According to the World Health Organization (WHO) estimates for the year 2020, approximately 1.5 million people will commit suicide, and at least 10 times that many will make an attempt. This paper offers a brief overview of the current state of the epidemiology of suicide, a burgeoning public health problem. The information provided is based in large measure on reports of suicide mortality from 130/193 countries. In order to contextualize these data, this paper explores the contribution of both individual and sociocultural factors that influence suicidal behavior, from which much has been learned. Outlining the history of attempts by international and national organizations like WHO, United Nations, member states in the European community and other countries to regularize identification and suicide reporting procedures, this paper also demonstrates that serious knowledge gaps remain. Minimal requirements for successful evidence-based interventions are presented.

A major hindrance to determining the underlying biology of suicide is the heterogeneity of the phenotype. Not only are there various forms of self-harm and suicidal behaviors but even the finite act of dying by suicide can occur in multiple psychosocial contexts. Of all the different forms of fatal and non-fatal suicidal behaviors, the one that received the most attention is the aggressive impulsive type, which seems to occur in younger people and to cut across nosological entities, although its most classical expression occurs in borderline personality disorder. This focus should not obscure the fact that other forms of suicidal behavior such as those related to demoralization or wounded honor (narcissism) may well have different underlying genetic diatheses.

Suicidal behavior is transmitted within families, above and beyond the transmission of psychiatric disorder. The familial phenotype of suicidal behavior includes suicide completion and attempts, but not suicidal ideation, the latter of which is transmitted along with depression. The familial transmission of early-onset suicidal behavior is co-transmitted with, and appears to be mediated by the transmission of impulsive aggression. Additionally, the familial transmission of suicidal behavior is, in part, mediated by the familial transmission of abuse. Moreover, high family loading for mood disorder and suicidal behavior are related to multi-generational abuse, impulsive aggression, and early-onset of mood disorder and of suicidal behavior.

It has been well established that suicidal behavior is familial. Twin studies provide a unique opportunity to distinguish genetic effects from other familial influences. Consistent with findings from previous twin studies, including case series and selected samples, data from the population-based Swedish Twin Registry clearly demonstrate the importance of genetic influences on suicide. Twin studies of suicidal ideation and suicide attempts also implicate genetic influences, even when accounting for the effects of psychopathology. Future work is needed to evaluate the possibility of age and gender differences in heritability of suicide and nonfatal suicidal behavior.

Alterations in a number of neurobiological systems have been associated with suicidal behavior including the serotonergic and noradrenergic systems and the hypothalamic-pituitary-adrenal axis. Altered functioning of these systems may stem from both genetic and developmental causes. Adversity in early-life has developmental consequences on these systems that persist into adulthood. Genetic differences may also contribute to alterations in functioning of neurobiological systems. Moreover, the interaction of early-life experiences of adversity and genetic vulnerability is increasingly thought to play a role, including via epigenetic mechanisms.

Suicidal behavior is a major health problem worldwide. The risk of suicide-related behavior is supposed to be determined by a complex interplay of sociocultural factors, psychiatric history, personality traits, and genetic vulnerability. Family and twin studies point towards a partial heritability of suicidal behavior. First molecular genetic studies concentrated on genes of the serotonergic system based on the biochemical evidence that serotonergic neurotransmission is implicated in this behavior. Furthermore, genes of e.g. the dopaminergic and noradrenergic neurotransmitter systems have also been the subject of investigations in this context. The aim of this article is to review molecular genetic studies in suicidal behavior beyond the serotonergic system and to emphasize findings on new genes.

Suicidal behaviour shows evidence of familial clustering and the twin data on completed suicide suggest moderate heritability. The extent to which the genetics of suicidal behaviour overlaps with the genetics of affective disorders is unclear but there is overwhelming evidence that both bipolar and unipolar disorder are substantially influenced by genes. So far, candidate gene studies of suicidality have provoked much interest, but recently, attention has also turned to candidate gene approaches to suicidal ideation emerging during antidepressant treatment. The advent of genome-wide association studies (GWAS) has had a major impact on studies of affective disorder with some provocative new findings. The GWAS approach is also beginning to be applied in the search for genes that underlie suicidal ideation and behaviour.

The ultimate consequence of mental ill-health, suicidal behavior (SB), is a significant problem in most societies of the world. Suicide causes about one million deaths worldwide each year, and 10–20 times more people attempt suicide. The causes of why certain people engage in SB are complex, involving for e.g., both environmental and genetic factors, and interactions in-between. Well-established environmental risk factors are events causing significant psychological stress, which are particularly difficult to cope with, e.g. exposure to physical and sexual abuse. Excessive stress have the potential to induce unfavorable effects in a variety of higher brain-functions, incurred as side-effects to maladaptive responses in the genetically controlled stress-responsive neurosystems, e.g. the hypothalamic-pituitary-adrenal (HPA) axis; a major and systemic stress-modulator, which is mainly controlled by the regulatory corticotrophin releasing hormone receptor 1 (CRHR1) gene. Variation in-between individuals in such stress-regulatory genes such as CRHR1, may underlie the causes of the increased susceptibility of certain individuals towards SB. Here we review some of the current knowledge on what is known about the roles of the HPA axis in SB, with a focus on CRHR1.

The negative effects of excessive alcohol use include dependence, psychiatric co-morbidity and increased risk for suicide. A dominating risk factor is heritage. A large number of studies have addressed the genetic basis, either “candidate genes” in the brain reward system, or searched for unknown genes in family studies by linkage analysis. It is clear that no single gene polymorphism is of use in preventive medicine. A consistent finding, however, is that polymorphism in the alcohol dehydrogenase cluster and other metabolic pathways are of some relevance on a population basis, suggesting a link between alcohol toxicity in general and dependence. An emerging concern is potential gender differences as women, who are generally more sensitive, acquire male drinking habits.

Suicidal behavior runs in families and is prevalent in adolescence. Case-control and family-based studies in this age group failed to find a genetic association that survived replications. Gene environment approach gave new hope for possible associations especially with the short allele of the serotonin transporter promoter polymorphism (5-HTTLPR). However, a recent meta-analysis raised doubts about the consistency of these findings. Some new structural and functional imaging data may shade light on the age-related and gender-related development of the brain. This review suggests a new approach to gene by environment and timing interaction to understand the interplay that leads to suicidality in adolescents and young adults.

Despite strong evidence for a role of biological factors in the etiology and pathology of suicide, the study of traditional neurotransmitter systems has been able to explain only a small proportion of the neurobiology of what is now recognized as a complex genetic trait. The use of microarrays to simultaneously examine the expression levels of thousands of gene transcripts has vastly expanded our capacity to detect the involvement of additional genes and pathways in suicidality, and has opened many new avenues for the discovery of the biological underpinnings of suicide completion. This review examines microarray studies which have been used to identify genes displaying altered expression in suicide completers, and highlights some of the important methodological considerations and metabolic pathways which have emerged from these analyses.

Pharmacogenetic influences on therapeutic response to e.g. antidepressant or neuroleptic treatment are poorly understood and the lack of efficacy in many of the patients together with side effects can both limit therapy and compliance. Thus the aim of pharmacogenetics and pharmacogenomics is to provide predictive tools for the response to psychopharmacologic agents in the therapy of psychiatric disorders and in that ways to provide a real personalized psychiatry. The following review will summarize the current stage of pharmacogenetics and pharmacogenomics and will critically discuss the possibilities of a personalized medicine.

This paper presents a tentative typology of genetic and environmental pathways to suicidal behavior. Ten pathways are proposed and briefly illustrated: (i) direct effects from psychiatric disorders; (ii) direct effects from personality; (iii) direct effects of early adversity; (iv) direct effects of current adversity; (v) indirect effects of genes on selection into adversity (gene–environment correlation); (vi) interactions between genetic risk and current adversity: gene–environment interaction; (vii) interactions between early and current adversity: environment–environment interaction; (viii) interactions between culture and genes; (ix) dynamic developmental pathways involving causal loops from genes to environment and back again; and (x) gene × environment × development interaction.

In summary, genetics, as well as foetal and early life environmental factors shape the size or capacity of our monoamine systems, of which the serotonergic one might play a leading role. Those constitutional properties then form the biological basis for personality traits, such as impulsiveness and “sensation seeking”, which interact with psychosocial settings and life events to form a pattern of reactivity to a current life event or psychosocial situation, shown as a high or low order of magnitude of gene-environment interaction. In the present paper emphasis is put on the role of genotypes of the serotonin transporter, of monoamine oxidases A and B, and of platelet monoamine oxidase B activity, which all have been shown to be of importance for behaviour and with obvious effects of interactions with environment. Under unfortunate circumstances constitutional properties might be strong enough to result in vulnerability for suicide, even with a modest influence of environment.

The etiology of suicide is complex in nature with both environmental and genetic causes that are extremely diverse. This extensive heterogeneity weakens the relationship between genotype and phenotype and as a result, we face many challenges when studying the genetic etiology of suicide. We are now in the midst of a genetics revolution, where genotyping costs are decreasing and genotyping speed is increasing at a fast rate, allowing genetic association studies to genotype thousands to millions of SNPs that cover the entire human genome. As such, genome-wide association studies (GWAS) are now the norm. In this article we address several statistical challenges that occur when studying the genetic etiology of suicidality in the age of the genetics revolution. These challenges include: (1) the large number of statistical tests; (2) complex phenotypes that are difficult to quantify; and (3) modest genetic effect sizes. We address these statistical issues in the context of family-based study designs. Specifically, we discuss several statistical extensions of family-based association tests (FBATs) that work to alleviate these challenges. As our intention is to describe how statistical methodology may work to identify disease variants for suicidality, we avoid the mathematical details of the methodologies presented.