Substantial evidence supports the role of genetic factors in suicide behaviors (SBs). The most recent and powered genome-wide association studies identified significant loci for suicide, suicide attempts, and suicide ideation. Nonetheless, more research is needed to fully understand its impact. A novel approach considering the genetic complexity of SBs is polygenic scores that, in conjunction with individual and environmental factors, may have promising results to inform suicide risk stratification. Communicating this information to patients and the open population may have ethical implications that need to be considered to avoid iatrogenic effects.
Key points
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Genome-wide association studies (GWASs) have identified some loci implicated in suicide behaviors (SBs). Larger sample size considering several ancestries will be necessary to give them solid biological support.
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Polygenic scores (PGSs) derived from co-occurring disorders and suicide itself consistently predict a fraction of the phenotypic variance of suicide behaviors.
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Integrating PGSs with individual psychosocial-environmental factors improves their predictive ability.
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SBs genetic counseling and prevention strategies may benefit in the future from this genomic information.
Introduction
For most readers, the deaths of Cleopatra, Shakespeare’s Juliet, Judas Iscariot’s, or Van Gogh can be quoted among the well-known accounts of suicides we can gather from history and world literature. Even though a somewhat heroic—romantic—redemption halo surrounds the above-cited examples, it is true that in most cases, suicide attempts and suicide are instead tragic outcomes carrying a high degree of prejudice and stigma. Ultimately, suicidal behaviors are and have been human traits ubiquitous to all cultures, geographic regions, and populations throughout history.
Suicide is a serious public health problem of worldwide proportions, occurring throughout the human lifespan. According to The World Health Organization, almost 700,000 deaths per year are related to the act of taking their own life, being the fourth leading cause of death in individuals aged 15 to 29 years. Additionally, many more persons have had failed attempts that, in most instances, were accompanied or preceded by suicidal thoughts or plans.
By 2016, suicide represented, at a worldwide level, one of the top leading causes of age-standardized years of life lost in the Global Burden of Disease Study. Additionally, self-harm, commonly associated with suicide behaviors, has been globally and persistently ranked among the leading causes of disability-adjusted life years in individuals aged between 10 and 24 years and, to a lesser degree, during the most productive labor years with a substantial economic and social burden. These tragic events leave a deep and long-lasting emotional imprint on relatives, friends, or loved ones.
Defining suicide behaviors
Derived from the different facets of suicide-related demeanors, an intricate kaleidoscope of behavioral trajectories and pathways is anticipated; therefore, a critical issue is to be explicit in their definitions and terminology. However, the complexity of the cognitive and emotional components underlying the intentions and motivations, as well as the contexts and circumstances surrounding suicide and other self-destructive behaviors, represent a supreme challenge in the attempt to define them in just a few sentences. The latter is especially critical in genetic and genomic research, where it has been stressed the requirement for harmonized codes to make the most of the information compiled from suicide-relevant clinical or epidemiologic data.
As cited in Silverman and colleagues,
… “The further benefit of clarifying terms would be to assist genetic studies in differentiating valid phenotypes from one another so that underlying genotypes can be more accurately identified. A valid and reliable nomenclature will allow the development of a classification for suicidality” …
In this sense, although the term suicidality is used as a representation of the broad spectrum of thoughts and behaviors related to suicide, including a single construct of suicidal ideations, and behaviors associated with suicidal attempts, and suicide, we deem it loses meaning, distinctiveness, and clarity. Here, we will employ the terms revised in Silverman and colleagues and definitions provided by the US Centers for Disease Control and Prevention, where it must be intrinsically explicit that the behavior must convey the act of intentionally ending one’s life ( Table 1 ).
| Term | Definition |
|---|---|
| Suicide | Death caused by self-directed injurious behavior with an intent to die as a result of the behavior |
| Suicide attempt | To engage in actual self-injurious behavior aimed primarily to end one’s life; a nonfatal, self-directed, potentially injurious behavior with an intent to die because of the behavior even if the behavior does not result in injury |
| Suicidal ideation | Acknowledging having thoughts about wanting to die or stop living, falling asleep and not waking up, or engaging in behaviors to stop living, thinking about, considering, or planning a suicide |
a The formulation of a specific method or strategy to succeed in the planned attempt.
To note, an agenda to recognize a SB disorder as an independent nosologic entity has been advocated on the basis that it would permit the leveraging of large health-related databases to discover clinical and biological markers of imminent and longer term suicide risk.
The genetic approach to suicide behaviors
A body of evidence supports the critical role of genetic factors not only in suicide but also in other SBs. For example, suicide and suicide attempts run in families and seem to segregate independently of the psychiatric-associated condition. Moreover, the risk of a suicide attempt is much higher in the offspring of parents with a history of suicide attempts. Additionally, although twins or adoption studies on suicidal behaviors are scarce, they also support the hypothesis of a heritable genetic component.
Two recent epidemiologic studies in the Swedish population support an influential role of shared genetic factors in the intergenerational transmission of SBs. Interestingly, the data also show that although there was a substantial cross-generational genetic correlation between attempts and suicide, their transmitted liabilities, that is, both the individual’s innate tendency to develop the disease but also the environmental milieu to which he is exposed, were not equal suggesting that they might be 2 partially independent phenotypes.
The advent of molecular genetics gave an extraordinary impetus to unravel the elements of the genetic component (ie, the genes) of psychiatric and behavioral phenotypes, including those suicide-related. Thus, multiple neurobiological systems of potential relevance were initially examined by employing the same models and tools used for other complex diseases and disorders. For example, based on evidence showing a decreased serotonergic neurotransmission in some forms of SBs, several studies applied a candidate gene association strategy, typifying polymorphism in the sequence of genes coding for the serotonin transporter tryptophan hydroxylase and monoamine oxidase A. This approach was extended to other archetypical neurotransmitter systems (eg, biogenic amines, gamma-aminobutyric acid [GABA], glutamate, neuropeptides, or endocannabinoids), the stress-related system, and even molecular factors relevant to neuroinflammation. Unfortunately, the strength of the genotype–phenotype associations reported has been generally small or inconsistent among studies. Hence, the contribution of the role of specific genes to suicide behaviors has yet to be deciphered. In any case, as shown below, the evidence strongly indicates the existence of a polygenic component.
The leap to genomics in the study of suicide behaviors
Further development of molecular technologies made it possible to analyze hundreds of thousands of genetic variants efficiently, typically single nucleotide polymorphisms (SNPs), allowing the carrying out of GWASs hypothesis-free for candidate genes.
More than 30 GWAS have been performed regarding various SBs. These studies require very large sample sizes to detect specific physical sites (loci) at a genome-wide significant (GWS) level. The first GWAS, published in 2010, analyzed approximately 10,000 patients with mood disorders, of which 28% presented at least a suicide attempt, while the most recent GWAS on this behavior included approximately 540,000 patients with several psychiatric disorders, of which 6% presented at least a suicide attempt. Since epidemiologic data suggest that suicide ideation, attempt, and suicide may have an independent genetic component, a similar effort has been made to identify genetic loci associated with each phenotype. To date, the most well-powered large-scale GWAS of suicide ideation, attempt, and suicide has identified several loci ( Table 2 ); nonetheless, it is still unknown to understand its biological implications.
| Phenotype | Ancestries Included | Sample Size | Chromosome (Chr) Location and SNP Identifier |
|---|---|---|---|
| GWAS in specific suicide outcomes | |||
| Suicide ideation | European (72%), African (19%), Asian (1%), and Hispanic (8%) | Cases: 99,814 Controls: 512,567 | Chr9:rs77641763 Chr16:rs7185007 Chr2:rs142785607 Chr6:rs6557168 |
| Suicide attempt | European (90%), African (4%), and Asian (6%) | Cases: 29,782 Controls: 519,961 | Chr7:rs62474683 Chr6:rs71557378 |
| Suicide | European (100%) | Cases: 3413 Controls: 14,810 | Chr13:rs34399104 Chr13:rs35518298 Chr13:rs34053895 Chr13:rs35502061 Chr13:rs66828456 Chr15:rs35256367 |
| GWAS study of SBs including most diverse ancestries | |||
| Suicidal behaviors | European (72%), African (19%), Hispanic (8%), and Asian (1%) | Cases: 121,211 Controls: 512,567 | All populations Chr6:rs6557168 Chr11:rs12808482 Chr9:rs77641763 Chr18:rs10671545 Chr14:rs36006172 European ancestry Chr6:rs13211166 Chr11:rs7127383 African ancestry Chr4:rs182921948 Hispanic ancestry Chr4:rs116015815 |
| Rare protein-coding variants associated with suicide | |||
| Suicide | European (100%) | Cases: 2672 Controls: 51,583 | Chr17:rs145053802 Chr6:rs149197213 Chr11:rs143883793 Chr14:rs75418419 Chr22:rs62223875 |
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