Critically Evaluate Recent Research On The Role Of Polymorphisms Of 5ht Transporter Gene

Depression and Anxiety are highly prevalent, debilitating disorders and twin studies reveal genetic components are involved (Kendler et al, 2008). Identifying candidate genes in the aetiology of these disorders is an attractive prospect to further understanding to develop more efficacious treatments. Serotonin (5HT) systems are believed to hold depressogenic genes as Selective Serotonin Reuptake Inhibitors (SSRIs) which directly target the serotonin transporter protein gene, SLC6A4, have proven efficacy. In 1994 the 5HTT gene-linked polymorphic region (5HTTLPR), a functional polymorphism in SLCA46 5' promoter region was discovered, with two variations; short (s) and long (l) allele. The s allele has reduced transcri ptional efficacy which reduces 5HT binding and reuptake which has been associated with increased risk of depression and anxiety in stress (Lesch et al, 1996).

A mile-stone study by Caspi et al (2003) reported the s allele significantly influenced the development of depression through gene-environment (GxE) interactions with stressful life events (SLE) and stress reactivity. This exciting discovery stimulated a multitude of studies attempting to replicate this finding. A number successfully found a significant GxE interaction of the s variation with SLE and subsequent depression (Kendler et al, 2005; Wilhelm et al, 2006; Cervilla et al, 2007). However findings failed to be consistently replicated particularly in older males, some implicated the l allele in depression which sparked debate over the validity of these findings (Chorbov et al, 2007; Power et al, 2008; Middledrop et al, 2008 Laucht et al, 2009, Ferguson et al, 2011). 2 meta-analyses failed to find a significant relationship between 5HTTLPR variants, SLE and depression however these came under scrutiny over the restrictive inclusion criteria, only including SLE studies and no objective measures (Risch et al, 2009; Munafo et al, 2009). Significantly higher proportions of non-replication studies were included therefore the analyses were considered biased (Uher & McGuffin, 2008). Conversely, Karg et al (2011) large meta-analysis found a robust and significant interaction between s variant, childhood maltreatment and specific stressors with depression, and increased stress sensitivity. SLE measures are problematic and vary widely. Measuring stress in depressed patients is subject to negative mood congruent retrieval, retrospective forgetfulness and effort after meaning and systematic bias (Caspi et al, 2010). Age, onset and measurement of SLE appear to be crucial determinants; objective measures were more likely to fully or partially replicate the GxE interaction whereas subjective self-reports failed to replicate the findings (Uher & McGuffin, 2011). Mueller et al (2011) support this only finding a significant interaction of genotype in young adults when the SLE occurred before 5 years of age. However, Ferguson et al (2011) used 5 different measures of adversity but still failed to find a significant interaction. An additional source of variability arises in L allele subtypes; LG and LA, the LG allele is functionally equivalent to the s allele, therefore studies include LG alleles in s/l and l/l genotypes may underestimate genotype effects (Hu et al, 2005). Zalsman et al (2006) confirmed this; LG and s alleles independently predicted depression and enhanced the impact of SLEs compared to LA alleles. It is important to note Caspi et al (2003) methodology was to a high standard that other studies were not able to replicate. The 23 year prospective study involved repeated measurement of SLEs which were confirmed by external sources, an objective stressor and a number of measures of depression. Given interaction studies are notoriously hard to replicate, it is unlikely one carried out to this standard will be consistently replicated. 5HTTLPR polymorphisms are thought to predispose traits of negative affectivity and neuroticism (N) (Caspi et al, 2010). Lesch et al (1996) reported a small, but significant link between 5HTTLPR s variant and neuroticism, a known risk factor for affective disorders. This has been related to an altered uncinate fasciculus which provides the connection between the amygdala and mPFC which is associated with trait anxiety (Kim & Whalen, 2009). One meta-analysis found a significant association between 5HTTLPR and neuroticism and significant relationship between s carriers and increased trait anxiety (Sen et al, 2004). However Schinka et al (2004) meta-analysis found no significant relationship between genotype and anxiety, stating the measurement of anxiety was key. Under EPQ instruments no significant relationship was found between N and 5HTTLPR but under the Five Factor Model s carriers had significantly higher scores of N. Blom et al (2011) found an association between the s allele and social anxiety symptoms whereas others report the l/l genotype increased vulnerability to social anxiety disorder particularly in younger subjects (Reinelt et al, 2013). Peterson et al (2012) found low 5HT transcri ptional efficacy of s and LG allele carriers was associated with more anxious and depressive symptoms in response to SLE particularly at ages 16 and 17. Grabe et al (2009) found a significant dose response relationship between LA / LA genotype and PTSD. Anxiety is multifaceted which may account for the differential effects of 5HTTLPR variants on the pathogenesis of the different subtypes. Neuropsychological imaging is more sensitive to genetic variations and consistently demonstrates 5HTTLPR variations affect brain functioning (Canli & Lesch, 2007). Negative attentional biases are a known risk factor in mood disorders; s carriers were more biased towards negative material while l/l carriers significantly avoided it (Fox et al, 2009). This suggests s carriers are more receptive to stress. During mother separation studies in rhesus macaques s carriers have increased HPA responses and anxiety which endures into adulthood (Barr et al, 2004; Spinelli et al, 2007). These effects mirror the GxE interactions seen in human depression. Healthy S carriers have increased amygdala reactivity to fearful and angry imagery (Hariri et al, 2002; Lau et al, 2009). This supports the notion that s alleles increase the risk for psychopathologies via stress reactivity. Therefore s and LG alleles may increase teenage risk of depression and anxiety by reducing PFC ability to modulate stress experienced by the amygdala (Peterson et al, 2012). Evidence thus far appears confirmatory of the 5HTT stress sensitivity hypothesis which suggests GxE interaction reflects serotonergic mediation of stress responses (Wankerl et al, 2010). The s allele was positively correlated with number of SLEs and cortisol response (Mueller et al, 2011). This suggests the 5HTTLPR relates to stress induced cortisol response. A relationship between 5HTTLPR variants and SSRI efficacy has been reported; s carriers displayed a significantly weaker response to escitalopram than l carriers with a significant interaction between 5HTTLPR, gender and drug (Huezo-Diaz, 2009). Conversely, Wilkie et al (2009) reported the s allele was significantly more prevalent in antidepressant responders. Stein et al (2006) report a linear relationship between l/l genotype and strength of response to SSRIs in GAD. These findings are significant as SSRI non-responders are an increasing problem and may be explained by differential pharmacogenetics across and within these disorders. The 5HTTLPR is not the only gene to be implicated in the eitology of anxiety and depression. Tineke van Veen et al (2012) posit distinct genetic factors contribute and found different gene sets in anhedonic depression and anxious arousal. OXTR rs2254298 and cannabinoid CNR1 have been implicated in the aetiology of anxiety and major depression (Thompson et al, 2011; Mitjans et al, 2013). Inconclusive evidence on the 5HTTLPR GxE interaction can be due to unaccounted epistatic effects. Conway et al (2010) suggest the val158met polymorphism of COMT gene moderates this relationship; a GxE interaction was only present in val158met homozygotes which conferred a protective effect on depression in l/l genotype carriers. It can be deduced 5HTT polymorphisms do appear to have a small effect on the eitology of depression and anxiety through stress reactivity. Despite inconclusive evidence the s allele is more highly implicated in these disorders. However this relationship is influenced by age, gender, and methodologies. Ethnicity sees differential relationships; the l allele appears more important in Japanese, Korean and Chinese samples (Kim et al, 2006; Long et al, 2013). Findings such as Caspi et al (2003) are being used in clinical, social and public domains as definite links; however these need to be consistently replicated before they can be considered valid predictors of vulnerability to disease. The evidence is not sufficiently robust or conclusive to draw stable and reliable conclusions. Integration of all research is required although difficulties arise due to heterogeneous methodologies. Epistatic mechanisms pose a challenge to research, a number of genes and other influences govern the eitology of complex, multifaceted disorders such as anxiety and depression.