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Marked for life?

6 April 2010
By Professor Derek Bolton
Professor of Philosophy & Psychopathology at the Institute of Psychiatry and the Centre for Humanities and Health, Kings' College London, and Honorary Consultant Clinical Psychologist at the South London & Maudsley NHS Foundation Trust
Appeared in BioNews 552
Genetics has made enormous advances towards understanding the causes of medical and psychiatric conditions. We know from the past few decades of research that many common psychiatric conditions have some contribution from genes, ranging from modest (30 to 40 per cent) to high (over 60 per cent). Moving on from this general finding, two questions dominate current research: Can we find the particular genes? And can we find the gene/environment interactions?

The answer to the first question - so far - seems to be yes and no. Yes, because many candidate genes associated with particular psychiatric conditions have been identified in studies, with some replications. No, because of the qualification that heritability depends, not on single genes or a few genes, but on multiple genes of small effect (1). The emphasis here is on both multiple and small.

Why does this matter? Well, in my view, the possibility has to be borne in mind that the science will get more and more complex, rather than increasingly simple. Moving towards simplicity is typical of successful reductive science, including some key areas of biomedicine. But nature does not always oblige, and it is possible that the science of genetic involvement in the mind and its disorders is characterised by complexity and resists simplification. In that case, the science would continue, but clear outcomes would be elusive.

This matters, especially in relation to treatment. What kinds of treatment or intervention options might psychiatric genetics open up? First, psychopharmacogenetics: if we can locate a gene implicated in a disorder among a group of patients, it may be possible to develop a compound that affects the activity of that gene - here genetics and pharmaceutical research meet 'personalised medicine'. Second, better targeted environmental interventions aimed at prevention. We already know much about the social/environmental determinants of health, particularly mental health, outcomes: childhood neglect and abuse, chronic unemployment, poverty and wealth inequality, to name just a few. Psychiatric genetics holds the promise of contributing information about these risks via genetic profiling. If we can identify a genetic profile that significantly adds risk to an already-known environmental risk then, in principle, we can use genetic and environmental profiling together to identify a high-risk group for preventative work. Both these treatment options are jeopardised by the complexities of genetic involvement in psychiatric disorders, because both rely on finding reasonably potent genes.

It's startling that amid the current - and I would say possibly chronic - complexity of findings, only a few clear findings with large treatment and prevention implications have shone through. One of these was a reported gene/environment interaction between a serotonin-related gene 5-HTT (5-hydroxy-tryptamine) and major life stressors, giving rise to depression (2). This generated enormous interest, as it seemed to bring to fruition the promise of a mature psychiatric genetics, identifying at risk groups and risky environments. So important was this finding that it spurred many research groups around the world to replicate it, and some did. However, two recent meta-analyses of these studies have independently concluded that replication has not been successful (3, 4). If this negative conclusion is correct then we are back amid complexity, with no clear finding.

So genetic inheritance does not 'mark for life' in relation to mental disorders. Many genes of small effect are involved, interacting with numerous different environmental risks and opportunities.

1) Kendler KS 'A gene for...': the nature of gene action in psychiatric disorders
American Journal of Psychiatry, 162, 1243-52 |  2005
2) Caspi, A., Sugden, K., Moffitt, T. E., Taylor, A., Craig, I. W., Harrington, H., McClay, J., Mill, J., Martin, J., Braithwaite, A., and Poulton, R. Influence of life stress on depression: Moderation by a polymorphism in the 5-HTT gene.
Science, 301, 386-389 |  2003
3) Munafò, M. R., Durrant, C., Lewis, G., and Flint, J. Gene X Environment interactions at the serotonin transporter locus.
Biological Psychiatry, 65, 211-219 |  2009
4) Risch, N., Herrell, R., Lehner, T., Liang, K.-L., Eaves, L., Hoh, J., Griem, A., Kovacs, M., Ott, J., and Merikangas, K. R. Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: A meta-analysis.
Journal of the American Medical Association, 301, 2462-2471 |  2009
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