Trends in suicidology: personality as an endophenotype for molecular genetic investigations.

Abstract

Psychopathology, especially depression, is the most important risk factor for suicidal behaviour [ 1, 2] with between 25% and 40% of depressed patients attempting suicide [ 3] and about 3.4% completing suicide eventually [ 4]. Given recent figures suggesting that the lifetime prevalence of a major depressive episode among the US population is 32.6–35.1 million [ 5], it is no surprise that suicide ranks among the top ten causes of death in many other countries [ 6]. Understanding the aetiology of a significant public health issue such as suicide is important but difficult because of its complex and multifactorial origins. Although most suicidal behaviour occurs within the context of a mood disorder, most depressed individuals never attempt suicide. Furthermore, no linear relationship between the severity of the depressive episode and the likelihood of suicide has been forthcoming [ 7], highlighting the importance of other factors in addition to psychiatric illness. These factors include substance abuse or alcoholism, a head injury, a dysfunctional family or childhood abuse [ 8], high rates of gun ownership [ 9], smoking [ 10], socioeconomic adversity [ 11], and personality factors [ 12]. Genetic factors may also be very important [ 13, 14]. Marusic and Farmer [ 15] argue that the variation in the suicide rate across European countries (7–43 per 100,000 inhabitants per year) cannot be explained by sociocultural factors alone and is probably due to shared genetic vulnerability. A case in point is the high suicide rate in Hungary and Finland, two populations with a common genetic origin but with divergent cultural and political trajectories [ 15]. Colours of Depression At the family level, the risk of suicide is higher in individuals with a family history of suicide [ 16, 17], and the suicide rate of adolescents is highly correlated with the suicide rate among their relatives [ 18]. Even studies that have controlled for levels of psychopathology have shown that relatives of suicide completers and attempters are at an increased risk for suicidal behaviour [ 19, 20]. Twin studies indicate that this familial clustering of suicidal behaviour has a partly genetic basis with heritability estimates of 17%–55% for suicidal behaviour [ 21, 22] and 20% for suicide [ 23] reported. The only adoption study we are aware of suggested that as far as suicidal behaviour is concerned, adoptees resemble their biological parents more than the adoptive family [ 24]. These data have catalysed the search for genes that predispose to suicidal behaviour, with more than 100 studies now published [ 25]. Post-mortem studies of people who committed suicide have led to the general consensus that a disturbance of the serotonergic system is associated with suicidal behaviour. Therefore, it is no surprise that most of the genes implicated in suicidal behaviour—the serotonin transporter (SERT), tryptophan hydroxylase (TPH), monoamine oxidase A (MAO-A), and the serotonin receptors, 5-HTR1A, 5-HTR2A, and 5-HTR1B—modulate central serotonergic function (see Table 1). As is the case with most complex traits, however, success tends to plateau at a point where good candidate genes are identified but conclusive causal inferences remain elusive because of replication failures. Table 1 Association Analyses of Genes Predisposing to Suicide or Suicidal Behaviour The unequivocal identification of genes related to psychiatric disorder is retarded by a complex interplay of latent environmental influences or gene–environment interactions; genetically and phenotypically heterogeneous samples; the possible effects of numerous loci of small effect size; and the difficulty of adequately correcting for multiple testing. Faced with these frustrations, the use of endophenotypes as an aid to molecular genetic investigations has become almost de rigueur. In the case of suicide, a number of researchers have advocated the use of personality traits as endophenotypes [ 12, 26].