5-HTTLPR

5-HTTLPR (serotonin-transporter-linked polymorphic region) is a degenerate repeat polymorphic region in SLC6A4, the gene that codes for the serotonin transporter.Since the polymorphism was identified in the middle of the 1990s,it has been extensively investigated, e.g., in connection with neuropsychiatric disorders.A 2006 scientific article stated that 'over 300 behavioral, psychiatric, pharmacogenetic and other medical genetics papers' had analyzed the polymorphism. While often discussed as an example of gene-environment interaction, this contention is contested. 5-HTTLPR (serotonin-transporter-linked polymorphic region) is a degenerate repeat polymorphic region in SLC6A4, the gene that codes for the serotonin transporter.Since the polymorphism was identified in the middle of the 1990s,it has been extensively investigated, e.g., in connection with neuropsychiatric disorders.A 2006 scientific article stated that 'over 300 behavioral, psychiatric, pharmacogenetic and other medical genetics papers' had analyzed the polymorphism. While often discussed as an example of gene-environment interaction, this contention is contested. The polymorphism occurs in the promoter region of the gene.Researchers commonly report it with two variations in humans: A short ('s') and a long ('l'), but it can be subdivided further. The short (s)- and long (l)- alleles have been thought to be related to stress and psychiatric disorders.In connection with the region are two single nucleotide polymorphisms (SNP): rs25531 and rs25532. One study published in 2000 found 14 allelic variants (14-A, 14-B, 14-C, 14-D, 15, 16-A, 16-B, 16-C, 16-D, 16-E, 16-F, 19, 20 and 22) in a group of around 200 Japanese and white people.The difference between 16-A and 16-D is the rs25531 SNP.It is also the difference between 14-A and 14-D. Some studies have found that long allele results in higher serotonin transporter mRNA transcription in human cell lines.The higher level may be due to the A-allele of rs25531, such that subjects with the long-rs25531(A) allelic combination (sometimes written LA) have higher levels while long-rs25531(G) carriers have levels more similar to short-allele carriers.Newer studies examining the effects of genotype may compare the LA/LA genotype against all other genotypes. The allele frequency of this polymorphism seems to vary considerably across populations, with a higher frequency of the long allele in Europe and lower frequency in Asia. Despite speculation to the contrary, the population variation in the allele frequency is more likely due to neutral evolutionary processes than natural selection. The 5-HTTLPR has been thought to predispose individuals to affective disorders such as anxiety and depression. There have been some studies that test whether this association is due to the effects of variation in 5-HTTLPR on the reactivity of the human amygdala. In order to test this, researchers gathered a group of subjects and administered a harm avoidance (HA) subset of the Tridimensional Personality Questionnaire as an initial mood and personality assessment. Subjects also had their DNA isolated and analyzed in order to be genotyped. Next, the amygdala was then engaged by having the subject match fearful facial expressions during an fMRI scan (by the 3-T GE Signa scanner). The results of the study showed that there was bilateral activity in the amygdala for every subject when processing the fearful images, as expected. However, the activity in the right amygdala was much higher for subjects with the s-allele, which shows that the 5-HTTLPR has an effect on amygdala activity. It is also important to note that there did not seem to be the same effect on the left amygdala. In the 1990s it has been speculated that the polymorphism might be related to affective disorders, and an initial study found such a link.However, another large European study found no such link. A decade later two studies found that 5-HTT polymorphism influences depressive responses to life stress; an example of gene-environment interaction (GxE) not considered in the previous studies. However, a 2017 meta-analysis found no such association. Earlier, two 2009 meta-analyses found no overall GxE effect, while a 2011 meta-analysis, demonstrated a positive result. In turn, the 2011 meta-analysis has been criticized as being overly inclusive (e.g. including hip fractures as outcomes), for deeming a study supportive of the GxE interaction which is actually in the opposite direction, and because of substantial evidence of publication bias and data mining in the literature. This criticism points out that if the original finding were real, and not the result of publication bias, we would expect that those replication studies which are closest in design to the original are the most likely to replicate—instead we find the opposite. This suggests that authors may be data dredging for measures and analytic strategies which yield the results they want. With the results from one study the polymorphism was thought to be related to treatment response so that long-allele patients respond better to antidepressants.Another antidepressant treatment response study did, however, rather point to the rs25531 SNP,and a large study by the group of investigators found a 'lack of association between response to an SSRI and variation at the SLC6A4 locus'. One study could find a treatment response effect for repetitive transcranial magnetic stimulation to drug-resistant depression with long/long homozygotes benefitting more than short-allele carriers.The researchers found a similar effect for the Val66Met polymorphism in the BDNF gene. There has been speculation that the 5-HTTLPR gene is associated with insomnia and sleep quality. Primary insomnia is one of the most common sleep disorders and is defined as having trouble falling or staying asleep, enough to cause distress in one's life. Serotonin (5-HT) has been associated with the regulation of sleep for a very long time now. The 5-HT transporter (5-HTT) is the main regulator of serotonin and serotonergic energy and is therefore targeted by many antidepressants. There also have been several family and twin studies that suggest that insomnia is heavily genetically influenced. Many of these studies have found that there is a genetic and environment dual-factor that influences insomnia. It has been hypothesized that the short 5-HTTLPR genotype is related to poor sleep quality and, therefore, also primary insomnia. It is important to note that research studies have found that this variation does not cause insomnia, but rather may predispose an individual to experience worse quality of sleep when faced with a stressful life event.