Scientists Working On MAO – Part 1



Dr. Olivier Cases
Senior Lecturer at Bâtiment de Pédiatrie
Hôpital de la Salpétrière, Paris, France.
Received his PhD in 1998.

To understand the cellular and molecular mechanisms of psychiatric diseases, such as autism, we develop genetic models using transgenic mice in which key genes are modified in both loss-of-function or gain-of-function approaches. By now we are interested in two transcription factors expressed in the cerebral cortex, CDP/cux1 a homeodomain transcription factor and the nuclear receptor, RORalpha.

 


Terrie Moffitt and Avshalom Caspi

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 (MAO A) was found to moderate the effect of maltreatment. As adults 85% of the severely maltreated children with a genotype conferring low levels of MAO A 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 MAO A 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 resistence to stress and trauma.

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 MAO A 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 MAO A 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 MAO A and maltreatment is replicated by other scientists, the finding suggests that:

(c) The combination of low-activity MAO A genotype and maltreatment predicts antisocial behaviors about as well as high cholesterol predicts heart disease. Moreover, although individuals having the combination of low-activity MAO A 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 MAO A 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 MAO A gene is found on the X chromosome. Males have one X chromosome while females have two. Some females having the at-risk low-activity MAO A gene on one X chromosome may have a protective high-activity MAO A 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 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 MAO A gene. This candidate gene has been well characterised in other research. It is known to be expressed functionally in the brain, where MAO A acts to maintain the healthy balance of several different neurotransmitters, including serotonin and dopamine. MAO A breaks down and recycles excess neurotransmitters. Brunner et al. showed that null MAO A activity has profound effects on neurotransmitter metabolism, and on this basis our research team assumed that a low level of MAO A activity affected neurotransmitter metabolism among the males in our study. The low-MAO A-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 MAO A genotype.

(d) Replication studies of the interaction between MAO A 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.

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

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: Dr. 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: Dr. 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

 

Role of Genotype in the Cycle of Violence in Maltreated Children, May 28, 2002

Link to article: 2002 Role of Genotype


Dale E. Edmondson
Professor of Biochemistry, Emory University School of Medicine
Adjunct Professor, Department of Chemistry, Emory University College of Arts and Sciences
received PhD University of Arizona, 1970

(image LEFT) Three-Dimensional Structure of Recombinant Human Monoamine Oxidase A.
The enzyme crystallizes as a monomer.
The blue area is the FAD coenzyme (in yellow) binding domain, the red area is the substrate binding domain, and the green area denotes the membrane binding domain.

(image RIGHT) Three-Dimensional Structure of Recombinant Human MAO B.
The enzyme Crystallizes as a dimer. The blue area is the FAD coenzyme (in yellow) binding domain, the red area is the substrate binding domain, and the green area denotes the membrane binding domain.

The determination of the structures of these two human enzymes now provides the structural information required for the design and development of specific drugs that will specifically inhibit each of these enzymes and will have clinical use as neuro-protective agents (MAO B) and as antidepressants (MAO A).

The determination of the structures of these enzymes was done in close collaboration of my laboratory ( Dr. Paige Newton-Vinson and Dr. Min Li) with Dr. Andrea Mattevi’s laboratory at the University of Pavia, Italy and his associates: Drs. Claudia Binda and Luigi DeColibus.

As a graduate student, one of my favorite pasttimes was playing pool (either 8-ball or straight pool). At that time, it was an inexpensive sport that did not take too much time away from my graduate studies and research. Since I always have been interested in physical principles, it afforded an in-depth understanding of Newtonian Mechanics.

Past the training years, my major favorite activity is travel to other countries, which allows one to learn as much as possible about different cultures and to taste the different foods from around the world. A career in science has facilitated this activity since a number of scientific meetings I attend are held in other countries. This activity has resulted in the development of friendships around the world.

 


Joanna S. Fowler
Senior Chemist
Director, Center for Translational Neuroimaging
Brookhaven National Laboratory
recevied PhD 1968 (chemistry, University of Colorado)

My research is in the area of radiotracer chemistry and molecular imaging using positron emission tomography (PET), a medical imaging method for visualizing and quantifying specific molecular targets (receptors, enzymes, transporters) and the movement of drugs in living animals and in humans.  I am particularly interested in developing radiotracers to probe enzyme activity and the effects of aging and drugs (including drugs of abuse on the human body) and in using mechanistic tools such as the deuterium isotope effect to probe radiotracer localization mechanisms in vivo in humans.  I am currently involved in a number of human studies of monoamine oxidase (MAO), an oxidative enzyme which regulates neurotransmitter activity and breaks down vasoactive dietary amines.  These studies relate to our observation that smokers have reduced MAO in brain and peripheral organs and to our current studies of the relationship of polymorphisms in the MAO gene to phenotype and to vulnerability to psychiatric disorders.  I am also interested in exploring imaging to enhance prediction of the behavior of chemical compounds in living systems with a view to facilitating the development of new PET radiotracers and to the introduction of new drugs into the practice of health care. I am supported by the Department of Energy, Office of Biological and Environmental Research and the National Institutes of Health.

http://www.bnl.gov/CTN/PET.asp

 


Daniel P. Holschneider, MD
Associate Professor
Dept. Psychiatry and the Behavioral Sciences
Laboratory for Vertebrate Functional Brain Mapping
University of Southern California

Advice: “Catch something as you are falling”

“It is of interest to note that while some dolphins are reported to have learned English – up to fifty words used in correct context – no human being has been reported to have learned dolphinese.”
– Carl Sagan