5-HTTLPR Genotype Research Articles

Correlation between curative effect and 5-HTTLPR polymorphism in treatment of diarrhea-predominant irritable bowel syndrome with acupuncture for regulating shen and strengthening spleen

To compare the curative effect on diarrhea-predominant irritable bowel syndrome (IBS-D) between acupuncture for regulating shen and strengthening spleen and pinaverium bromide, and explore the relevant mechanism of curative effect of acupuncture in view of polymorphism of 5-hydroxytryptamine transporter gene-linked polymorphic region (5-HTTLPR). A total of 231 patients with IBS-D were randomized into an acupuncture group (154 cases) and a western medication group (77 cases) at the ratio of 2 to 1. In the acupuncture group, acupuncture was applied to acupoint regimen for regulating shen and strengthening spleen, i.e. Baihui (GV 20), Yintang (GV 29), Tianshu (ST 25), Shangjuxu (ST 37) and Zusanli (ST 36), etc. The treatment was given once every 2 days, 3 times a week. In the western medication group, pinaverium bromide was prescribed for oral administration, 50 mg each time, 3 times daily. The duration of treatment was 6 weeks in each group. Separately, before treatment, after treatment and in 3-month follow-up, the IBS symptom severity scale (IBS-SSS) and IBS quality of life scale (IBS-QOL) scores were adopted in assessment. After treatment, the curative effect and safety were compared between the two groups. Before treatment, 5-HTTLPR genotypes were determined in the patients. After treatment and in follow-up, the total scores of IBS-SSS in the patients of the two groups were all reduced as compared with those before treatment (P<0.01) and the scores in the acupuncture group were lower than those in the western medication group (P<0.01). After treatment and in follow-up, the total scores of IBS-QOL in the two groups were all increased as compared with those before treatment (P<0.01) and the score in the acupuncture group was higher than the western medication group in follow-up (P<0.01). The total effective rate was 79.2% (122/154) in the acupuncture group, higher than 58.4% (45/77) in the western medication group (P<0.01). There was no severe adverse reaction found in the two groups. The difference in the total score of IBS-SSS before and after treatment in the patients with LS and SS genotypes was greater than that in the patients with LL in the acupuncture group (P<0.01). The difference in the total score of ISB-SSS before and after treatment in the patients with SS genotype was greater than that in the patients with LL in the western medication group (P<0.01). The difference in the total score of IBS-SSS before and after treatment in the patients with LS and SS genotypes in the acupuncture group was greater than that in the patients with the same genotypes in the western medication group (P<0.01). Acupuncture for regulating shen and strengthening spleen achieves the more curative effect on IBS-D as compared with pinaverium bromide. The acupuncture regimen effectively relieves the clinical symptoms and improves the quality of life in patients as well as presents a satisfactory long-term effect and safety. The clinical curative effect of acupuncture is correlated with 5-HTTLPR polymorphism, in which, the curative effect of acupuncture may be more effective in the patients with LS and SS genotypes.

Association of DRD4 exon III and 5-HTTLPR VNTR genetic polymorphisms with psychiatric symptoms in hemodialysis patients.

Mental illness is prevalent among hemodialysis (HD) patients. Given that the dopaminergic and serotonergic pathways are involved in the etiology of psychiatric disease, this study evaluated the genetic association of dopamine D4 receptor (DRD4) and serotonin transporter (SLC6A4) genes with psychiatric symptom susceptibility among HD patients. Hospital Anxiety and Depression Scale (HADS) was used to assess anxiety and depressive symptoms among patients (n = 265). Genetic polymorphisms of DRD4 (48 bp VNTR) and SLC6A4 (5-HTTLPR VNTR and rs25531) were examined using a conventional polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique, as appropriate. Significant differences were observed in the distribution of 5-HTTLPR genotypes, SLC6A4 tri-allelic-phased genotype, and DRD4-Exon III VNTR genotypes/alleles between patients with anxiety symptoms versus those with normal/borderline conditions (p<0.05). Binary logistic regression analyses showed that the heterozygous 4,5 VNTR genotype of DRD4 was associated with a higher risk of anxiety symptoms after adjusting for other covariates (odds ratio = 4.25, p = 0.028). None of the studied polymorphisms was linked to depression in HD patients. Collectively, the current findings provide genetic clues to psychopathology in HD patients and suggest that the DRD4 exon III VNTR polymorphism is involved in the etiology of anxiety in this patient population.

Therapygenetic effects of 5-HTTLPR on cognitive-behavioral therapy in anxiety disorders: A meta-analysis

There is a recurring debate on the role of the serotonin transporter gene linked polymorphic region (5-HTTLPR) in the moderation of response to cognitive behavioral therapy (CBT) in anxiety disorders. Results, however, are still inconclusive. We here aim to perform a meta-analysis on the role of 5-HTTLPR in the moderation of CBT outcome in anxiety disorders. We investigated both categorical (symptom reduction of at least 50%) and dimensional outcomes from baseline to post-treatment and follow-up. Original data were obtained from ten independent samples (including three unpublished samples) with a total of 2,195 patients with primary anxiety disorder. No significant effects of 5-HTTLPR genotype on categorical or dimensional outcomes at post and follow-up were detected. We conclude that current evidence does not support the hypothesis of 5-HTTLPR as a moderator of treatment outcome for CBT in anxiety disorders. Future research should address whether other factors such as long-term changes or epigenetic processes may explain further variance in these complex gene-environment interactions and molecular-genetic pathways that may confer behavioral change following psychotherapy.

Individual Differences in Autistic Traits are Associated with Serotonin Transporter Gene Polymorphism Through Medial Prefrontal Function: A Study Using NIRS

Autism spectrum disorder (ASD) is a heritable neurodevelopmental disorder that can vary considerably in severity. Autistic traits are distributed continuously across populations, even in sub-clinical individuals. Serotonin transporter-gene polymorphic region (5-HTTLPR) has been studied as a candidate genetic factor related to ASD, however results have been inconsistent. 5-HTTLPR is implicated in the function of medial prefrontal cortex (mPFC), a region associated with the social abnormalities found in ASD. Here we hypothesize that autistic traits are affected by the 5-HTTLPR genotype indirectly through mPFC mediation. Using near-infrared spectroscopy (NIRS), we first examined mPFC activation in people with ASD when they performed a facial affect-labeling task. Compared with a typical development group, the ASD group showed significantly lower mPFC activation during the task. Using the same task paradigm, we next investigated the relationship between autistic traits and 5-HTTLPR in sub-clinical participants, and whether associations were mediated by mPFC function. Correlation analyses indicated that participants with a large number of 5-HTTLPR L-alleles had high-level autistic traits related to social skills and low right mPFC activation. We also observed a significant negative correlation between autistic traits related to social skills and right mPFC activation. Structural equation analysis suggested a significant indirect effect of 5-HTTLPR on Autism-Spectrum Quotients, with right mPFC activation acting as a mediator. These results suggest that the diverse autistic traits related to social skills seen in the general population are associated with the 5-HTTLPR genotype, and that this association is mediated by right mPFC function.

Association of serotonin transporter-linked polymorphic region (5-HTTLPR) with heat pain stimulation and postoperative pain in gastric cancer patients.

BackgroundThe aim of this study was to assess whether the genotype of the serotonin transporter-linked polymorphic region (5-HTTLPR) in gastric cancer patients is associated with postoperative pain and pain threshold.MethodsWe conducted a prospective cohort study of 251 patients scheduled for gastrectomy from May to September 2019. All patients enrolled in the study were asked to complete the Hospital Anxiety and Depression Scale questionnaire. Heat pain threshold (HPT), cold pain threshold (CPT) and Pressure pain threshold (PPT) were measured for all participants one day prior to surgery. Blood samples were collected for genetic testing. All patients were connected to a patient-controlled intravenous analgesia (PCIA) pump at the end of the surgery. After exclusion of 15 patients, the postoperative conditions of 236 patients were recorded.ResultsDistribution of homozygous long (L/L), heterozygous (L/S), and homozygous short (S/S) 5-HTTLPR genotypes among participants were 26 (11.0%), 91 (38.6%), and 119 (50.4%), respectively. Heat pain threshold (P = 0.038) and Numerical rating scale (NRS) in the 1st postoperative 24 h (P = 0.026) were significantly different between long (L/L) and short (S/S) genotype carriers.ConclusionsIn patients with gastric cancer, heat pain stimulation is associated with 5-HTTLPR polymorphism, and postoperative pain may be related to 5-HTTLPR polymorphism.

Role of serotonin transporter-linked polymorphic region in suicide: Beyond association, meta-analysis, and future prospects

Serotonin transporter-linked polymorphic regions (5-HTTLPR) have been investigated intensively in suicide with inconsistent findings. However, a recent meta-analysis has observed an association of S allele with violent attempted suicide. The S allele causes a lower expression of 5-HTTLPR and is correlated with higher amygdala response to unpleasant stimuli. However, studies show that effect 5-HTTLPR genotype on mRNA expression is additive and linear. It suggests that apart from genotype, the expression of 5-HTTLPR is also controlled by epigenetic factors. Therefore, the purpose of this narrative review is to re-evaluate the findings of retrospective studies 5-HTTLPR in suicide with their limitations and highlight a new approach to understand the role of 5-HTTLPR in suicide. Reviews, meta-analysis, research articles, brief reports, and scientific correspondence were searched through PubMed, library web portal of Sikkim University, Bio-Med, and Science Direct using the terms such as “serotonin or serotonin system and suicide,” “5-HTTLPR and suicide,” “5-HTTLPR and attempted suicide,” “5-HTTLPR and completed suicide,” “5-HTTLPR meta-analysis and suicide,” and “5-HTTLPR and epigenetics.” The articles written in English were initially screened by title and later selected by abstract for possible inclusion. After the literature review, it was observed that previous studies were limited by variability of sample size, heterogeneous populations, varied social stressors, and variations in the assay and statistical methods. Hence, the cumulative study of environmental factors, 5-HTTLPR gene polymorphism, and epigenetic factors is hereby proposed in the well-defined ethnic population to understand the role of 5-HTTLPR in suicide.

Serotonin transporter gene polymorphisms and depressive symptoms in patients with chronic obstructive pulmonary disease

ABSTRACT Background: We examined the relationship between polymorphisms in the promoter region of the serotonin transport (SERT) gene (5-HTTLPR, short ‘S’ and long ‘L’ alleles) and in intron 2 variable number tandem repeat (STin2VNTR, 9, 10, or 12-repeat alleles) with depression or anxiety in patients with COPD. Methods: 302 patients with moderate to severe COPD participated in SERT study. History and number of prior depressive episodes were measured using the Structured Clinical Interview for Depression; Hospital Anxiety Depression Scale (HAD) depression ≥8 or a Patient Health Questionnaire-9 (PHQ-9) >,10. Results: 240 (80%) male sample had a mean age of 68.0 years. Current depression was 22% (HAD) or 21% (PHQ-9), anxiety was 25% (HAD), and suicidal ideation (6%). 5-HTTLPR or STin2 VNTR genotypes were not associated with current depressive or anxiety symptoms. The mean number of prior depressive episodes was higher for patients with the 5-HTTLPR genotype S/S or S/L compared with L/L (4.4 ± 6.1; 5.3 ± 6.8; 4.0 ± 6.1, p < 0.001) and with STin2VNTR high-risk genotype (9/12 or 12/12), medium risk (9/10 or 10/12) compared to low risk (10/10) genotypes (5.1 ± 6.8; 4.9 ± 6.7; 2.7 ± 4.5, p < 0.001). Conclusions: SERT 5-HTTLPR and STin2-VNTR polymorphisms were not associated with current depressive and anxiety symptoms, but the high-risk STin2-VNTR genotypes and S/L were associated with the number of prior depressive episodes.

Association of Serotonin Transporter Gene (5-HTTLPR/rs25531) Polymorphism with Comorbidities of Panic Disorder

Introduction: Panic disorder (PD) has many comorbidities such as depression, bipolar disorder (BPD), and agoraphobia (AG). PD is a moderately heritable anxiety disorder whose pathogenesis is not well understood. Recently, a tri-allelic serotonin transporter (5-HTTLPR/rs25531) polymorphism was reported to be more sensitive to personality traits compared to the bi-allelic 5-HTTLPR polymorphism. We hypothesized that the 5-HTTLPR/rs25531 polymorphism may lead to a pathological anxious state depending on the presence or absence of a comorbidity in PD. Methods: In this study, we investigated the relationship between comorbidities in PD and tri-allelic 5-HTTLPR polymorphisms. A total of 515 patients with PD (148 males, 367 females) were genotyped, and the Revised NEO Personality Inventory as well as anxiety-related psychological tests were administered. Depression, BPD, and AG were diagnosed as comorbidities. Results: For the tri-allele 5-HTTLPR genotype, a significant interaction effect was found between openness to experience and comorbid depression. Examination of the interaction between AG and the tri-allelic 5-HTTLPR genotype revealed that L’ allele carriers are associated with higher trait anxiety than the S’S’ genotype group in PD without AG. Conclusion: Some anxiety and personality traits can be characterized by the tri-allelic gene effect of 5-HTTLPR. These results suggest that tri-allelic 5-HTTLPR genotypes have genetic effects on the presence of comorbidities of PD.

The interaction of 5-HTT variation, recent stress, and resilience on current anxiety levels in adolescents and young adults from the general population.

Previous work on gene-environment (GxE) interplay concerning anxiety has focused on the interaction of 5-HTTLPR with childhood adversities or traumatic events whereas the impact of recent stressors is understudied, as is the integration of resilience. The current study aimed to investigate the interactive effect of 5-HTTLPR and recent stress on anxiety in adolescents considering resilience as buffer of a GxE risk constellation. In a random population-based sample of 14-21 years old from Dresden, Germany, (N = 1180; genotyped = 942) recent stress (Daily Hassles [DH] Scale, Perceived Stress Scale, Screening Scale of the Trier Inventory for the Assessment of Chronic Stress), resilience (Connor-Davidson resilience scale) and anxiety (Patient Reported Outcome Measurement Information System Anxiety Short Form) were assessed via questionnaire in 2015 or 2016. Fractional regression models revealed that resilience interacted with recent stress in form of DH as well as recent chronic stress and 5-HTTLPR regarding anxiety. Participants carrying the more active LA LA genotype reported consistently higher levels of anxiety when experiencing more DH or more recent chronic stress and having low levels of resilience. When the resilience scores were high, LA LA carriers reported the lowest anxiety scores despite DH or recent chronic stress. Findings revealed an interactive relationship between 5-HTTLPR genotype and recent stress suggesting resilience to function as an additional dimension buffering the impact of a GxE risk constellation. Early interventions to build resilience may be useful to prevent an escalation of distress and associated unfavorable health outcomes.

Threat-Avoidance Tendencies Moderate the Link Between Serotonin Transporter Genetic Variation and Reactive Aggression.

The short (S) allele of the serotonin transporter-linked promoter region (5-HTTLPR) polymorphism has been linked to reactive aggression in men, but this association is less consistent in females. Reactive aggression has been particularly described as a result of fear-driven defense to threat, but how this interaction between defensive behavior and aggression is expressed in S-allele carriers remains unknown. In order to explore this interplay between 5-HTTLPR genotype, defensive behavior and reactive aggression, we combined genotyping with objective measures of action tendencies toward angry faces in an approach-avoidance task (AAT) and reactive aggression in the Taylor aggression paradigm (TAP) in healthy females, N = 95. This study shows that female S-allele carriers in general display increased implicit reactive aggression (administering aversive white noise) toward opponents. Furthermore, we found that threat-avoidance tendencies moderate the association between 5-HTTLPR genotype and aggression displayed on the TAP. Together, these findings indicate a positive correlation between avoidance of angry faces in the AAT and reactive aggression in the TAP exclusively present in S-allele carriers.

Association of antibody titers and 5-HTTLPR gene polymorphisms in pediatric autoimmune neuropsychiatric disorder associated with streptococci

Introduction. It has been hypothesized that pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS) etiology results from an abnormal immune response to streptococcal infection. There is evidence that the serotonergic system is involved in both obsessive-compulsive disorder (OCD) physiopathology and immunological processes. In the 5’ promoter region of 5-HTT, gene encoding for the serotonin transporter we can find the 5-HTTLPR polymorphism that has been associated with OCD. Being PANDAS a disorder with OCD symptoms and likely immune abnormalities, 5-HTT polymorphisms may be particularly relevant for this disorder. Objective. This study aimed to test the association between the 5-HT genotypes and the presence of serum antibodies in patients with PANDAS. Method. We compared the genotype frequencies and serum anti-streptococcal, anti-neural, and anti-enolase antibodies titers between 56 patients with PANDAS and 20 healthy controls from Mexico and Cuba. Results. Antibody titers were higher (anti-enolase, anti-streptococcal) in PANDAS patients compared to healthy controls. No differences in anti-neural antibody levels between both groups were detected. The anti-enolase and anti-neural antibody titer increased according to the polymorphism of the PANDAS patients as follows: LL &gt;SL &gt;SS. Discussion and conclusion. This is the first study evaluating the association between the 5-HTTLPR genotypes and antibody titers in PANDAS patients. Associations between polymorphisms in serotonergic genes and immune response could provide valuable information about the interaction between both systems. Our results suggest an association between the S allele and elevated antibody levels in PANDAS patients.

The role of the 5-HTTLPR polymorphism in acquired capability for suicide.

According to the Interpersonal Psychological Theory of Suicide, capability for suicide comprises two dimensions: fearlessness about death and elevated pain tolerance. The short (S) allelic variant of the serotonin transporter gene-linked polymorphic region (5-HTTLPR) has repeatedly been associated with more violent and lethal suicide methods and lethality of suicide attempts. The current study aimed to investigate whether 5-HTTLPR allelic variants are associated with fearlessness about death and pain tolerance/persistence and whether it moderates the relationship between childhood maltreatment and acquired capability for suicide. A cohort of 208 inpatients hospitalized due to a recent suicide attempt or severe suicidal ideation was genotyped for the 5-HTTLPR and assessed for childhood maltreatment. Subjective pain tolerance and fearlessness about death as well as objective pain persistence was assessed using a pressure algometer. Fearlessness about death, pain tolerance, and pain persistence did not differ between 5-HTTLPR genotypes. However, there was a significant correlation between self-reported childhood maltreatment and fearlessness about death that emerged exclusively in homozygous S-allele carriers. Results suggest that there are no "high-risk"-alleles that generally increase capability for suicide. However, in terms of future suicide-related behaviors exposure to childhood maltreatment events could exert a particularly negative influence on homozygous S-allele carriers by increasing their fearlessness about death.

Childhood maltreatment, serotonin transporter gene, and risk for callous and unemotional traits: A prospective investigation

Previous studies have reported associations between the serotonin transporter 5-HTTLPR genotype and antisocial and aggressive traits and between child maltreatment and antisocial traits. However, few studies have examined whether 5-HTTLPR moderates the influence of childhood maltreatment on callous and unemotional traits, a hallmark of psychopathy. Using a prospective cohort design, children with documented cases of maltreatment and matched controls were followed up and interviewed in adulthood. DNA was extracted from blood and saliva (N = 414) and callous-unemotional (CU) traits were assessed. Childhood maltreatment predicted higher CU scores in adulthood, whereas the effect of 5-HTTLPR was not significant. The effect of child maltreatment on CU traits did not differ by genetic risk (high or low activity 5-HTTLPR), whereas controls with the LL genotype had higher CU scores than controls with the SS genotype. Similar results were found for females and White, non-Hispanics, but not for males and Blacks. Variations in 5-HTTLPR did not affect the impact of child maltreatment on CU traits in adulthood. Genetic risk had a stronger effect on adults with lower environmental risk (controls). Having a history of child maltreatment or the LL genotype placed participants at risk for higher levels of callous and unemotional trait scores.

Association between Genetic Polymorphism of 5-HTTLPR, and SGOT, SGPT and Catalase with Alcoholism of Iraqi People

A case- control study on the relationship of 5-HTTLPR gene polymorphism with alcohol abuse among Iraqi individuals was conducted during period from December 2018 to June 2019. DNA was extracted from the blood samples of the study subjects. The genetic polymorphism analysis was conducted by Restriction Fragment Length Polymorphism (RFLP-PCR) for SLC6A4 gene. The results raveled that the odd ratio for the LL genotype was 1.697 indicating that homo mutant genotype were at higher risk for alcoholism than the wild type SS. This result showed that L allele frequency was (0.78) in alcoholism group and (0.53) in control group whereas S allele frequency was (0.22) in the alcoholism group and (0.47) in the control group. So, the results showed there was a significant difference in allele frequencies of SLC6A4gene between case and control (P&lt;0.01; OR=1.697; 95% CI=0.86-1.64). There was a significant positive correlation between the SGOT activity and the genotype of 5-HTTLPR (SS, SL, LL).Additionally, there was a significantly increased level of liver enzymes (GOT and GPT) and catalase in serum samples of alcoholic males compared with non-alcoholic males.

Learning from amyloid trials in Alzheimer's disease. A virtual patient analysis using a quantitative systems pharmacology approach.

BackgroundMany trials of amyloid‐modulating agents fail to improve cognitive outcome in Alzheimer's disease despite substantial reduction of amyloid β levels.MethodsWe applied a mechanism‐based Quantitative Systems Pharmacology model exploring the pharmacodynamic interactions of apolipoprotein E (APOE), Catechol ‐O ‐methyl Transferase (COMTVal158Met), and 5‐HT transporter (5‐HTTLPR) rs25531 genotypes and aducanumab.ResultsThe model predicts large clinical variability. Anticipated placebo differences on Alzheimer's Disease Assessment Scale (ADAS)‐COG in the aducanumab ENGAGE and EMERGE ranged from 0.77 worsening to 1.56 points improvement, depending on the genotype‐comedication combination. 5‐HTTLPR L/L subjects are found to be the most resilient. Virtual patient simulations suggest improvements over placebo between 4% and 20% at the 10 mg/kg dose, depending on the imbalance of the 5‐HTTLPR genotype and exposure. In the Phase II PRIME trial, maximal anticipated placebo difference at 10 mg/kg ranges from 0.3 worsening to 5.3 points improvement.DiscussionThese virtual patient simulations, once validated against clinical data, could lead to better informed future clinical trial designs.

5-HTTLPR polymorphism and depression risk in Parkinson's disease: an updated meta-analysis.

The relationship between the 5-hydroxytryptamine transporter gene-linked polymorphic region (5-HTTLPR) and depression in Parkinson's disease (PD) has remained controversial. Therefore, we conducted this meta-analysis to evaluate the relationship between 5-HTTLPR polymorphisms and depression in PD. Relevant online databases were searched for cross-sectional, case-control or cohort studies examining relations between 5-HTTLPR polymorphisms (S/L) and the risk of developing depression of PD using a meta-analysis. Odd ratios (ORs) of 5-HTTLPR polymorphisms (S/L allele genotype) were calculated between depression in PD and PD for each study. Five observational studies were identified. Overall ORs for 5-HTTLPR S-Allele genotype was 1.98 (95% CI 0.92-4.26) in the dominant model, 1.43 (95% CI 1.08-1.90) in the recessive model, 2.64 (95% CI 1.01-6.88) in the additive model, independently. The overall ORs of S-Allele genotype was 1.51 (95% CI 0.63-3.64) for the Caucasian subgroup, and 1.44 (95% CI 1.05-1.98) for the non-Caucasian subgroup in the recessive model. This meta-analysis indicates that the 5-HTTLPR genotype (S/S-Allele) is correlated with an increased depression risk in PD, and this highlights the needs for these people to take some effective approaches (if any) in prevention of depression of PD before its onset.

Influence of psychosocial stress on activation in human brain regions: moderation by the 5-HTTLPR genetic locus

Variants of the serotonin transporter linked polymorphic region (5-HTTLPR) of the serotonin transporter gene SLC6A4 have been related with the onset of depression, anxiety, and other mental disorders. Homozygotes for the short 5-HTTLPR variant, referred to as the SS genotype, have greater cortisol responses to experimentally induced psychosocial stress. In the current study, we used functional magnetic resonance imaging (fMRI) to compare regional brain activations across 5-HTTLPR genotypes in subjects performing the Montreal Imaging Stress Task (MIST). Subjects with an SS genotype had significant greater increases in cortisol concentrations after the task than subjects with at least one long 5-HTTLPR allele. Additionally, relative to L carriers, the SS group had greater activation in the dorsomedial prefrontal cortex(dmPFC), dorsal anterior cingulate cortex, anterior insula.

Structural brain changes with lifetime trauma and re-experiencing symptoms is 5-HTTLPR genotype-dependent

ABSTRACT Background: Findings on structural brain alterations following trauma are inconsistent due probably to heterogeneity in imaging studies and population, clinical presentations, genetic vulnerability, and selection of controls. This study examines whether trauma and re-experiencing symptoms are associated with specific alterations in grey matter volumes and if this varies according to 5-HTTLPR genotype. Methods: Structural MRI was used to acquire anatomical scans from 377 community-dwelling older adults. Quantitative regional estimates of 22 subregional volumes were derived using FreeSurfer software. Lifetime trauma was assessed using the validated Watson’s PTSD inventory, which evaluates the most severe trauma experienced according to DSM criteria. Analyses adjusted for age, sex, total brain volume, head injury, and comorbidities. Results: Of the 212 participants reporting lifetime trauma, 35.4% reported re-experiencing symptoms and for 1.9%, this was severe enough to meet criteria for full threshold PTSD. In participants with the SS 5-HTTLPR genotype only, re-experiencing symptoms were associated with smaller volumes in middle and superior temporal, frontal (lateral orbital, rostral and caudal middle) and parietal (precuneus, inferior and superior) regions. The trauma-exposed participants without re-experiencing symptoms were not significantly different from the non-trauma-exposed participants except for smaller precuneus and superior parietal region in traumatized participants and a larger amygdala in traumatized women specifically. Conclusions: In the non-clinical sample, lifetime trauma and re-experiencing symptoms were associated with smaller volume in prefrontal, temporal and parietal cortex subregions, and this varied according to serotonergic genetic vulnerability, 5-HTTLPR SS individuals being most susceptible.

Interactions between the combined genotypes of 5-HTTLPR and BDNF Val66Met polymorphisms and parenting on adolescent depressive symptoms: A three-year longitudinal study

BackgroundThe importance of multiple genes-environment interaction (G × E) has been highlighted in studies on depressive symptoms. 5-HTTLPR and BDNF Val66Met polymorphisms, with functional interconnection, have been implicated in the pathophysiology of depressive symptoms. However, little is understood about whether the interaction of 5-HTTLPR, BDNF Val66Met and parenting fits better with the epistatic or cumulative manner. Methods865 adolescents (T1: Mage = 12.32, 50.2% girls) were included in a three-year interval longitudinal design. Standardized questionares about parenting and depressive symptoms were collected. Saliva samples were collected for genotyping. ResultsNeither the concurrent nor longitudinal interaction of 5-HTTLPR, BDNF Val66Met and parenting (G × G × E) showed significant effects on depressive symptoms. The interaction between cumulative genotypes and positive parenting (CG × E) was significant, with the strong differential susceptibility model, for depressive symptoms concurrently but not longitudinally after statistical correction. Adolescents who carried 3 (i.e. SS and Val/Met, L allele and Val/Val) and 4 (i.e. SS and Val/Val), not 1 (i.e. L allele and Met/Met) or 2 cumulative susceptibility alleles (i.e. SS and Met/Met, L allele and Val/Met), reported fewer depressive symptoms if they had experienced higher levels of positive parenting, and more symptoms under lower levels of positive parenting. LimitationsThis study did not examine the 5-HTTLPR triallelic (rs25531) marker and did not include an external sample. ConclusionsThe combined effects of 5-HTTLPR and BDNF Val66Met polymorphisms functioned in a manner of cumulative rather than epistatic in response to positive parenting on early adolescent depressive symptoms.

The association between childhood maltreatment and empathic perspective taking is moderated by the 5-HTT linked polymorphic region: Another example of "differential susceptibility".

Previous research has suggested that the short (S)-allele of the 5-HT transporter gene-linked polymorphic region (5-HTTLPR) may confer "differential susceptibility" to environmental impact with regard to the expression of personality traits, depressivity and impulsivity. However, little is known about the role of 5-HTTLPR concerning the association between childhood adversity and empathy. Here, we analyzed samples of 137 healthy participants and 142 individuals diagnosed with borderline personality disorder (BPD) focusing on the 5-HTTLPR genotype (S/L-carrier) and A/G SNP (rs25531), in relation to childhood maltreatment and empathy traits. Whereas no between-group difference in 5-HTTLPR genotype distribution emerged, the S-allele selectively moderated the impact of childhood maltreatment on empathic perspective taking, whereby low scores in childhood trauma were associated with superior perspective taking. In contrast, L-homozygotes seemed to be largely unresponsive to variation in environmental conditions in relation to empathy, suggesting that the S-allele confers "differential susceptibility". Moreover, a moderation analysis and tests for differential susceptibility yielded similar results when transcriptional activity of the serotonin transporter gene was taken into account. In conclusion, our findings suggest that the S-allele of the 5-HTTLPR is responsive to early developmental contingencies for "better and worse", i.e. conferring genetic plasticity, especially with regard to processes involving emotional resonance.