The Involvement of Genes in Adolescent Depression: A Systematic Review

Introduction

Depression is a common disorder affecting an estimated 350 million people worldwide. Long-lasting depression with moderate or severe intensity is a serious medical condition that can lead to suicide. An estimated 1 million deaths each year are related to suicide. Although treatments for depression are effective, fewer than half of all individuals with depression around the world (in some countries, fewer than 10%) take anti-depressants (WHO, 2014a). Barriers to effective care include a lack of resources, a lack of trained health care providers, and social stigma associated with mental disorders (WHO EMRO, 2014). Inaccurate assessment and incorrect diagnosis of depression in its early stages can also prevent the effective care of individuals with depression. It is commonly believed that depression is a result of the complex interaction of social, psychological, and biological factors. Numerous studies have reported the involvement of abnormal gene expression or single nucleotide polymorphisms (SNPs) of genes in the development of depression (Bufalino et al., 2013).

Depression is also the leading cause of disability in young people worldwide. An estimated nine percent of children and adolescents in the US are affected by depression (Dunn et al., 2011). Although the diagnostic criteria for children and adolescent depression are no different from those for adults, one epidemiological study showed that there are different risk factors for the onset of depression in young people and in adults (Jaffee et al., 2002). For example, depressive adolescents experienced more perinatal insults, caretaker instability, and criminality than adult-onset depressive patients. Also, depressive adolescents have more behavioral and socioemotional problems than the adult-onset patients. In contrast, the adult-onset patients experienced more sexual abuse in their childhood than depressive adolescents (Jaffee et al., 2002).

Moreover, studies in neuroscience have demonstrated that adolescence is a special period of development characterized by significant changes in the structure and connectivity of the brain, as well as changes in cognition and behavior (Cousins and Goodyer, 2015). These neurological changes may interplay between genes and the environment (Paus, 2013). Results from several family and twin studies suggest that etiologic genetics do exist in depression during adolescence (Rice, 2009). A few reviews or meta-analyses have also summarized the gene × environment interaction in adolescents with depression (Franić et al., 2010; Rice, 2010; Dunn et al., 2011). However, the age range for adolescence was not accurately defined. Heterogeneity within a group of depressive patients may be problematic for the development of theory, research, and treatment of depressive patients (Jaffee et al., 2002). It is therefore necessary to summarize the findings in adolescents with an accurately defined age range: (1) to update the findings on gene expression or polymorphism in adolescent depression and (2) to evaluate the value of all genes as a biomarker of adolescent depression. The WHO defines adolescence as having an age range of 10–19 years old and as a dynamic period with biological, social, and psychological changes (WHO, 2014b). In this study, the age range of 10–19 years was defined as adolescence while an age range of 20–25 years was defined as young adult for analysis.

The goal of the current review is to systematically analyze studies that tested the role of a gene in the development of depression or as a risk factor of depression in adolescents. We focused specifically on the findings and ultimately provide substantive conclusions on which gene expression or polymorphism could be a biomarker of depression in adolescents.

Methods

Eligibility Criteria

A systematic review of original studies on gene expression or genetic polymorphisms in adolescents with depression was conducted. Reports on gene expression or polymorphisms measured in peripheral blood or postmortem studies in adolescents were eligible for review. A study was included in the analysis when: (1) adolescents with depression or depressive symptoms fell into the range of 10–19 years old (WHO, 2014b) or young adult at an age of 20–25 years and (2) original research with the age range and gene being clearly identified. Studies were excluded if: (1) a study had subjects with age not in the two age ranges; (2) a study only provided a mean age; (3) A study contained anxious adolescents only; (4) studies that were conducted in animals or in vitro; or (5) review or studies that were not written in English.

Information Sources

Studies were pulled from the electronic databases of PubMed, Embase, and Web of Science.

Search Strategy

The primary search strategy was carried out using both the keywords and test words: “depression” and “adolescent” and “gene”; “depression” and “adolescent” and “polymorphism”; “depression” and “adolescent” and “genetics”; “depression” and “adolescent” and “genetic variants”; and “depression” and “adolescent” and “genotype”.

Data Collection Process

The abstract of each study was screened and the full-text articles of potentially relevant studies were then retrieved and assessed. Data were extracted from the retrieved papers by two authors (LX and SY) independently. Disagreements were resolved by discussion in a meeting that included several experts from within the Department. The study selection process was presented in a flow diagram (Figure 1).

FIGURE 1

Figure 1. A flowchart of literature search strategy. A flowchart of the inclusions and exclusions of studies in the current study.

Data Items

Data on age range, study design, demographic characteristics of patients, and control individuals, gene expression or polymorphism, tissue type, and the results were extracted.

Outcomes

The association of gene expression or polymorphisms with disease risk, severity of depressive symptoms, and treatment outcomes.

Risk of Bias in Individual Studies

Risk of bias was assessed by evaluating choice of study design, selection of study population, allocation of control individuals, and quality of assay used.

Data Synthesis

Data was summarized for each gene including the main outcomes or conclusion, positive and negative association with depression.

Results

The literature search identified 1334 articles from PubMed, EMbase, and Web of Science using the keywords mentioned above after the removal of duplicates. The end date for the search is August 29, 2015. The abstracts of the 1334 articles were screened one by one and articles not written in English, review articles not for depression in adolescents, comments, and articles for animal or in vitro studies were excluded from this study. The studies where the gene name could not be identified in the abstract were also excluded from further analysis. A total of 282 studies were finally used for extracting full-length articles. However, only 261 full-length articles were downloaded for careful identification. Full-length articles of screening studies, studies in non-adolescents or with a mixed sample with the age beyond the range of 10–19 years for adolescents or 20–25 years for young adults, studies with only the mean age, studies without clearly identified gene expression or polymorphism, or others was excluded from the analysis. Finally, 47 full-length articles (Eley et al., 2004; Mamalakis et al., 2004; Burcescu et al., 2005; Miraglia del Giudice et al., 2006; Sjöberg et al., 2006; Geng et al., 2007; Hilt et al., 2007; Pandey et al., 2007, 2012; Feng et al., 2008; Aslund et al., 2009; Duncan et al., 2009; Goodyer et al., 2009, 2010; Guo and Tillman, 2009; Laucht et al., 2009; Nilsson et al., 2009; Nobile et al., 2009; Benjet et al., 2010; Brent et al., 2010; Mata et al., 2010; Nederhof et al., 2010; Uddin et al., 2010, 2011; Bouma et al., 2011; Hankin et al., 2011; Jenness et al., 2011; Mata and Gotlib, 2011; Thompson et al., 2011; Chen et al., 2012, 2013; Petersen et al., 2012; Buchmann et al., 2013; Bobadilla et al., 2013; Comasco et al., 2013; Cutuli et al., 2013; Kohen et al., 2013; Otten and Engels, 2013; Oppenheimer et al., 2013; Priess-Groben and Hyde, 2013; Stavrakakis et al., 2013; Banducci et al., 2014; Cicchetti and Rogosch, 2014; Cruz-Fuentes et al., 2014; Little et al., 2014; Zhang et al., 2015) in adolescents and three studies (Hammen et al., 2010; Starr et al., 2013; Thompson et al., 2014) in young adults were included in this study (Figure 1). The 47 studies in adolescence included 20 genes or gene families while the three studies in young adults included three genes (Table 1).

TABLE 1

Table 1. Summary of literature and outcomes in adolescents.

Among the studies in early adolescence, only three articles reported the association between gene expression and depression in adolescents (Mamalakis et al., 2004; Pandey et al., 2007, 2012) and one study reported a linkage analysis (Feng et al., 2008). 91.5% (43/47) of articles reported the results of nucleotide polymorphism analysis of a gene in adolescents with depressive disease or depressive symptoms (Table 1). Most studies were related to neurotransmitter receptors and their associated metabolic enzymes, including the dopaminergic system (DRD2, DRD4, and COMT) and serotonergic system (serotonin 2A, 5-HTT, MAOA, and TPH). 5-HTT (5-HTTLPR polymorphism) is the most frequently examined gene (26 articles) followed by Brain-derived neurotropic factor (BNDF; 12 articles). Thirteen genes were only reported in one article. Seven genes (COMT, serotonin 2A, MAOA, estrogen receptor α and β, AR, glucocorticoid receptor, and adipose polyunsaturated fatty acid gene) showed no association with depression in adolescents. Four genes (DRD2, DRD4, TPH1/2, and CREB/CREB1) were reported by two or three articles with inconsistencies. The 26 studies on 5-HTTLPR contained a total of 14,616 samples, and the 12 studies on BDNF contained a total of 7646 samples.

Approximately 92.3% (24/26) of studies for the association between 5-HTTLPR polymorphism and depression in adolescents yielded a positive outcome (Table 2). Among the 26 studies for 5-HTTLPR polymorphism, 22 studies analyzed the association between polymorphism and depressive symptoms (two studies showed negative findings), while four studies analyzed the role of 5-HTTLPR polymorphism in depression. Only one study analyzed the association between 5-HTTLPR polymorphism and the severity of depressive symptoms. It appears that 5-HTTLPR polymorphism is associated with both the risk and severity of depression in adolescents. There was no study to compare the role of 5-HTTLPR polymorphism in anxiety and depression. The association between 5-HTTLPR polymorphism and different types of depression (i.e., anxiety vs. irritability vs. cognitive dysfunction) was not analyzed in this study because only a few studies analyzed the association between 5-HTTLPR polymorphism and the cognitive dysfunction and the irritability.

TABLE 2

Table 2. Outcomes of studies on the relationship between 5-HTTLPR and depression in adolescents.

BDNF was the second most frequently studied gene in adolescents. All 12 studies analyzed the association between BDNF Val66Met genotype/gene plasticity index and depressive symptoms. Among them, one study investigated the BDNF gene plasticity index in adolescents with depressive symptoms without observing any association. Eleven studies (Hilt et al., 2007; Duncan et al., 2009; Goodyer et al., 2010; Mata et al., 2010; Chen et al., 2012, 2013; Buchmann et al., 2013; Comasco et al., 2013; Stavrakakis et al., 2013; Cicchetti and Rogosch, 2014; Cruz-Fuentes et al., 2014) investigated the association between the BDNF Val66Met genotype and adolescent depressive symptoms with only one study showing no association (Nederhof et al., 2010; Table 3). However, no study analyzed the association between BDNF Val66Met genotype and severity of depressive symptoms. No study compared the role of BDNF Val66Met genotype in anxiety and depression. The association between BDNF Val66Met genotype and different types of depression was not analyzed in this study because no studies analyzed the BDNF Val66Met genotypes and irritability. Only one study investigated the association of BDNF Val66Met genotypes with cognitive dysfunction. Two studies reported the association of genetic variants in the dopaminergic system with adolescent depression (Bobadilla et al., 2013; Stavrakakis et al., 2013; Table 3).

TABLE 3

Table 3. Outcomes of studies on the relationship between BDNF and dopaminergic pathway and depression in adolescents.

Only three studies investigated the gene polymorphism and the risk of depression in young adults at an age range of 20–25 years. Thompson et al. (2014) study found that OXTR (oxytocin receptor gene) polymorphism influences the development of depressive symptoms. Starr et al. (2013) study showed that 5-HTTLPR S-allele can predict relative increases in probability of depression among boys. Hammen et al. (2010) study revealed that chronic family stress at age 15 predicted higher depression scores at age 20 among females with one or two S alleles of 5-HTT gene (Table 4).

TABLE 4

Table 4. Summary of literature and outcomes in young adult.

Risk of bias was evaluated for the study design, allocation of control individuals, and quality of assay methods. There was a wide variation in methods and analysis. Most studies did not include age or gender-matched control individuals. Most studies did not provide detailed information about current medical treatment in the full study sample. Most studies did not provide observer-based rating scores of depressive symptom severity.

Discussion

Studies in twins, families, and populations have revealed the genetic influences on depression (Rice, 2009). Deregulated gene expression and specific functional genetic polymorphisms have been demonstrated to be risk factors of depression or to be associated with the severity of depressive symptoms (Dunn et al., 2011). Numerous studies have confirmed the existence of biological etiology in the development and progression of depression during childhood and adolescence (Dunn et al., 2011; Paus, 2013; Cousins and Goodyer, 2015). However, the published reviews did not summarize the up to date biological findings in only adolescents with defined age ranges. Heterogeneity within study subjects is a main concern for the research in depressive patients because the risk factors for the onset of depression in adolescents and in adults are different. Moreover, the depressive adolescents may experience more psychopathology, behavioral and socioemotional problems than adult-depressive patients (Jaffee et al., 2002). It is therefore important to summarize the biological findings in depressive patients with a defined age range. This study updated the genetic findings in adolescent depression with an age range of 10–19 years defined by WHO as adolescence and 20–25 years as young adult. This study demonstrated that genetic polymorphism or expression of 13 genes was associated, but seven tested genes were not associated with the risk or severity of depression in early adolescence, while the polymorphism of three genes was associated with the risk of depression in late adolesence. This review highlighted the role of several genes or gene families as risk factors for the development of depression in adolescents. This study improved our understanding of the etiology of adolescent depression, and also identified 5-HTTLPR and BDNF Val66Met polymorphisms as the most studied biomarkers in adolescent depression.

Low serotonin-receptor levels in the brain have been widely recognized to be a key cause of depression. Polymorphisms of the 5-hydroxytryptamine (serotonin) transporter gene-linked polymorphic region (5-HTTLPR) have been widely demonstrated to be a risk factor for depression following adverse life experiences. In this review, a total of 26 articles reported an association between 5-HTTLPR variations and depression in adolescents. About 92.3% of studies (n = 24) identified positive associations of 5-HTTLPR polymorphism with the risk for or susceptibility to depression, new depressive episodes, and more severe depressive symptoms. The most commonly examined polymorphism was the 5-HTTLPR variable number tandem repeat (VNTR), which consists of the s/s, s/l, and l/l genotypes. In most studies, the short (S) allele or heterozygote genotype carriers (s/l) of 5-HTTLPR might experience a greater reduction in depressive symptoms over time compared with adolescents with the 5-HTTLPR l/l genotype (Table 2). A recent meta-analysis of the association between the 5-HTTLPR, stress, and the development of depression contained 81 studies with a mean age from 9–77 years. A significant relationship between the short form of the 5-HTTLPR and depression was confirmed (p = 0.0000009). However, nearly 26% of the 81 studies failed to show any significant association, and four studies even showed opposite results (Sharpley et al., 2014). Only two studies investigated the 5-HTTLPR polymorphism and the risk of depression in young adults at an age range of 20–25 years. These two studies showed a positive association between 5-HTTLPR S-allele and the increased probability of depression in adolescents (Hammen et al., 2010; Starr et al., 2013). These findings suggest that 5-HTTLPR polymorphism is a risk factor for both early onset and late onset depression.

Tryptophan hydroxylase-2 (TPH2) gene has been acknowledged for many years as the only form of tryptophan hydroxylase (TPH) responsible for the synthesis of serotonin in the brain and peripheral tissues. A recent report suggested that TPH2 gene expression in the dorsal raphe nuclei of depressed suicidal patients is upregulated [14]. This review included 2 studies on TPH2 in adolescents (Nobile et al., 2009; Stavrakakis et al., 2013). However, adolescents’ depressive symptoms are not associated with the gene plasticity index of TPH2 (Stavrakakis et al., 2013). Monoamine oxidase A is a monoamine oxidase encoded by the MAOA gene that preferentially deaminates norepinephrine, epinephrine, serotonin, and dopamine. Studies in adolescents demonstrated that depressive symptoms are not associated with gene plasticity index of the MAOA gene (Stavrakakis et al., 2013), whereas gene × environment interaction of the 5-HTTLPR was further moderated by MAOA activity level (Nobile et al., 2009).

BDNF is the most abundant neurotrophin in the mammalian central nervous system, and reduced BDNF level in the hippocampus has been revealed to be related to the onset of depression (Bai et al., 2012). A single nucleotide polymorphism (SNP) in the BDNF gene (Val66Met) has been shown to influence the activity of the BDNF protein and cause subsequent memory impairment and harm avoidance (Jiang et al., 2005). A significant interaction between BDNF Val66Met and life stress in depression was widely observed in adults (Hosang et al., 2014). In this review, the BDNF gene is the second most frequently studied gene in adolescents with depression. Two studies on the BDNF gene plasticity index and BDNF level showed controversial outcomes. The depressive symptoms were not associated with gene plasticity index of the BDNF gene in adolescents (Stavrakakis et al., 2013), whereas BDNF mRNA level correlated with symptom improvement in adult patients with depression (Cattaneo et al., 2010). Seven studies investigated the association between BDNF Val66Met polymorphism and adolescent depression. Two studies showed no association between BDNF Val66Met polymorphism and depression score, but 10 studies found significant correlations between BDNF polymorphism and adolescent depression. A recent meta-analysis of the interaction between the BDNF Val66Met polymorphism and stress in depression contained 22 studies with a mean age range from 8.85–65 years. Results showed that the Met allele of BDNF Val66Met significantly moderates the relationship between life stress and depression (p = 0.03; Hosang et al., 2014). This review only contained three studies with an age range from 9–19 years. Moreover, a meta analysis of genes and suicide in 16 studies showed that hypermethylation of BDNF is associated with individuals that died of suicide (Lockwood et al., 2015). The involvement of genetic polymorphisms in the BDNF gene in peripheral tissues of patients with depression may reflect changes in the BDNF level in their brain. The Val66Met polymorphism has been demonstrated to impair the packaging and secretion of BDNF and subsequently reduces hippocampal volume and impairs memory (Kimpton, 2012; Harrisberger et al., 2015).

Dopamine is a major neurotransmitter in the central nervous system, and dysregulation of the dopaminergic-system is widely reported in people with depression. The hypofunction of the mesolimbic dopaminergic pathway has been linked to anhedonia, one of the major symptoms of depression (Leggio et al., 2013). Studies that directly link genetic polymorphisms in the dopaminergic pathway to depression are abundant but show inconsistent findings (Lawford et al., 2006). For example, Lawford et al study demonstrated that patients with DRD2*A1/A2 genotype had significantly higher depression scores compared to those with the DRD2*A2/A2 genotype (Lawford et al., 2006). An interaction between DAT1 polymorphism and perceived maternal rejection can influence the onset of depressive disorder and suicidal ideation (Haeffel et al., 2008). A significant association between the 48 bp repeat polymorphism of DRD4 and depression was reported (Manki et al., 1996). In contrast, Frisch et al. (1999) found no association of polymorphisms in DRD4, DAT1, and COMT with depression. Kirov et al. (1999) found that six dopaminergic genes (DBH, DAT1, COMT, DRD2, DRD3, and DRD5) played no role in bipolar disorder. However, the roles of genetic polymorphisms in the dopaminergic pathway in adolescent depression have not been summarized. In this study, three studies reported associations between genetic variants in the dopaminergic system and adolescent depression (Bobadilla et al., 2013; Stavrakakis et al., 2013). Significant associations between DRD2, DRD4, and COMT polymorphisms and the risk of depression, as well as the severity of depressive symptoms, were reported.

Selective serotonin reuptake inhibitors (SSRIs) are the first line treatment for depression in the clinic. These inhibitors work by increasing serotonin levels in the brain to counteract the low serotonin-receptor levels. A meta-analysis has demonstrated that the 5-HTTLPR long-allele carriers had higher probability of response than patients with short-allele homozygotes of 5-HTTLPR with heterogeneity effect (Serretti et al., 2007). No study investigated the effect of 5-HTTLPR polymorphism on the efficacy of SSRIs treatment at an age range from 9–19 years. Rotberg et al. (2013) study in 83 children and adolescents aged 7–18 years showed that the 5-HTTLPR ss genotype was associated with a poorer clinical response to citalopram with regards to depressive symptoms. A recent meta analysis showed that the BDNF Met carriers had a better response rate to SSRI than Val/Val, while Met/Val carriers had a weak effect of response to SSRIs than Val/Val carriers (Yan et al., 2014). Based on the report from Hammen et al. (2010) study that patients younger than 18 years old have an increased risk of suicidal thoughts or behaviors (4% with SSRIs vs. 2% with placebo) with an antidepressant (Gordon and Melvin, 2013), FDA suggests that adolescents taking SSRIs must be closely monitored to reduce the risk for suicide. However, the risk is small and the risk hasn’t been replicated very well in studies of adolescent depression treated with SSRIs. For example, Hetrick et al. (2012) study showed that no significant increase in suicide-related outcomes was observed in children and adolescents after using individual SSRIs, such as paroxetine, fluoxetine, sertraline, citalopram, and escitalopram.

In conclusion, there are more published positive associations between the genetic polymorphisms in the serotoninergic system, dopaminergic system, and the Val66Met polymorphism of BDNF with adolescent depression. However, some biases should be considered: (1) the publication bias for positive findings; (2) numerous negative findings may be unpublished; (3) a bias for investigations of these three polymorphisms first because of the high profile papers that brought them to attention; and (4) the polymorphisms can be easily genotyped. Although the expression or polymorphism of 18 genes has been reported to be or not be associated with the risk of depression, they were reported by only a few studies. Therefore, further studies are needed to accurately identify their roles in depression in adolescents.

Author Contributions

LX: data extraction, data analysis, and manuscript writing. SY: study design, data extraction, data analysis, critical revision of manuscript, and a guarantor of the review.

Funding

This study is supported by grants from the National Natural Science Foundation of China (81471384 to SY).

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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