Behavioural Genetics of the Serotonin Transporter

Abstract

The serotonin transporter is a key regulator of the bioavailability of serotonin and therefore any modulation in the expression or action of the transporter would be expected to have consequences on behaviour. The transporter has therefore become a target for pharmaceutical intervention in behavioural and mood disorders. The search for polymorphic variants in the transporter that would associate with neurological disorders has been extensive but has become focused on two domains which are both termed variable number tandem repeat (VNTR)polymorphisms. Both of these VNTRs are in non-coding DNA and therefore proposed to be mechanistically involved in a disorder through their ability to modulate transcriptional or post-transcriptional regulation of the transporter. The most extensively studied is in the promoter and is a bi-allelic insertion/deletion found in the 50 promoter region of the gene 1.2 kb upstream of the transcriptional start site. This VNTR, termed, 5-HTTLPR was initially identified as two variants containing either, 14 (short/deletion) or 16 (long/insertion) copies of a 22 bp repeat. A second widely studied VNTR found in the non-coding region of the transporter is located within intron 2 and comprises 9, 10 or 12 copies of a16–17 bp repeat termed, STin2.9, STin2.10 and STin2.12, respectively. These VNTR polymorphisms have been associated with a range of behavioural and psychiatric disorders including depression, OCD, anxiety and schizophrenia, however often the lack of reproducibility in different cohorts has led to debate on the actual association of the polymorphisms with this extensive range of neurological conditions. Here we review these two polymorphic VNTRs in depth and relate that to pharmaceutical response, their ability to regulate differential transporter expression, their core involvement in gene-environment interaction and their genetic association with specific disorders.

Characterisation of the potential function of SVA retrotransposons to modulate gene expression patterns

“…Superimposed on these regulatory parameters could be modulation of their activity by the polymorphic nature of the distinct domains within the SVA such as the VNTR elements. There is an extensive literature on VNTR domains both being differentially associated with disease and transcriptional properties based on the copy number of the repeats [29,50]. In this study we addressed firstly the site of integration of SVA elements, secondly the potential secondary structures formed and finally a detailed analysis of the PARK7 SVA’s ability to support reporter gene expression and its polymorphic nature.…”

“…This differential regulator property has been correlated with copy number of the VNTR in some genes [30,34-43]. For example, we and others have demonstrated that VNTRs located in the promoter and second intron of the human serotonin transporter gene ( SLC6A4 ) are differential as both risk factors for mental health and tissue specific regulators in the context of reporter gene constructs, in vivo and in vitro based on the copy number of the repeat [29,31,35]. …”

Serotonin transporter genotype and mild traumatic brain injury independently influence resilience and perception of limitations in veterans

“…The promoter region of this gene has either 14 (short) or 16 (long) copies of a 22 base pair repeat polymorphism ( 5-HTTLPR ) located 1200 nucleotides upstream of the transcriptional start site (Lesch et al, 1996; Haddley et al, 2012). The classic long “L” and short “S” alleles (rs4795541) (Lesch et al, 1996) were determined by PCR amplification of DNA to yield a 181 base pair (bp) fragment for the L allele and a 138 bp fragment for the S allele (Hu et al, 2005).…”

Lack of serotonin reuptake during brain development alters rostral raphe-prefrontal network formation

“…Apart from being expressed in 5-HT neurons, the 5-HTT is also transiently expressed in non-aminergic neurons, belonging to many topographically distinct brain areas (Lebrand et al, 1998; Zhou et al, 2000; Narboux-Neme et al, 2008; Kalueff et al, 2010). In humans, the 5-HTT gene-linked polymorphic region (5-HTTLPR), composed of a short and a long version (Canli and Lesch, 2007; Neumann et al, 2011; Haddley et al, 2012), affects 5-HTT expression and function. The short (s) variant has been associated with robust neurodevelopmental changes in corticolimbic structures, and increased risk for depression in the context of stress (Canli and Lesch, 2007).…”