Genetics of Suicidal Behavior: Candidate Association Genetic Approach
Zalsman, Gil, Frisch, Amos, Apter, Alan, Weizman, Abraham, The Israel Journal of Psychiatry and Related Sciences
Abstract: Suicidal behavior runs in families and seemed to be genetically determined in part and independent of the presence of psychiatric disorders. This review presents the current knowledge of candidate gene association studies in the field of suicidology. Concordance for monozygotic twins is about 13% Vs. 0.7% in dizygotics. It seems that there is a relationship to intermediate phenotypes such as impulsivity and aggression. The problem of studying complex traits and of ethnic stratification in heterogeneous population are major concerns in studying genetics of suicide. Family-based methods is one of the strategies to overcome stratification. We found a possible association of tryptophane hydroxylase gene polymorphism with depression and serotonin transporter promoter gene to violence traits by family-based methods. Recent data from the study of COMT, MAO and serotonin receptors genes polymorphisms are controversial at this stage. Future directions for research includes alternative phenotypes, endo-phenotypes and genome scan.
Suicide is a destructive act of aggression directed towards the self, and is often associated with violent and impulsive traits (1). It is the second leading cause of death in the 14-24-year-old group in Israel, in whom the incidence is 11.7 deaths per 100,000 for male and 2.5 for female (2). Higher figures have been reported for the United States. Male to female ratio is 4.5:1 among 15-19-year-olds and 6:1 in 20-24year-olds (3). Suicidality is common in depressed individuals, but may also be found in patients suffering from other psychiatric disorders and in apparently "normal" individuals (4-6).
The presence of low serotonin metabolite levels, 5-hydroxyindoleacetic acid (5HIAA) in the cerebrospinal fluid (CSF) of suicidal individuals is one of the most stable findings in biological psychiatry (7). Several biochemical studies have reported an association between serotonergic dysfunction and both suicide and suicide-related behaviors (7-12). The alterations in pre- and post-synaptic serotonin binding sites were localized to the ventrolateral prefrontal cortex of suicide victims (10). Although this finding is true for both depressed and non-depressed individuals (13), the study of genetics of suicide is usually conducted as part of investigation into the genetics of affective disorders. Faraone et al. (14), in a recent review of the genetics literature on affective disorders, differentiated between two types of studies: quantitative models of genetic transmission and linkage analyses. The types of genetic models were: single major locus models, multifactorial polygenic models, and mixed models of the two. They found no specific support for any of the quantitative models, while findings for the linkage analyses were equivocal.
It is of note that the complexity of the gene-environment interactions needs to be taken into account. For example, Merikangas and Spiker (16) found that depressed subjects tend to select mates with psychiatric illness and therefore increase the genetic risk for depression and suicide in their offspring.
The aim of the present review is to discuss the current knowledge in the new field of genetics of suicidal behavior as well as our own findings from family-based association studies. It is important to emphasize that suicidal behavior is not a uniform homogenous syndrome or a disorder and thus the phenotype needs to be clearly defined before any conclusion can be reached.
Heritability of Suicidality Family studies
Genetic studies of suicidal behavior are still sparse. Adoption studies suggest that there may be a genetic susceptibility to suicide, which is partially independent of the presence of a psychiatric disorder (17-19). Roy et al. (18) showed that the concordance rate for suicide in monozygotic twins is 11.3% compared with only 1.8% for dizygotic twins. When these results were considered together with results from earlier twin studies, even greater differences were noted: 13. …