The minor allele 'C' is almost always in phase with the long (L) allele of 5-HTTLPR [R].
Whereas T would indicate the short (S) allele.
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 T-allele of rs25531, such that subjects with the long-rs25531(T) allelic combination (sometimes written LA) have higher levels while long-rs25531(C) carriers have levels more similar to short-allele carriers.
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 questionnaire, 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 2006 review 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, based on over 4000 subjects, the largest study that used the NEO PI-R found no association between variants of the serotonin transporter gene (including 5-HTTLPR) and neuroticism, or its facets (Anxiety, Angry-Hostility, Depression, Self-Consciousness, Impulsiveness, and Vulnerability).
In a study published in 2009, authors found that individuals homozygous for the long allele of 5-HTTLPR paid more attention on average to positive affective pictures while selectively avoiding negative affective pictures presented alongside the positive pictures compared to their heterozygous and short-allele-homozygous peers. This biased attention of positive emotional stimuli suggests they may tend to be more optimistic. Other research indicates carriers of the short 5-HTTLPR allele have difficulty disengaging attention from emotional stimuli compared to long allele homozygotes. Another study published in 2009 using an eye tracking assessment of information processing found that short 5-HTTLPR allele carriers displayed an eye gaze bias to view positive scenes and avoid negative scenes, while long allele homozygotes viewed the emotion scenes in a more even-handed fashion. This research suggests that short 5-HTTLPR allele carriers may be more sensitive to emotional information in the environment than long allele homozygotes.
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 intensively as for the anxiety-related traits.
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. 5-HTTLPR short allele–driven amygdala hyperreactivity was confirmed in a large (by MRI study standards) cohort of healthy subjects with no history of psychiatric illness or treatment. Brain blood flow measurements with positron emission tomography brain scanners can show genotype-related changes. 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.
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.
The effect that the 5-HTTLPR gene had on sleep quality was tested by Brummett in a study conducted at Duke University Medical Center from 2001-2004. The sleep quality of 344 participants was measured using The Pittsburgh Sleep Quality Index. The study found that caregivers with the homozygous s-allele had poorer sleep quality, which shows that the stress of caregiving combined with the allele gave way to worse sleep quality. Although the study found that the 5-HTTLPR genotype did not directly affect sleep quality, the 5-HTTLPR polymorphism's effect on sleep quality was magnified by one's environmental stress. It supports the notion that the 5-HTTLPR s-allele is what leads to hyperarousal when exposed to stress; hyperarousability is commonly associated with insomnia.
However, in a 2007 study conducted by a sleep laboratory in Germany, it was found that the 5-HTTLPR gene did have a strong association with both insomnia and depression both in participants with and without lifetime affective disorders. This study included 157 insomnia patients and a control group of 836 individuals that had no psychiatric disorders. The subjects were then genotyped through polymerase chain reaction (PCR) techniques. The researchers found that the s-allele was greater represented in the vast majority of patients with insomnia compared to those who had no disorder. This shows that there is an association between the 5-HTTPLR genotype and primary insomnia. However, it is important to consider the fact that there was a very limited number of subjects with insomnia tested in this study.