1. Do variations in the 5-HT
transporter predispose to
clinical depression ?
Supervisor: Dr Joan Jarman
Ayaa Mahdee
2. Aim
To discuss the association between varying levels of the 5-HT
transporter due to genetic polymorphisms in the serotonin transporter
and the possible predisposition to clinical major depression in
individuals.
3. Methodology
• Search engine: PubMed , Science direct, Bio of psychiatry, Google scholar
,Journals of affective and Psych-INFO disorders.
• 5-HT transporter, major depression, serotonin genetic polymorphism,
Serotoninergic pathway.
• Inclusion criteria: relevancy to the 5-HT transporters, and 5-HTT gene, SERT
polymorphism ( primary literature)
• Exclusion criteria: Patients with current psychosis history.
4. Major depression
• Monoamine hypothesis states: changing levels in the monoamine transmitters
norepinephrine and serotonin(5-HT) in the brain.
• Impairment of the central modulatory system monoamine transmitters,
norepinephrine and serotonin.
• Symptoms: Fatigue, low mood and loss of appetite.
6. Polymorphism of the 5-HTT
• Polymorphism of the 5-HTT is affected by the variation of the promoter
region of the 5-HTT gene SLC6A4.
• The promoter region of the 5-HTT gene has two variant allele, long L
and small s.
• Long allele L associated with higher levels of gene expression and short
allele s associated with lower expression of the 5-HTT.
7. Environmental and gene interaction
• Genetic inheritance: The heritability of MDD is 0.33 which indicates inherited
factor account of 33% (Sullivan et al., 2000).
• An earlier childhood maltreatment including physical abuse, neglecting and
violence has a major impact on individual’s vulnerability to
depression(Vranceanu et al., 2007).
8. Study Result
(Lazary et al., 2008) • Subjects with s-allele of 5-HTTLPR have a high
ZSDS score.
• S allele variation of 5-HTTLPR could be altered in
the middle region of the rs 140700 gene, carries a
significant role in environmental and gene
interaction affecting individuals depressive
phenotype.
(Hoefgen et al., 2005) Significant difference in allele frequency distribution
with a statistically significant association of the 5-
HTTLPR short variant with major depressive disorder.
(Rominger et al., 2015) found an alteration of SERT binding to [123]-2β-CIT
radioligand in major depressive disorder
(Noskova et al., 2008) Significant allele frequency difference between women
and men p<0.001.
9. Study Result
(Mendlewicz et al., 2004) No significant difference were found between
major affective disorder and control group.
(Murthy et al., 2010) Polymorphic variation in the 5-HTTLPR has shown to
have no influence on the 5-HTT expression in adult
human brain measured by [11C] DASB.
12. Conclusion
• Low levels of SERT are found among depressed patients in the promoter
region of the SLC6A4 that has been show to affect transcriptional activity of
the 5-HTTLPR among MDD Patients.
• Difference of the s and l allelic levels was shown to cause varying
susceptibility levels to developing major depression.
13. References
• Bear M, Connors B and Paradiso M. (2006) Neuroscience. Baltimore, Md.: Lippincott Williams & Wilkins.
• Kupfer D, Frank E, and Phillips M. (2012) Major depressive disorder: new clinical, neurobiological, and treatment perspectives. The Lancet 379(9820): 1045-1055.
• Murthy N, Selvaraj S, Cowen P, Bhagwagar Z, Riedel W, Peers P, Kennedy J, Sahakian B, Laruelle M, Rabiner E and Grasby P. (2010) Serotonin transporter polymorphisms (SLC6A4 insertion/deletion and rs25531) do not affect the availability of 5-HTT to [11C] DASB binding in the
living human brain. NeuroImage 52(1): 50-54.
• Sullivan PF, Neale MC and Kendler KS. (2000) Genetic epidemiology of major depression: review and meta-analysis. Am J Psychiatry 157:1552–62.
• Vranceanu, A., Hobfoll, S. and Johnson, R. (2007). Child multi-type maltreatment and associated depression and PTSD symptoms: The role of social support and stress. Child Abuse & Neglect, 31(1), pp.71-84.
• Lazary J, Lazary A, Gonda X, Benko A, Molnar E, Juhasz G and Bagdy G. (2008) New Evidence for the Association of the Serotonin Transporter Gene (SLC6A4) Haplotypes, Threatening Life Events, and Depressive Phenotype. Biological Psychiatry 64(6):498-504.
• Hoefgen B, Schulze T, Ohlraun S, von Widdern O, Höfels S, Gross M, Heidmann V, Kovalenko S, Eckermann A, Kölsch H, Metten M, Zobel A, Becker T, Nöthen M, Propping P, Heun R, Maier W and Rietschel M. (2005) The power of sample size and homogenous sampling: Association
between the 5-HTTLPR serotonin transporter polymorphism and major depressive disorder. Biological Psychiatry 57(3): 247-251.
• Rominger A, Cumming P, Brendel M, Xiong G, Zach C, Karch S, Tatsch K, Bartenstein P, la Fougère C, Koch W and Pogarell O. (2015) Altered serotonin and dopamine transporter availabilities in brain of depressed patients upon treatment with escitalopram: a [123I]β-CIT SPECT
study. European Neuropsychopharmacology [Preprint]. Available at: http://dx.doi.org/10.1016/jeuroneuro 2014.12.010 (Accessed: January 2015)
• Noskova T, Pivac N, Nedic G, Kazantseva A, Gaysina D, Faskhutdinova G, Gareeva A, Khalilova K, Khusnutdinova E, Kovacic D, Kovacic Z, Jokic M and Seler D. (2008) Ethnic differences in the serotonin transporter polymorphism (5-HTTLPR) in several European populations. Progress in
Neuro-Psychopharmacology and Biological Psychiatry 32(7): 1735-1739.
• Mendlewicz J, Massat I, Souery D, Del-Favero J, Oruč L, Nöthen M, Blackwood D, Muir W, Battersby S, Lerer B, Segman R, Kaneva R, Serretti A, Lilli R, Lorenzi C, Jakovljevič M, Ivezič S, Rietschel M, Milanova V and Van Broeckhoven C. (2004) Serotonin transporter 5HTTLPR
polymorphism and affective disorders: no evidence of association in a large European multicenter study. Eur J Hum Genet 12(5): 377-382.
• Murthy N, Selvaraj S, Cowen P, Bhagwagar Z, Riedel W, Peers P, Kennedy J, Sahakian B, Laruelle M, Rabiner E and Grasby P. (2010) Serotonin transporter polymorphisms (SLC6A4 insertion/deletion and rs25531) do not affect the availability of 5-HTT to [11C] DASB binding in the
living human brain. NeuroImage 52(1): 50-54.
Editor's Notes
The short one causes reduced transcriptional efficiency of
the gene, resulting in decreased serotonin transporter expression
in the neuron
The Zung Self- Rating is the first report of a significant interaction between rs140700
and TLE in the depressive phenotypeDepression rs140700 is a tag SNP
located in the sixth intron of SLC6A4. Certain studies had failed to replicate the
association of G E interaction with depression (18–20).
Discrepancies among the results of these studies could result
from several factors. In light of our results, we suggest that in
addition to the promoter region, the middle region of the SLC6A4
gene has a modifying effect on gene function.
Study by (Hoefgen et al., 2005) examined 5-HTTLPR serotonin transporter polymorphism in major depressive. Significant difference in the allele frequency distribution with a statistically significant association of the 5-HTTLPR short variant with major depressive disorder, this publication agrees with (Collier et al., 1996; Furlong et al., 1998). However (Anguelova et al., 2003), results conflicted with negative findings of such an association. The discrepancy of these results could be due to difference in ethnicity of subjects and sample size in these studies.
Study by (Noskova et al., 2008), assessed whether ethnic difference across European population has an effect on the 5-HTTLPR. Results in figure4, below indicate ethnicity is found to have a major impact on genetic variations between individuals from different ethnicities. Significant allele frequency difference between women and men was found, as well as significant difference found in genotype and allelic frequencies of 5-HTTLPR among individuals of different ethnicities by (Noskova et al., 2008). Largest difference between individuals living in Croatia and Russian Federation, the underlying reason for this difference is Croatia population is homogenous sample whilst individuals from Russian were from areas with great ethnicity overlap of heterogeneous population. This difference will impact susceptibility to depression. This study has not indicated any statistics regarding gender differences and number of precipitants figure 4b, which might give a better insight of the differences in ratios found between genders.
(Mendlewicz et al., 2004) assessed the association of 5-HTTLPR polymorphism and affective disorders. Study found no association between 5-HTTLPR polymorphism in subjects with bipolar affective disorder and subjects with unipolar affective disorder, bipolar (fig 8 b,c) results agrees with pervious findings. Unipolar studies failed to show any association of the 5-HTTLPR polymorphism,large sample size
(Murthy et al., 2010), 5-HTT polymorphism and 5-HTT availability in depressed and control subject. polymorphic variation in the 5-HTTLPR has shown to have no influence on the 5-HTT expression in adult human brain measured by [11C] DASB(fig6).The finding of this study could reflected by the small sample size which might have affected the results. These findings agree with pervious finding by (Shioe et al., 2003; Parsey et al., 2006) The contradictory of these results with earlier studies might be due seasonal changes which could be the underlying reason for results variation regarding this particular 5-HTTLPR, changes in food intake might affect plasma concentrations of the serotonin precursor tryptophan and as a results cerebral serotonin levels will be effected (Kalbitzer et al., 2010).
