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.

Alleles
The polymorphism occurs in the promotor region of the gene. Researchers commonly report it with two variations: A short ("s") and a long ("l"), but it can be subdivided further. 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 Caucasian 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.

Neuropsychiatric disorders
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.

Treatment response
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.

Personality traits
5-HTTLPR may be related to personality traits: Two 2004 meta-analyses found 26 research studies investigating the polymorphism in relation to anxiety-related traits. The initial and classic 1996 study found s-allele carriers to on average have slightly higher neuroticism score with the NEO PI-R personality questionaire, and this result was replicated by the group with new data. Some other studies have, however, failed to find this association, nor with peer-rated neuroticism, and a review from 2006 noted the "erratic success in replication" of the first finding. A meta-analysis published in 2004 stated that the lack of replicability was "largely due to small sample size and the use of different inventories". They found that neuroticism as measured with the NEO-family of personality inventories had quite significant association with 5-HTTLPR while the trait harm avoidance from the Temperament and Character Inventory family did not have any significant association. A similar conclusion was reached in an updated 2008 meta-analysis. However, a 2005 meta-analysis came to the opposite conclusion: That NEO neuroticism and 5-HTTLPR were not associated while TCI/TPQ harm avoidance and 5-HTTLPR were. The largest (as of 2004) individual study on the personality genetics of anxiety-related traits is Australian involving 759 subjects. It used the Eysenck Personality Questionnaire and could not detect any difference between the short and long allele subjects with respect to neuroticism.

Another research group have given evidence for a modest association between shyness and the long form in grade school children. This is, however, just a single report and the link is not investigated as intensive as for the anxiety-related traits.

Neuroimaging
Molecular neuroimaging studies have examined the association between genotype and serotonin transporter binding with positron emission tomography (PET) and SPECT brain scanners. Such studies use a radioligand that binds&mdash;preferably selectively&mdash;to the serotonin transporter so an image can be formed that quantifies the distribution of the serotonin transporter in the brain. One study could see no difference in serotonin transporter availability between long/long and short/short homozygotes subjects among 96 subjects scanned with SPECT using the iodine-123 &beta;-CIT radioligand. Using the PET radioligand carbon-11-labeled McN 5652 another research team could neither find any difference in serotonin transporter binding between genotype groups. Newer studies have used the radioligand carbon-11-labeled DASB with one study finding higher serotonin transporter binding in the putamen of LA homozygotes compared to other genotypes. Another study with similar radioligand and genotype comparison found higher binding in the midbrain.

Associations between the polymorphism and the grey matter in parts of the anterior cingulate brain region have also been reported based on magnetic resonance imaging brain scannings and voxel-based morphometry analysis. Brain blood flow measurements with positron emission tomography brain scanners can show genotype-related changes. Furthermore, the glucose metabolism in the brain has also been investigated with respect to the polymorphism, and the functional magnetic resonance imaging (fMRI) brain scans have also been correlated to the polymorphism.

Especially the amygdala brain structure has been the focus of the functional neuroimaging studies.