of Child Health and Human Development, <suomis@lce.nichd.nih.gov>, ss148k@nih.gov On the ethical and legal contexts of behavioural genetics research into antisocial behavior: Tor Lezemore, Assistant Director, Nuffield Council on Bioethics, London, <vlezemore@nuffieldfoundation.org> Copyright 2006 Terrie Moffitt and Avshalom Caspi Reproduced with permission for Ethical Emporium, 2006.
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