Serotonin Transporter Polymorphism5HTTLPR Genotype

Is There A Link Between the 5-HTTLPR Genotype and Emotional Vulnerability?

Mary Redding

Liberty University

Running head: IS THERE A LINK BETWEEN THE 5-HTTLPR GENOTYPE AND1

IS THERE A LINK BETWEEN THE 5-HTTLPR GENOTYPE AND1

Abstract

This paper is an analysis of combined data spanning from 1996 to present and attempts to answer the question that remains under debate and is the subject of much controversy in the world of neuroscience and psychological research: What, if any, is the relationship between a mutated short (s/s) allele and the development of stress- induced maladies? Studies have shown that psychosocial stress vulnerability leading to the development of PTSD, depression and other anxiety disorders (not inclusive) related to a polymorphism in the promoter region of the neurotransmitter serotonin transporter gene (5-HTTLPR) has been found to affect the transcription rate of the gene, with the short (s) allele less efficient than the alternate long (l) allele. This paper will revisit the 2003 Caspi longitudinally designed study and examine subsequent research to examine the relationship between 5-HTTLPR, stressful life events, depression, PTSD and the genetic implications therein.

Is There A Link Between the 5-HTTLPR Genotype and Emotional Vulnerability?

If depression becomes an issue after a traumatic event, did the stress cause the depression? If depression was not present before a stressful life event, then it certainly is feasible to assume that the stressor caused the subsequent depression and to make that diagnosis without much ado. However, in the world of science and research nothing can ever be so cut and dry and no stone goes unturned nor any question unasked in the quest for better information leading to the best information; the search remains on to uncover and improve on what is already known. It has long been recognized that there is a genetic link in depression and that the neurotransmitter serotonin is in the spotlight concerning depressions; but it is not known exactly how. According to a Mental Health Research Group, depression runs in families and has a heritability rate of about 40%(2012) .There is no one answer and theories abound from studies showing a possibility of depressed people having a smaller hippocampus and thus less serotonin receptors to an excess of the stress hormone cortisol being released and having a toxic effect on the hippocampus. In the endless array of theories on stress and depression it is difficult to choose one or ten that might be the answer to the age-old questions of stress, the vulnerability to it and the host of maladies that result from it.

The question of genetics is common in most psychological and physical abnormalities or afflictions and by far one of the most interesting and controversial topics is that of 5-HTTLPR and the debate concerning functional variants of genes that involve 5-HT, known in layman terms as serotonin (5-Hydroxytriptamine), a monoamine neurotransmitter involved in controlling many behavior(s) including sleep, anxiety, mood swing etc. Serotonin is synthesized from the amino acid precursor tryptophan packaged into vesicles, and released into the synapse following an action potential. Once in the synapse, serotonin can interact with both the pre- and postsynaptic receptors (http://www.bencoslife.com/researchgroups.aspx?grp=2&nav=64f0d5de-3dc5-4eea-83a9-edc36c6c97dl). The serotonin system of the brain is located in the raphe nuclei, a moderate-size cluster of nuclei found in the pons part of the hindbrain portion of the brain stem. Their main function is to release serotonin to the rest of the brain. A detailed image is shown to enhance the text:

The most widely used treatment for depression is the selective serotonin reuptake inhibitors (SSRIs) because they are generally safe, treat moderate to severe depression and have fewer side effects than do other anti-depressants. SSRIs work by blocking the reuptake of serotonin into the presynaptic cell, resulting in the buildup of available serotonin in the synaptic cleft which in turn binds to the postsynaptic receptor and increases mood stability. An example of the effect of SSRIs on serotonin in the synaptic cleft are shown as follows:

https://docs.google.com/viewer?a=v&q=cache:DgR7CQJ32A4J:fire.biol.wwu.edu/

A polymorphism (tiny dissimilarity in the DNA) of the serotonin transporter (5-HTT or SLC6A4) gene causes a variation of efficiency involving re-uptake of the neurotransmitter into the cells and taken together, the scientific stamp for this variation is known as 5-HT=serotonin, 5-HTT=serotonin transporter gene and LPR=Linked Promoter Region. The 5-HT or mid-brain raphe system harmonizes emotion, cognition, neuroendocrine and circadian rhythms, food intake and reproductive activity to identify a few, and any imbalance in the transportation of serotonin to the cells will alter the delicately and finely-tuned neuronal networks and can result in neurological deficits and in turn promote a negative behavioral affect.

According to Goldman, Glei, Lin, & Weinstein, (2010)

More than a decade ago, a polymorphism in the promoter region of the gene

encoding 5-HTT, referred to as 5-HTTLPR, was identified by Heils et al. [1]: a

44bp deletion/insertion generated two alleles of 5-HTTLPR, with the 14-repeat

short (S) variant having less transcriptional activity and lower serotonin uptake

than the 16-repeat long (L) variant. Researchers speculated that the differential

transcriptional activity caused by this polymorphism would influence complex

traits and diseases, including affective disorders {1,2} (p.260).

Humans have two 5-HTT genes and for purposes of simplicity, it will be stated that there is a long (l) gene (allele) and a short (s) gene (allele). In the human population, the frequency of the long allele of 5-HTT is about 57% that of the short allele is 43% (OMIM, 2003). The common variants are L/L, L/S, and S/S. The mechanisms of serotonin transporter protein causes reuptake of serotonin from the synapse, and by doing so it influences the amount of serotonin present in the synapse, and thus the serotonin effects on the receiving neurons receptor. The short variant (s) of this polymorphism impairs the transcriptional efficiency of the 5-HTT gene promoter, culminating in decreased 5-HTT expression and 5-HT reuptake. The polymorphism allele (s) has been attributed to many disorders ranging from major depression, stress, attentional bias of angry faces, cardiovascular disease, seasonal affective disorder (SAD) sociopathic tendencies and anxiety (not exhaustive). The following image exhibits

the likelihood of a depressive episode as it relates to genotype with the l/l appearing to be the most stable (non-depressive), as would be expected because the transcription rate of the neurotransmitter serotonin remains steadfast moving at an upward rate while the s/l variation shows a higher inclination for depression because the (s) allele produces less serotonin, thus resulting in a lesser overall amount. The next image clarifies that the polymorphism actually does not occur within the open reading frame of the 5-HTT gene itself, but in the 5' regulatory region. Thus, the terms "short" and "long" actually refer to two different lengths of the sequences in the gene's regulatory region (http://www.bio.davidson.edu/courses/genomics/2003/mccord/5-htt.html).

According to Caspi, Hariri, Holmes, Uher, & Moffitt (2010)

....1996 study in Science magazine reported that a repeat length polymorphism in

the promoter region of the human serotonin transporter gene regulates gene

expression in vitro. Furthermore, individuals carrying one or two copies of the

relatively low-expressing short (s) allele of the serotonin transporter linked

polymorphic region (5-HTTLPR) exhibit elevated neuroticism, a personality trait

involved in the propensity to depression (p. 509).

A 2002 research study in Science using MRI imaging reported that carriers of the (s) allele displayed heightened amygdala reactivity to threatening stimuli; it was these two studies that were the protagonists for the 2003 Caspi study, which has been cited nearly 5,000 times in the area of scientific brain research.

The Duke Psychologist Avshalom Caspis discovery of a"depression gene" was among the first to be associated with mental illness and inspired many similar studies. While researchers had suspected that 5-HTTLPR played a significant role in the risk of depression, Caspi was the forerunner in the establishment of an association by studying depressed people who had also experienced a stressful life event (SLE). Caspi and colleagues (2003) state:

A functional polymorphism in the promoter region of the serotonin transporter

(5-HT T) gene was found to moderate the inuence of stressful life events on

depression. Individuals with one or two copies of the short allele of the 5-HT T

promoter polymorphism exhibited more depressive symptoms, diagnosable

depression and suicidality in relation to stressful life events than individuals

homozygous for the long allele. This epidemiological study thus provides

evidence of a gene-by-environment interaction, in which an individuals response

to environmental insults is moderated by his or her genetic makeup

(Caspi et al., 2003, p. 386).

It is known that a SLE is sometimes responsible for an onset of depression; there are stress theories that show that the propensity to stress sensitivity is genetic and behavioral genetics research supports this finding. The research used in the Caspi study displays irrefutable evidence that a series of SLEs does cause major depression.

The study involved 847 Caucasians (representative birth cohort) Life events and response to life events were monitored over a >26 year period -- starting at birth. Genotypes in this population of individuals: ss n=147 (17%), sl n= 435 (51%), ll n = 265 (31%)

(Caspi et al., 2003, figure 1)

Fig. 2. Results of regression analysis estimating the association between childhood maltreatment (between the ages of 3 and 11 years) and adult depression (ages 18 to 26), as a function of 5-HT T genotype.

Among the 147s/s homozygotes, 92 (63%), 39 (27%), and 16 (11%) study

members were in the no maltreatment, probable maltreatment, and

severe maltreatment groups, respectively.

Among the 435 s/l heterozygotes, 286 (66%), 116 (27%), and 33 (8%)

were in the no, probable, and severe maltreatment groups.

Among the 265 l/l homozygotes, 172 (65%), 69 (26%), and 24 (9%) were

in the not, probable, and severe maltreatment groups.

(Caspi et al., 2003, figure 2)

Fig. 3. The percentage of individuals meeting diagnostic criteria for depression at age 26, as a function of 5-HT T genotype and number of stressful life events between the ages of 21 and 26.

The figure shows individuals with either one or two copies of the short allele (left) and individuals homozygous for the long allele (right). In a hierarchical logistic regression model, the main effect of genotype (coded as s group = 0 and l group = 1) was not significant, b = 0.15, SE = 0.21, z = 0.72, P = 0.47; the main effect of number of life events was significant, b = 0.34, SE = 0.06, z = 5.70, P < 0.001;

and the interaction between genotype and number of life events was significant, b = 0.30, SE

= 0.15, z = 1.97, P = 0.05.

(Caspi et al., 2003, figure 3)

In conclusion, 17% of the participants had reported a major depressive episode in the prior year and 3% reported having felt suicidal. The negative effects of adverse experiences were stronger among people with one s allele and stronger still for those with two s alleles. For people with two s alleles (17% of the group), the probability of a major depressive episode rose to 43% among those who had been through four or more stressful experiences. That was more than double the risk for the subjects with two l's, who made up 31% of the group. The average score on a depression symptom inventory was likewise more than twice as high for stressed people with two s alleles as for those with two l versions.

Looking back on their records of childhood abuse for the cohort, the researchers found an additional link between 5-HTT gene variants and depression: Abuse as a child predicted depression after the age of 18 only in people carrying at least one s allele. Among the 11% who had experienced severe maltreatment, the double s-allele subjects ran a 63% risk of a major depressive episode, and the l-allele participants averaged a 30% risk, regardless of whether or not they had been abused as children (http://fire.biol.wwu.edu/trent/trent/depressionpolymorph.htm).

References

Caspi, A., Hariri, A. R., Holmes, A., Uher, R., & Moffitt, T. (2010, May). Genetic sensitivity to the environment: The case of the serotonin transporter gene and its implications for studying complex diseases and traits. American Journal of Psychiatry, 167(5), 509-527. http://dx.doi.org/doi: 10.1176/appi.ajp.2010.09101452

Caspi, A., Sugden, K., Moffitt, T. E., Taylor, A., Craig, I. W., Harrington, H., Braithwaite, A. (2003, July 18). Influence of life stress on depression: Moderation by a polymorphism in the 5-HTT gene. Science, 301, 386-389. http://dx.doi.org/10.1126/science.1083968

Goldman, N., Glei, D. A., Lin, Y., & Weinstein, M. (2010, March). The serotonin transporter polymorphism (5-HTTLPR): Allelic variation and links with depressive symptoms. PMC, 27(3), 260-269. http://dx.doi.org/10.1002/da.20660

Karg, K., Burmeister, M., Shedden, K., & Sen, S. (2011, May). The Serotonin Transporter Promoter Variant(5-HTTLPR), Stress, and Depression Meta-analysis Revisited. ARCH GEN PSYCHIATRY, 68(5), 444-454. http://dx.doi.org/doi:10.1001/archgenpsychiatry.2010.189

Osinsky, R., Losch, A., Hennig, J., Alexander, N., & MacLeod, C. (2012,). Attentional Bias to Negative Information and 5-HTTLPR Genotype Interactively Predict Students Emotional Reactivity to First University Semester. Emotion, 12(3), 460-469. http://dx.doi.org/10.1037/a0026674

Sadeh, N., Javdani, S., Jackson, J., Reynolds, E. K., Potenza, M. N., Gelernter, J., ... Verona, E. (2010). Serotonin transporter gene associations with psychopathic traits in youth vary as a function of socioeconomic resources. Journal of Abnormal Psychology, 119, 604-609. http://dx.doi.org/10.1037/a0019709

Starr, L. R., Hammen, C., Brennan, P., & Najman, J. M. (2012). Serotonin transporter gene as a predictor of stress generation in depression. Journal of Abnormal Psychology, 121(4), 810-818.

http://dx.doi.org/10.1037/a0027952