The Biological and Genetic Dimensions of Suicide Risk

Gustavo Turecki, MD, PhD

Reprinted from "Suicide" issue of Visions Journal, 2005, 2 (7), p. 13-14

Despite the prominence of suicide as a leading cause of death throughout most of the world, the biological basis of suicide remains poorly understood and inadequately studied. While several psychosocial factors associated with suicide have been described in detail, numerous studies have also supported the role of biological factors in suicide predisposition. For example, the intergenerational transmission of suicidal behaviour is well documented and suggests that the discovery of genetic factors for suicide could, in the long run, lead to improvements in prevention.

The causes of suicidal behaviour likely overlap with causes of other psychiatric disorders, owing to the high rates of depression and other mental illnesses amongst individuals who die by suicide. However, numerous studies have indicated that an individual’s likelihood to engage in suicidal behaviour is independent from the genetic factors that increase susceptibility for major psychiatric problems.1 Other factors, like impulsive-aggressive behaviours, also play a critical role in suicide predisposition.

Perspectives on the neurobiological basis of suicide have begun to converge in recent years on several key areas. The primary biological focus of suicide studies has been oriented upon serotonin, a neurotransmitter involved in communication between neurons. Neurons are cells that are responsible for the transmission of information in our nervous systems. In the 1970s, researchers observed that those with the highest suicide risk had the lowest levels of a serotonin by-product.2 Subsequent studies investigating serotonin receptors in the prefrontal brain cortex of suicide completers have supported the idea that suicide is associated with low serotonin levels.3 These observations, together with a series of other findings obtained using different research methods, imply that both serotonin and the prefrontal brain region play a role in suicide.

Our brains, however, are very complex. They are composed of many brain regions, which communicate amongst themselves through multiple circuits. Moreover, neurons employ more than one neurotransmitter to transmit information. For a behaviour as complex as suicide, it would appear that multiple neurotransmitters, brain regions and circuits may be involved in individuals’ increased risk for suicide.4 Within this perspective, recent findings point to the possible implication of molecules involved in intra-neuronal communication and the way they influence how individual neurons affect the transmission of information. More specifically, findings with respect to protein kinase A and C are encouraging.

Another interesting lead supported by several lines of evidence is an intriguing association between low cholesterol levels and suicidal behaviour. The mechanisms explaining how serum cholesterol levels may have an effect on behaviour, however, are unclear. In any case, the investigation of lipid (i.e., fats) metabolism in the neurobiology of suicide and related behaviours has gained renewed interest in light of the growing evidence of essential roles for cholesterol in promoting brain plasticity and connectivity between cells. Evidence also suggests that the composition of brain sterol (a class of chemicals that play a role in the brain analogous to that of hormones in the rest of the body) could be involved in this association.

In recent years, there has been growing interest in specific genes that may be involved in suicide predisposition. The evidence supporting the role of genes in suicide is based on the following: 1) suicide often runs in families, and 2) twin and adoption studies suggest that genes are likely to account for familial clustering of suicidal behaviour.

An individual’s likelihood to engage in suicidal behaviour is independent from the genetic factors that increase susceptibility for major psychiatric problems.

The emphasis of the studies investigating specific genes on suicidal behaviour has been on those genes that play a role in controlling the production and activity of serotonin. Although some of the findings have been consistent—particularly those im- plicating a genetic variant in the regulatory region of the gene coding for the serotonin transporter (the target molecule of most commonly used antidepressants)—the results of this type of study are preliminary at best.

One of the problems with the current findings on the role of genes is that the types of studies investigating these relationships often have key methodological shortcomings such as the infrequency of suicide completion and the degradation of genetic material over time. Another issue is that genes are just one component of suicide risk. Other biological, psychiatric and psychosocial factors are also likely to influence suicide risk, and most of the studies that examined genetic factors have focused exclusively on these. In the face of multiple factors influencing suicide risk, the power of the methods used thus far is limited.

Nevertheless, an encouraging finding recently came out using a methodology that allows testing the influence of genes, while taking into account developmental and life experience dimensions. The study indicated that individuals with a certain regulatory variant of the serotonin transporter gene are more likely to display suicidal behaviour when exposed to life stressors.8 These promising results need to be replicated and better investigated.

Several technologies also show promise for the study of suicide. One such technology is microarray analysis of gene expression, a technique that has become increasingly used in the study of complex conditions such as suicide. This method allows for the simultaneous monitoring of tens of thousands of genes at the same time. Though the wide-scale implementation of microarray technology in studies of psychiatric conditions and behaviours has only just begun, it shows promise—particularly regarding the discovery of previously unknown aspects of suicide neurobiology. As these types of studies become more common place, a better picture of the genes involved in the pathophysiology of suicidal behaviours will emerge. This clearer perspective will allow researchers to then focus on particular pathways and genes. The search for the biological basis of suicide is an enormous challenge. However, progressive re- search strategies are enabling us to both understand and move beyond some of the more customary domains of study. Eventually, suicide risk assessment will be less subjective, and we will be able to develop more effective treatment intervention strategies for susceptible individuals.

 
About the Author

Dr. Turecki holds a William Dawson Chair, and is Director of the McGill Group for Suicide Studies at Douglas Hospital, McGill University, in Montreal, PQ

Footnotes
  1. For more information, see Kim, C.D., Seguin, M., Therrien, N.et al. (2005). Familial aggregation of suicidal behavior: A family study of male suicide completers from the general population. American Journal of Psychiatry, 162(5):1017-1019.

  2. Asberg, M., Traskman, L., & Thoren, P. (1976). 5-HIAA in the cerebrospinal fluid. A biochemical suicide predictor? Archives of General Psychiatry, 33(10), 1193-1197.

  3. For a review, see Mann, J.J. (2003). Neurobiology of suicidal behaviour. Nature Reviews Neuroscience, 4(10), 819-828.

  4. Pandey, G.N. & Dwivedi, Y. (2005). Focus on protein kinase A and protein kinase C, critical components of signal transduction system, in mood disorders and suicide. International Journal of Neuropsychopharmacology, 8(1), 1-4.

  5. For an introduction to this area, see Turecki, G. and Lalovic, A. (2005). The biology and genetics of suicidality. In J. Licinio & M.-L. Wong (Eds.). Biology of depression: From novel insights to therapeutic strategies (pp. 287316). Weinheim, Germany: Wiley-VCH.

  6. For a review, see Kaplan, J.R., Muldoon, M.F., Manuck, S.B. et al. (1997). Assessing the observed relationship between low cholesterol and violence- related mortality. Implications for suicide risk. Annals of the New York Academy of Sciences, 836, 57-80.

  7. For an introduction, see Brent, D.A. & Mann, J.J. (2005). Family genetic studies, suicide and suicidal behavior. American Journal of Medical Genetics Part C: Seminar in Medical Genetics, 133(1), 13-24.

  8. Caspi, A., Sugden, K., Moffitt, T.E. et al. (2003). Influence of life stress on depression: Moderation by a polymorphism in the 5-HTT gene. Science, 301(5631), 386-389

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