ReviewGene environment interaction studies in depression and suicidal behavior: An update
Introduction
Major depression (MD) and suicidal behavior (SB) are important public health issues because of their high prevalence and incidence in the population (Borges et al., 2010, Gelenberg, 2010). According to the World Health Organization (WHO) (see also Kessler et al., 2005), between 10% and 15% of the general population will experience a clinical depressive episode in their lifetime, and 5% of men and 9% of women will experience a depressive disorder in a given year (Hirschfeld, 2012). With regard to SB, in 2005, the overall suicide rate in the United States was 11/100,000 (National Center for Injury Prevention and Control (NCIPC), 2005), whereas, according to the WHO, the worldwide rate is 900,000/year (World Health Organization, 2001), with global rates of 17.7/100,000 for females and 10.7/100,000 for males (Mathers et al., 2006).
Although SB can occur in different psychopathological conditions (personality disorders, severe anxiety disorders, Schizophrenia and other major psychosis), patients affected by depressive disorders have the highest risk of attempting or committing suicide. Indeed, a meta-analysis of approximately 250 studies, spanning over 30 years, found that mood disorders (both unipolar and bipolar forms) carry the highest risk of SB compared to any other psychiatric and medical illness (Harrison and Burnet, 1997). Extensive literature has documented a substantial overlap between MD and SB with regard to familial risk, treatment (antidepressants and lithium salts are efficacious for MD and reduce SB risk) and environmental risk factors. Nevertheless, it has also been reported that SB may aggregate in families independently from the familial transmission of MD (Brent and Mann, 2006), suggesting that independent genetic risk factors for SB may exist.
MD has largely been recognized as a heritable disease (McGuffin and Katz, 1986). The estimated risk of disease in first-degree relatives of a proband is 3-times higher than that in the general population, although some studies have reported a 10-fold increased risk in siblings, when a more stringent definition of depression is applied (Farmer et al., 2000). Population-based studies support a heritability for depression of 30–40% (Kendler et al., 1992). Twin studies in bipolar disorder showed an increased rate of concordance for both unipolar and bipolar mood disorder, with an estimated heritability of 80% (Bertelsen et al., 1977, McGuffin et al., 2003). With regard to SB, less evidence has been reported, since it mostly occurs within the context of various psychopathological conditions. However, twin studies have consistently documented genetic influences in SB, even when accounting for the effects of psychopathology. Concordance rates ranging from 6% to 35% have been reported in different studies of identical twins (see Pedersen and Fiske, 2010).
A number of biological factors and candidate genes have been tested in MD and SB (see Elder and Mosack, 2011, Mandelli et al., 2009, Rujescu et al., 2007, Tsai et al., 2011). However, to date, only a few consistent findings have been reported. One major challenge is that SB and MD are complex and heterogeneous disorders that are caused by a combination of variations in multiple genes, each exerting a small effect on both disease risk and symptomatologic aspects. Furthermore, consistent evidence supports a critical role of environmental factors in modulating or triggering a genetic predisposition to SB (Roy et al., 2009, Saveanu and Nemeroff, 2012). Indeed, both early adversity and recent acute/chronic stress (loss, separation, interpersonal or family problems, occupational stress/unemployment, poor social contacts/support, among others) have long been recognized to play a pivotal role in both MD and SB (Paykel, 1976). For this reason, in the early 2000s, investigators focused on studying the interplay between genetics and environmental risk factors. Gene × environment (G × E) studies are useful in identifying correlations or interactions between risk genes for a specific disease and environmental factors (Cooper, 2001). In addition to the chance to provide a better characterization of already identified genes involved in the disease, these studies may enable the identification of new genes, in which their effects are dependent on the level of exposure to a specific environment.
In the present article, after a brief review of the genetic factors involved in MD and SB, we will review the studies focused on G × E in these disorders/behavioral disturbances, highlighting the major and interesting findings obtained so far and discussing the potential added benefit of G × E investigation compared to simple genetic association studies. Furthermore, we will discuss the potential helpfulness of the G × E approach in the overall context of psychopathology, together with the need of novel methods of study within a multidisciplinary framework.
Section snippets
Literature search
Published G × E studies in MD and SB were screened using several literature search strategies. Up to January 2013, appropriate search terms (gene, genetics, heritability, suicide, suicide attempt, completed suicide, suicidality, suicidal behavior, suicidal ideation, suicide intent, major depression, depressive disorder, and mood disorders) were entered into the common scientific literature databases (PubMed, SCOPUS and ISI Web of Science). The same terms were also entered in conjunction with
Genetic basis of major depression (MD) and suicidal behavior (SB)
Hundreds of candidate genes in MD and, to a lesser extent, in SB have been tested in several studies (most frequently examining candidates related to monoamine signaling, neurotrophins, neuroendocrinology or immunology/inflammation processes). Genes that have been most consistently associated with MD and SB (i.e., found positive in 2 or more independent studies and/or reported as associated in large meta-analyses) are reported in Table 1.
Not surprisingly, several genes have been reported as
Main monoaminergic central systems (serotonin, dopamine and noradrenalin)
The serotonin transporter gene (SLC6A4) has been the focus of much investigation in MD and SB (see above). Thus, it is not surprising that a leading G x E study in MD conducted by Caspi et al. (2003) investigated the common 5-HTTLPR polymorphism in SLC6A4. The study provided evidence that the S-allele in 5-HTTLPR increased depressive symptoms, risk of developing a depressive episode and suicidal ideation after exposure to SLEs in a large prospective community cohort. Subsequently, several
Discussion and conclusions
It has been well recognized that single genes may not explain the full risk of developing complex diseases, particularly, mental/behavioral disturbances, and that heritable factors, when taken together, may account for approximately 50% of the variance in risk (Kendler, 2001). Furthermore, evolutionary forces rapidly eliminate large gene effects, and complex highly prevalent diseases, such as mental disorders, are associated with minor gene effects (Risch, 1994). Thus, it is more likely that
Disclosure of interest
The authors declare no conflict of interest or conflicting financial support.
Acknowledgement
The authors would like to thank Dr. Ciro Marangoni for his collaboration in the drafting of a preliminary version of this paper.
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