Biological Aspects of Suicidal Behavior

W. P. Kaschka, D. Rujescu

• Publisher: S. Karger
• Year: 2015
• ISBN:
  9783318055849
• Topic: Medicine
• Subtopic: Neurology

Suicide is one of the most important causes of death in modern societies. To develop more effective preventive measures, we have to be aware of and learn more about its neurobiological foundations. In recent years, the tools of modern neurosciences have increasingly been utilized to characterize the pathophysiology of complex human behaviors such as suicide. To improve suicide risk assessment and suicide prevention, a better understanding of its pathophysiology is crucial. This includes research from a variety of disciplines such as neuropsychological, psychosocial and cultural studies but also findings from biochemistry, neuropathology, electrophysiology, immunology, neuroimaging, genetics, and epigenetics. Important results have, for example, been obtained in the field of gene-environment interaction and suicidal behavior. We have just begun to understand how early-life adversity may increase suicide risk by epigenetic mechanisms. Based on such insights, novel therapeutic interventions and preventive measures can be developed. Furthermore, a better understanding of the pathophysiological mechanisms involved in suicidal behavior could reveal the mechanism of compounds like lithium salts. In this book, suicidal behavior and its prevention is discussed by international experts in the light of the most recent results from a broad spectrum of neurosciences.

Genetics

Kaschka WP, Rujescu D (eds): Biological Aspects of Suicidal Behavior.
Adv Biol Psychiatry. Basel, Karger, 2016, vol 30, pp 51-62 (DOI: 10.1159/000438468)

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Genetics of Suicidal Behavior

Ina Giegling · Dan Rujescu

Department of Psychiatry, Psychotherapy and Psychosomatics, Martin Luther University Halle-Wittenberg, Halle, Germany

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Abstract

Suicidal behavior is multidimensional. As well as medical, psychological, psychosocial, social, cultural, and socioeconomic parameters, it also includes biological, especially genetic, risk factors. The heritability is about 55% assuming a polygenic risk model. First linkage and candidate gene studies have focused mainly on the serotonergic system. Interestingly, most associations were found not with suicidal behavior per se but with personality traits like aggression and impulsivity. Newly started genome-wide association studies are promising but actually mostly do not show genome-wide significant results. The main reason seems to lie in the sample size. Exome and whole genome sequencing studies are in their earliest beginnings and will hopefully help to dissect the genetic risk proportion of suicidal behavior.

© 2016 S. Karger AG, Basel

Heritability of Suicidal Behavior

Someone commits suicide worldwide every 40 s. This makes over 1 million people each year. The number of suicide attempts is 10-fold higher. Suicide accounts for 2% of the world's death. It has emerged as one of the leading causes of death among adolescents. Suicide is the second leading cause of death among 15- to 29-year-olds [1]. Attempted suicide is regarded as the most important predictor of a future death from suicide [2]. Almost one quarter of suicides are preceded by nonfatal suicidal behavior in the previous year [3]. Nearly 2% of suicide attempters end their own life during the 12 months subsequent to the index event [4].

Suicidal behavior is complex and mostly a consequence of interactions of risk factors like medical (e.g. mental disorders), psychological (e.g. hopelessness, impulsivity, aggression), psychosocial (e.g. social isolation), social (e.g. lack of social support), cultural (e.g. religion), socioeconomic (e.g. unemployment), and biological factors (e.g. genetics, disorders in brain functioning) [5]. The genetic risk is supported by family, twin and adoption studies, indicating that suicidal acts have a genetic contribution that is independent of the heritability of psychopathology [6, 7].

One of the largest epidemiological studies by Mittendorfer-Rutz et al. [8] including 14,440 suicide attempters and 144,440 healthy controls showed that the risk of suicide attempts increased by a factor of 4.2 when the biological mother had committed a suicide attempt or by a factor of 3.3 when the father was affected. Furthermore, the risk was increased by 4.5 when siblings showed suicidal behavior or by a factor of 3.7 if any family member was involved. If suicide attempts were present in 2 or more family members the risk for an own suicide attempt increased by a factor of 7.3 [8]. This familial accumulation of suicidal behavior could be partly due to genetic risk factors. Twin studies compare the concordance for suicidal behavior in monozygotic twins, which mostly share 100% of their genes, with dizygotic twins sharing 50% of them. This allows us to separate effects due to a shared environment from genetic factors. Roy et al. [9] examined 62 monozygotic and 114 dizygotic twin pairs and reported concordance rates of 11.3 and 1.8%, respectively. An Australian twin study with a total of nearly 6,000 twins estimated the heritability of suicide attempts at 55% [10]. Interestingly, Voracek and Loibl [11] found convergent evidence from a multitude of research designs (adoption, family, genome scan, geographical, immigrant, molecular genetics, surname, and twin studies of suicide) suggesting genetic contributions to suicide risk. Their work focused on twin studies. A total of 32 studies located through extensive literature search strategies were analyzed (19 case reports, 5 twin register-based studies, 4 population-based epidemiological studies, 4 studies of surviving co-twins). The literature was based on publications between 1812 and 2006 in six languages and reports data from 13 countries. A meta-analysis of all register-based studies and all case reports aggregated showed that concordance for completed suicide was significantly more frequent among monozygotic (24.1%) than dizygotic twin pairs (2.3%). The totality of evidence from twin studies of suicide strongly suggests genetic contributions to liability for suicidal behavior [11]. Adoption studies have been less commonly performed and classical studies often used the same Danish health statistics register [12-14]. The investigation of Schulsinger [13] identified 57 suicide victims among early adopted Danish citizens and defined them as index cases. The biological relatives of these index cases showed a 6-fold higher suicide rate (4.46%) than the biological relatives of a matched, nonsuicidal adoptee control group (0.74%). Furthermore, there was no suicide among the adoptive relatives of the index cases. von Borczyskowski et al. [15] presented a very large study based on the Swedish registry with a total of 2,471,496 people, including 27,600 adoptees, supporting the role of a genetic risk.

Association Studies of Suicidal Behavior

Serotonergic System

The involvement of serotonin in suicidal behavior is already known since the 70s. Clinical studies found lower levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), a putative indicator for low serotonin turnover, in suicidal patients [16, 17]. Furthermore, many studies investigating postmortem brains of suicide victims have shown alterations of the serotonergic system, especially in the prefrontal cortex [18]. Besides that, low CSF 5-HIAA is associated with aggressiveness, low social affiliation, high-risk behavior, and premature mortality [19, 20]. In humans, 5-HIAA in the CSF correlates inversely with various aggressive behaviors, as demonstrated in healthy and psychiatric samples throughout the life span. Most genetic association studies have focused on genes involved in serotonergic neurotransmission. Serotonergic function was regarded as crucial for the regulation of impulsive and aggressive behavior, which in turn has been demonstrated to correlate with suicidal behavior in various studies [21].

Tryptophan Hydroxylases 1

Serotonin (5-hydroxytryptamine, 5-HT) is a monoamine neurotransmitter. Biochemically, L-Tryptophan is converted to 5-hydroxy-L-tryptophan through tryptophan hydroxylase (TPH). This enzyme is a rate-limiting step to 5-hydroxytryptophan. To find genetic risk factors for suicidal behavior, early studies concentrated on single nucleotide polymorphisms (SNPs) in these genes. A first meta-analysis [22] did not find an association of the commonly studied intron 7 A218C (TPH1) SNP with suicidal behavior per se. A further meta-analysis summarized the results of 7 studies investigating the A218C SNP in Caucasians and found a higher frequency of the A218 allele in patients [23]. Another meta-analysis including 9 studies confirmed the association for the A218C polymorphism [24]. Li et al. [25] provided a meta-analysis of 22 studies and showed further support for association. Additional support for the involvement of THP1 (SNP rs1800532) and suicidal behavior was provided by the meta-analysis by Clayden et al. [26].

Recently, a meta-analysis was conducted with a total of 37 genetic association studies of TPH1 (A218C and A779C). Subgroup analyses were done by Caucasian and Asian populations. In the case of TPH1 gene variants (A218C and A779C), 5,683 cases and 11,652 controls were involved. The analyses provided evidence that A218C/A779C TPH1 variants may be risk factors for the presentation of suicidal behavior, which is in agreement with previously reported meta-analyses [27].

Interestingly, this risk allele ‘A’ was also associated with aggression and anger [28]. This result was further supported by Rujescu et al. [29], who showed that A carriers had higher scores on the Trait Anger Scale of the STAXI (State Trait Anger Expression Inventory) in 2 independent samples (healthy controls and suicide attempters). An involvement of TPH1 in anger and aggression phenotypes was furthermore presented by Baud et al. [30], who reported that suicide attempters carrying the AA genotype scored significantly lower on the anger control subscale than C allele carriers. A number of further studies showed the involvement of TPH1 in personality traits. For example, Cicchetti et al. [31] explored the hypothesis that TPH1 interacted with maltreatment subtype to predict peer reports of antisocial behavior. TPH1 polymorphisms also moderated the effects of maltreatment subtype on adult reports of antisocial behavior; genetic effects were strongest for children who were abused. Additionally, TPH1 moderated the effect of developmental timing of maltreatment and chronicity on adult reports of antisocial behavior [31]. Andre et al. [32] reported that the number of TPH1 A alleles was associated with increasing levels in novelty seeking (NS) scores 1 and 2 and decreasing levels in harm avoidance (HA) 1 and 2 between TPH1 A218C genotypes. TPH1 genotype and treatment response had an interactive effect on both HA1 and HA2 and to a lesser degree on NS2 scores. Additionally, an interaction between remission status and TPH1 A218C genotype was found to be associated with the end point HA score, with a more marked effect of the interaction between the CC genotype and remission status compared to A...