5HTTLPR Genetic Variant and Major Depressive Disorder: A Review
Abstract
:1. Introduction
2. Materials and Methods
2.1. Search Strategy
2.2. Filters, Inclusion, and Exclusion Criteria
2.3. Data Extraction
3. Results
4. Discussion
4.1. HTTLPR Variant Genotypic Distribution in the Population
4.2. HTTLPR Variant and the Nervous System
4.3. HTTLPR Variant and MDD Risk Factors
4.4. HTTLPR Variant and Pharmacotherapy
Limitations and Recommendations
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Author | Title | Objective | Year | Country | Sample (N) | Genetic Variant | Laboratory Tests | Results | p-Value | Genotypic Frequency |
---|---|---|---|---|---|---|---|---|---|---|
Basu et al. [17] | A preliminary association study between serotonin transporter (5HTTLPR), receptor polymorphisms (5-HTR1A, 5-HTR2A) and depression symptom- clusters in a north Indian population suffering from Major Depressive Disorder (MDD) | Detect associations between any factorial structure and the serotonin transporter (5HTTLPR) and the receptor (5HTR1A, 5HTR2A) polymorphisms in the northern Indian population. | 2019 | India | 80 | VNTR | Sequencing and MALDI-TOF | The studied population had a frequency of 72% in the S allele and no LL genotype. Despite finding a significant association between the L allele and the “detachment” factor, definite conclusions cannot be drawn. | Polymorphism × Psychic Anxiety = 0.96 | VNTR = LS |
SNP (rs6295) | Polymorphism × Detachment = 0.07 | |||||||||
SNP (rs6311) | Polymorphism × vegetative function = 0.42 | |||||||||
SNP (rs6313) | Polymorphism × Pessimistic humor = 0.31 | |||||||||
Camarena et al. [18] | Association Study Between Serotonin Transporter Gene and Fluoxetine Response in Mexican Patients with Major Depressive Disorder. | Analyze the clinical association between 5HTTLPR polymorphism and the response to fluoxetine in Mexican MDD patients. | 2019 | Mexico | 150 | SNP (rs25531) | PCR | There was an increased frequency of low activity (S, Lg) alleles in patients who did not respond to fluoxetine when compared to those who did. Nonetheless, there was no statistical difference in the allelic analyzes. | Genotypic = 0.165 Allelic = 0.0637 | S/La |
Mendonça et al. [19] | Epigenetic variation at the SLC6A4 gene promoter in mother–child pairs with major depressive disorder | Investigate the association of the 5HTTLPR polymorphism and the CpG (5mC) DNA methylation levels of the AluJb repeat element in the SLC6A4 promoter region of a mother and child exposed to maternal depression. | 2019 | Brazil | 40 | VNTR | PCR, sequencing and real-time | Most participants (mothers and children) had the SS genotype (53.4%). In the findings, approximately 70% of children living with depressed mothers exhibited a psychiatric disorder, such as depression, generalized anxiety disorder, and attention deficit hyperactivity disorder. Differences in methylation levels appear to be influenced by the S allele. | Polymorphism × Mother and child ≤ 0.999 | SS |
Sarmiento-Hernández et al. [20] | Association between 5HTTLPR polymorphism, suicide attempt and comorbidity in Mexican adolescents with major depressive disorder. | Determine the association of SLC6A4 gene polymorphic variants in Mexican adolescents with MDD and attempted suicide and its comorbid disorders. | 2019 | Mexico | 200 | VNTR | PCR | There was a statistical difference in allelic distribution between the case and control groups. The S allele (251) frequency, in the case group, is higher than the L allele (149). Moreover, the findings support the hypothesis that the increase in SS genotypic frequency contributes to suicidal behavior in people with depression. | Genotypic = 0.004 * Allelic = 0.0009 * | LS |
Ozçurumez et al. [21] | No Interaction Between Childhood Maltreatment and Serotonin Transporter Gene in Recurrent Major Depressive Disorder: A Clinical Sample | Investigate the interaction between specific forms of childhood mistreatment and the 5HTTLPR polymorphism in recurrent MDD in a clinical sample. | 2019 | Turkey | 70 | VNTR | PCR | Most recurrent MDD participants had the SL genotype (47.1%); this was mainly seen in the case group (43.4%). There was no interaction between child abuse and the 5HTTLPR polymorphism in relation to recurrent MDD. | Polymorphism × Heredity ≤ 0.001 * Mistreatment × Polymorphism = 0.28 | LS |
Fleurkens et al. [22] | Automatic approach-avoidance tendencies as a candidate intermediate phenotype for depression: Associations with childhood trauma and the 5HTTLPR transporter polymorphism | Investigate the role of the automatic influence of approach-avoidance trends as an intermediate phenotype candidate for depression, in the context of genes (5HTTLPR polymorphism) and childhood trauma. | 2018 | Netherlands | 209 | SNP (rs25531) | PCR | The group with S/Lg genotype carriers and no childhood trauma had most of the research participants (94 individuals). S/Lg heterozygous patients (higher of risk of depression) and suffered childhood trauma avoid sad facial expressions more than those with the LaLa genotype and who suffered trauma. Additionally, the automatic approach-avoidance trends may be an intermediate candidate phenotype for depression. | Polymorphism × Adversity in childhood = 0.128 | La/Lg |
Han et al. [23] | The effects of 5HTTLPR and BDNF Val66Met polymorphisms on neurostructural changes in major depressive disorder | Investigate the effects of the 5HTTLPR and BDNF Val66Met genetic variants polymorphisms and their interactions with MDD on the cortical volume and white matter integrity. | 2018 | Republic of Korea | 95 | VNTR | Magnetic resonance and genotypic analyzes, according to the protocols of Han et al. [24]; Smits et al. [25]; Wang et al. [26] | Of the 95 MDD participants, the most (54 individuals) had the SS genotype. Significant effects of the LL + LS genotypes were observed, when compared to the SS genotype, on the cortical volume in the right anterior midcingulate gyrus and left anterior midcingulate gyrus. | L Allele × Volume in the right anterior midcingulate gyrus = 0.001 * L Allele × Cortical volume = 0.001 * | SS |
Kao et al. [27] | 5HTT mRNA level as a potential biomarker of treatment response in patients with major depression in a clinical trial | Investigate whether the serotonin transporter mRNA level (5HTT or SERT or SLC6A4) may be used as a biomarker of treatment response in MDD patients treated with different antidepressants while controlling related factors. | 2018 | China | 119 | VNTR (Stin2) SNP (rs25531) | PCR, RFLP, RNA extraction, real-time | Among the research participants, the majority of MDD patients treated with duloxetine or paroxetine had the SS genotype (72.2% and 66.2%, respectively). The increase in the 5HTT mRNA level correlated with the response to treatment. | Polymorphism × Fluoxetine = 0.042 * | VNTR = SS rs 25531 = S’S’ (Lg/Lg + Lg/S + SS) |
Schneider et al. [28] | Association of Serotonin Transporter Gene AluJb Methylation with Major Depression, Amygdala Responsiveness, 5HTTLPR/rs25531 Polymorphism, and Stress | Investigate whether AluJb methylation on the SLC6A4 promoter is associated with MDD, amygdala reactivity to emotional faces, 5HTTLPR/rs25531 polymorphism, and recent stress. | 2018 | Germany | 122 | SNP (rs25531) | Sequencing and Magnetic Resonance | Most of the research participants in the MDD group had the LaSa genotype (48 individuals). People with two alleles with inherent risk appear to have lower AluJb methylation compared to carriers of an allele without risk. | AluJb methylation × polymorphism = 0.003 * | La/Sa |
Bansal et al. [29] | Serotonin Signaling Modulates the Effects of Familial Risk for Depression on Cortical Thickness | Assess whether the effects of family risk were modulated by the polymorphic action linked to the serotonin transporter region (5HTTLPR). | 2017 | United States | 129 | VNTR | Magnetic Resonance and PCR | The S allele frequency was higher in the high-risk of MDD developing group (40.8%) than in the low-risk group (34.9%). The 5HTTLPR polymorphism modulated the familial risk effects of depression on the cortex, probably by modulating brain plasticity. | S Allele = 0.3390 | LS |
Schneck et al. [30] | Relationship of the serotonin transporter gene promoter polymorphism (5HTTLPR) genotype and serotonin transporter binding to neural processing of negative emotional stimuli | Examine the relationship between the 5HTTLPR genotype and the in vivo 5HTT binding, quantified by PET, with the amygdala reactivity to negative emotional stimulation. | 2017 | United States | 21 | SNP (rs25531) | Genotyping per Parsey et al. [31], functional magnetic resonance imaging, and positron emission computed tomography (PET) | Among the research participants, 10 had the LS genotype. The S allele presence did not correlate with the current severity of depression nor the number of depressive episodes throughout life. As for the amygdala reactivity, the 5HTTLPR gene was not associated. | S allele × Depression severity = 0.72 S allele × Depressive episodes = 0.09 | L’S’ |
Kostić et al. [32] | A pilot study on predictors of brainstem raphe abnormality in patients with major depressive disorder | Analyze the possible association of brainstem raphe abnormal echogenicity in MDD patients compared to healthy individuals, and evaluate MDD clinical and genetic correlates. | 2017 | Serbia | 53 | SNP (rs25531) | PCR, RFLP, and transcranial ultrasound | There was no statistical difference between depressed participants with abnormalities in the brainstem’s raphe nucleus compared to the depressed group without abnormalities. However, the short allele (S) homozygote prevalence was significantly higher in depressed patients with abnormalities in the raphe nucleus. The LS genotype was the most prevalent in general. | Polymorphism × with or without raphe abnormality = 0.048 * | SL |
Talati et al. [33] | Associations between serotonin transporter and behavioral traits and diagnoses related to anxiety | Examine the correlation between the 5HTTLPR variant and the anxiety and depression associated behavioral characteristics, verify this association with the clinical diagnosis, and explore whether the behavioral characteristics mediate the association between 5HTTLPR and anxiety/MDD. | 2017 | United States | 203 | SNP (rs25531) | PCR | The majority of the participants with at least some disorder had the SL genotype (116 participants, 57%). The same occurred in MDD participants (60 participants). In high-risk participants, the 5HTTLPR variant was associated with panic disorder and phobias. | Polymorphism× impulsivity = 0.0013 * Polymorphism × hostility = 0.017 * Polymorphism × neuroticism = 0.013* | SL |
Jaworska et al. [34] | The influence of 5HTTLPR and Val66Met polymorphisms on cortical thickness and volume in limbic and paralimbic regions in depression: a preliminary study | Evaluate the influence of 5HTTLPR and Val66Met polymorphisms on cortical thickness in the cingulate, frontal, and parahippocampal regions, and the insula (areas modulated more consistently by these polymorphisms). | 2016 | Canada | 43 | SNP (rs25531) | Magnetic Resonance and PCR | Most MDD participants were S/La heterozygous (20 participants). In the MDD group, more significant volumes in the left thalamus and putamen were observed in the LA/LA homozygotes. | Polymorphism × Volume in putamen = 0.004 * Polymorphism × Volume in the thalamus = 0.005 * | S/La |
Sun et al. [35] | Effects of polymorphisms of serotonin transporter promoter (5HTTLPR) and brain derived neurotrophic factor gene (G196A rs6265) on the risk of major depressive disorder in the Chinese Han population | Explore the 5HTTLPR and BDNF genes (rs6265) polymorphism and their possible interaction with the risk of MDD. | 2016 | China | 459 | VNTR | PCR | The majority of participants had the LL 5HTTLPR genotype, 232 in the case group and 231 in the control group. The LS heterozygous genotype promotes a significantly higher risk of developing MDD than the SS or LL homozygous genotype. | LS genotype × Depression = 0.02 * | SS |
Manoharan et al. [36] | Serotonin transporter gene (SLC6A4) polymorphisms are associated with response to fluoxetine in south Indian major depressive disorder patients | Investigate the influence of the 5HTTLPR and rs25531 gene variants in response to fluoxetine treatment. | 2016 | India | 126 | VNTR SNP (rs25531) | Genotyping according to Kaiser et al. [37], and PCR real time | Most of the 5HTTLPR participants had the LS genotype, while in the rs25531 had the La genotype. The LL genotype and the LaLa haplotype of SLC6A4 are associated with favorable treatment response to fluoxetine in MDD patients. | 5HTTLPR × fluoxetine = 0.0066 * rs25531 × fluoxetine = 0.0818 | VNTR = LS rs25531 = S/La |
Ramasubb et al. [38] | Amygdala responses to quetiapine XR and citalopram treatment in major depression: the role of 5HTTLPR-S/Lg polymorphisms. | Examine the impact of two antidepressants with differential actions on the serotonin transporter and the 5HHTLPR polymorphisms on tonsil responses in MDD. | 2016 | Canada | 57 | SNP (rs25531) | PCR and RFLP | The La/Sa genotype was the most frequent in the groups. Citalopram did not affect amygdala responses in MDD patients with S or Lg alleles at weeks 1 and 8 compared to baseline. In contrast, Quetiapine decreased amygdala responses in MDD patients with S or Lg alleles, and changes in amygdala responses at week 8 correlated with a reduction in depression scores. The effectiveness of both treatments was comparable. | Medications in S/Lg genotype × Score HAM-A = 0.07 * Drugs in S/Lg genotype × Score HDRS = 0.11 | La/Sa |
Tatham et al. [39] | The 5HTTLPR and BDNF polymorphisms moderate the association between uncinate fasciculus connectivity and antidepressants treatment response in major depression | Assess whether the white matter integrity indices linked to 5HTTLPR serotonin transport and Val66Met brain-derived neurotrophic factor (BDNF) polymorphisms predict the magnitude of change in depressive symptoms after treatment with antidepressants. | 2016 | Canada | 46 | SNP | Magnetic Resonance, PCR, and RFLP | Most of the MDD participants (45.95%) had the SL genotype. When evaluating the effect of medication and the 5HTTLPR genotype, it was noted that most patients with remission had SL genotype. Moreover, the combined white matter integrity measures and genetic factors may help predict improvements in depressive symptoms after antidepressant treatment. | Treatment × Polymorphism = 0.55 | L’S (La/Lg or La/Sa) |
Tatham et al. [40] | White matter integrity in major depressive disorder: Implications of childhood trauma, 5HTTLPR and BDNF polymorphisms | Evaluate the influence of childhood trauma, 5HTTLPR and BDNF polymorphisms on myelin integrity in the brain of MDD patients. | 2016 | Canada | 55 | SNP | PCR, RFLP, and imaging exams | Most participants in the MDD group had the heterozygous SL genotype (49%). The SS genotype was not associated with reports of severe trauma when compared to the LL genotype. The results suggest that the frontal and limbic regions were affected by depression and influenced by childhood traumatic experiences and genetic risk factors. | Polymorphism × Trauma = 0.574 | ‘L’S (La/Lg or La/Sa) |
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Fratelli, C.; Siqueira, J.; Silva, C.; Ferreira, E.; Silva, I. 5HTTLPR Genetic Variant and Major Depressive Disorder: A Review. Genes 2020, 11, 1260. https://0-doi-org.brum.beds.ac.uk/10.3390/genes11111260
Fratelli C, Siqueira J, Silva C, Ferreira E, Silva I. 5HTTLPR Genetic Variant and Major Depressive Disorder: A Review. Genes. 2020; 11(11):1260. https://0-doi-org.brum.beds.ac.uk/10.3390/genes11111260
Chicago/Turabian StyleFratelli, Caroline, Jhon Siqueira, Calliandra Silva, Eduardo Ferreira, and Izabel Silva. 2020. "5HTTLPR Genetic Variant and Major Depressive Disorder: A Review" Genes 11, no. 11: 1260. https://0-doi-org.brum.beds.ac.uk/10.3390/genes11111260