5-HTTLPR LL Genotype Research Articles

Decreased serotonin transporter activity in the mitral valve contributes to progression of degenerative mitral regurgitation.

Degenerative mitral valve (MV) regurgitation (MR) is a highly prevalent heart disease that requires surgery in severe cases. Here, we show that a decrease in the activity of the serotonin transporter (SERT) accelerates MV remodeling and progression to MR. Through studies of a population of patients with MR, we show that selective serotonin reuptake inhibitor (SSRI) use and SERT promoter polymorphism 5-HTTLPR LL genotype were associated with MV surgery at younger age. Functional characterization of 122 human MV samples, in conjunction with in vivo studies in SERT-/- mice and wild-type mice treated with the SSRI fluoxetine, showed that diminished SERT activity in MV interstitial cells (MVICs) contributed to the pathophysiology of MR through enhanced serotonin receptor (HTR) signaling. SERT activity was decreased in LL MVICs partially because of diminished membrane localization of SERT. In mice, fluoxetine treatment or SERT knockdown resulted in thickened MV leaflets. Similarly, silencing of SERT in normal human MVICs led to up-regulation of transforming growth factor β1 (TGFβ1) and collagen (COL1A1) in the presence of serotonin. In addition, treatment of MVICs with fluoxetine not only directly inhibited SERT activity but also decreased SERT expression and increased HTR2B expression. Fluoxetine treatment and LL genotype were also associated with increased COL1A1 expression in the presence of serotonin in MVICs, and these effects were attenuated by HTR2B inhibition. These results suggest that assessment of both 5-HTTLPR genotype and SERT-inhibiting treatments may be useful tools to risk-stratify patients with MV disease to estimate the likelihood of rapid disease progression.

Impact of Serotonin Pathway Gene Polymorphisms and Serotonin Levels in Suicidal Behaviour

Objective: Suicide is a significant public health issue and a major cause of death in all ages worldwide. Previous studies have shown the involvement of genetics in suicidal behaviour. This study aimed to assess the role of the genetic variants of the serotonin transporter genes (5HTTLPR, SLC6A4 intron 2) and receptor gene (5HTR2AT102C) in individuals who died of suicide. The study compares the serum levels of serotonin between the cases and controls. Methods: We conducted a case-control study with 120 cases and 126 controls. Socio-economic details of the subjects were collected using a semi-structured proforma, and psychological autopsy was used to collect details of medical and other clinical conditions. Blood was drawn after taking informed consent and serum levels of serotonin were estimated by enzyme-linked immunosorbent assay. Genotyping was performed using appropriate primers followed by polymerase chain reaction and a restriction fragment length polymorphism. Results: Mean age was 32.59 ± 12.58 for cases and 33.64 ± 9.78 for controls. The risk-associated LL genotype of 5HTTLPR was higher among cases. The heterozygous 12/10 genotype of SLC6A4 intron 2 polymorphism was increased among controls. Serum levels of serotonin were lower among cases. Variant genotypes of all the 3 polymorphisms showed significant interaction (OR = 39.26) indicating that this model may increase suicidal tendency. Conclusion: The findings of this study suggest that low serum levels of serotonin and two variants of the serotonin gene may influence suicide behaviour in a south Indian population.

Study on the Relationship between 5-HttLPR Gene and BDNF Gene Polymorphism and Post-Traumatic Stress Disorder in Li and Han Nationality of Hainan Province

Objective: To investigate the correlation between 5-HTTLPR (5-and serotonin transporter linked polymer region) gene polymorphism and BDNF (brain derived neural factor) gene polymorphism and PTSD (post traumatic stress disorders) in Li and Han nationalities in Hainan Province. Methods: 167 Hainan Li PTSD patients, 141 Hainan Han PTSD patients and 158 healthy volunteers (control group) were investigated by ETI, caps, Toh, WCST, TMT and WAIS-RC. The polymorphisms of rs6265 locus of 5-HTTLPR and BDNF genes were detected by PCR (polymerase chain reaction) and page (polycylamide gel electrophoresis), and the correlation with PTSD was analyzed. Logistic regression analysis was used to analyze the influencing factors of PTSD. Results: The ETI score, total PTSD score and TMT time of Li PTSD patients were significantly higher than those of Han PTSD patients (P 0.05). SS genotype of 5-HTTLPR and (GA + AA) genotype of rs6265 locus may increase the risk of PTSD in Hainan Han population. AA and GA + AA genotypes at rs6265 locus may increase the risk of PTSD in Li population (P < 0.05). Among Li PTSD patients, the ETI score, PTSD total score, TMT time, Toh planning time and execution time of AA genotype at rs6265 locus were significantly higher than those of GG genotype; the total scores of comprehension and operation IQ, and Toh in WAIS-RC were significantly lower than those in GG genotype (P < 0.05). Among Han PTSD patients, the ETI score, PTSD total score and TMT time of SS genotype of 5-HTTLPR were significantly higher than those of LL genotype, and the comprehension, arithmetic and block diagram in WAIS-RC were significantly lower than those of LL genotype; The ETI score, PTSD total score and TMT time of patients with (GA + AA) genotype at rs6265 locus were also significantly higher than those of patients with GG genotype. The comprehension and block diagram in WAIS-RC were significantly lower than those of patients with GG genotype. The number of WCST errors in patients with AA genotype was significantly higher than those of patients with GG genotype, and the operational IQ in WAIS-RC was significantly lower than those of patients with GG genotype (P < 0.05). Conclusion: The LL genotype of 5-HTTLPR and the GG genotype of rs6265 locus are related to PTSD of Li and Han nationalities in Hainan, which are important protective factors for PTSD of Li and Han nationalities in Hainan.

Impact of serotonin transporter gene on rTMS augmentation of SSRIs for obsessive compulsive disorder.

ObjectiveRepetitive transcranial magnetic stimulation (rTMS) is beneficial for treatment-resistant patients with obsessive-compulsive disorder (OCD). The serotonin transporter gene (SLC6A4) may be associated with OCD. We aimed to determine whether SLC6A4 impacts the beneficial effects of rTMS in patients with OCD treated with selective serotonin reuptake inhibitors (SSRIs).MethodsFifty-seven untreated patients with OCD were randomly assigned to receive active or sham rTMS in a 4-week double-blind study. The participants received 1-Hz rTMS over the supplementary motor area once per day, for 5 days a week, for 4 weeks. One of the widely employed SSRIs was utilized at the initiation of active or sham rTMS. Yale–Brown obsessive–compulsive scale (Y-BOCS) scores were used for assessing the symptoms. The most-researched polymorphism of SLC6A4, 5-HTTLPR (L/S), was also examined.ResultsY-BOCS scores in the active group at the completion of the treatment were significantly lower than those in the sham group. Interestingly, the improvement in Y-BOCS scores in patients with the LL genotype treated with active rTMS was significantly (p<0.05) greater than in those treated with sham rTMS. Conversely, rTMS did not produce significant improvements in S allele carriers.ConclusionsThe findings of this study suggest that rTMS can augment the beneficial effects of SSRIs in OCD patients with the LL genotype of 5-HTTLPR. Therefore, the presence of 5-HTTLPR (L/S) in SLC6A4 may be a predictable biomarker for the beneficial effects of rTMS, although more studies using larger sample sizes are warranted for confirming the results.

The Association between Serotonin Transporter Polymorphism, Platelet Serotonin Concentration and Insomnia in Non-Depressed Veterans with Posttraumatic Stress Disorder.

The role of serotonin transporter and its functional gene polymorphism (5-HTTLPR, serotonin transporter linked polymorphic region) was investigated in sleep disturbances in various mental disorders, with conflicting findings. Here, the association of particular sleep disturbances with 5-HTTLPR genotypes and platelet serotonin (5-HT) concentration was determined simultaneously in veterans with posttraumatic stress disorder (PTSD), who were subdivided into those with or without comorbid depression. Croatian male, medication-free war veterans with PTSD (N=325), subdivided into those with or without comorbid depression, and subdivided further according to the various sleep disturbances, were evaluated using the Structured Clinical Interview, the Hamilton Rating Scale for Depression and the Clinician Administered PTSD Scale. Genotyping and platelet 5-HT concentration measurements were conducted using PCR and spectrofluorimetric methods, respectively. Nominally higher frequency of the 5-HTTLPR LL genotype compared to S carriers (p=0.026; χ2 test) and significantly higher platelet 5-HT concentration (p=0.001; one-way ANOVA) were detected in non-depressed veterans with PTSD with early insomnia, compared to matched veterans without early insomnia. Over-representation of the LL genotype of the 5-HTTLPR and higher platelet 5-HT concentrations were detected in veterans with PTSD who did not develop comorbid depression but had severe early insomnia. These results suggest that 5-HTTLPR genotypes and platelet 5-HT concentration are associated with early insomnia in non-depressed veterans with PTSD. Limitations of the study were the cross-sectional nature of the study, biallelic assessment of the 5-HTTLPR, and a lack of use of the specific sleep measurement scales. These results should be replicated in larger samples, validated on different populations, using specific sleep measurement scales and triallelic 5-HTTLPR assessment.

The 5-HTTLPR polymorphism of the serotonin transporter gene and child's sex moderate the relationship between disaster-related prenatal maternal stress and autism spectrum disorder traits: The QF2011 Queensland flood study.

The 5-HTTLPR polymorphism of the serotonin transporter has been shown to play a role in autism spectrum disorders (ASD). Moreover, disaster-related prenatal maternal stress (PNMS) has also been shown to be associated with ASD. However, no study to date has examined whether these two factors, either individually or in combination, are predictive of ASD traits in the same sample. We hypothesized that children, particularly boys, with the LL genotype exposed to high levels of disaster-related PNMS would exhibit higher levels of ASD traits compared to boys with the LS or SS genotypes and girls regardless of genotype. Genotype and ASD levels obtained using the Australian normed Autism Spectrum Rating Scales - Short Form were available for 105 30-month-old children exposed to varying levels of PNMS following the 2011 Queensland Flood. For boys, higher ASD traits were associated with the 5-HTTLPR LL genotype in combination with either a negative maternal appraisal of the flood, or high levels of maternal composite subjective stress, PSTD-like or peritraumatic dissociation symptoms. For girls, maternal peritraumatic dissociation levels in combination with the 5-HTTLPR LS or SS genotype were associated with higher ASD traits. The present findings are the first to demonstrate that children's genotype moderates effects of disaster-related PNMS on ASD traits, with different pattern according to child sex.

Serotonin transporter 5-HTTLPR genotype is associated with intrusion and avoidance symptoms of DSM-5 posttraumatic stress disorder (PTSD) in Chinese earthquake survivors

ABSTRACTBackground and Objectives: Prior studies have found that the serotonin transporter gene-linked polymorphic region (5-HTTLPR) interacts with trauma exposure to increase general risk for Posttraumatic Stress Disorder (PTSD). However, there is little knowledge about the effects of the interaction on distinct symptom clusters of PTSD. This study aimed to investigate the relation between the interaction of 5-HTTLPR and earthquake-related exposures and a contemporary phenotypic model of DSM-5 PTSD symptoms in a traumatised adult sample from China.Design: A cross-sectional design with gene-environment interaction (G × E) approach was adopted. Methods: Participants were 1131 survivors who experienced 2008 Wenchuan earthquake. PTSD symptoms were assessed with the PTSD Checklist for DSM-5 (PCL-5). The 5-HTTLPR polymorphism was genotyped with capillary electrophoresis (CE) in ABI 3730xl genetic Analyzer.Results: Although there was no significant interaction between 5-HTTLPR and traumatic exposure on total PTSD symptoms, respondents with the LL genotype of 5-HTTLPR who were highly exposed to the earthquake experienced lower intrusion and avoidance symptoms than those with the S-allele carriers.Conclusions: The findings suggest that the 5-HTTLPR may have an important impact on the development of PTSD and add to the extant knowledge on understanding and treating of posttraumatic psychopathology.

Serotonin transporter gene (SLC6A4) polymorphisms are associated with response to fluoxetine in south Indian major depressive disorder patients

Up to 30-40% of the major depressive disorder patients do not respond sufficiently to antidepressant treatment. Genetic variations in the serotonin transporter gene have been implicated in modulating treatment response to selective serotonin reuptake inhibitors, and this association is influenced by ethnicity. We investigated the influence of serotonin transporter gene variants 5-HTTLPR and rs25531 in Indian population on fluoxetine response. One hundred and two major depressive disorder patients were started on fluoxetine treatment and after 6weeks, classified as responders (n=56) and non-responders (n=46) using Hamilton depression rating scale and genotyped. Fisher's exact test was used to compare genotype frequencies between responders and non-responders. One-way analysis of variance and student t test were used to compare the percentage reduction (week 0-6) in Hamilton depression rating scores between genotype and haplotype groups. We observed a significant association between LL genotype of 5-HTTLPR and fluoxetine treatment response (p=0.0066, OR (95%)=4.0 (1.45-11.03)) but not with the functional groups of 5-HTTLPR -rs25531. However, there was a significant difference in percentage reduction in HAM-D scores (week 0-6) between 5-HTTLPR genotypes (LL vs. LS+SS, p=0.0036; LL vs. LS, p=0.0109) as well as the functionally grouped haplotypes of 5-HTTLPR -rs25531 (LALA carriers vs. non-carriers of LALA, p=0.0118; LALA vs. LAS+ LALG, p=0.0419). The LL genotype and LALA haplotype of SLC6A4 are associated with favorable treatment response to fluoxetine in south Indian major depression patients.

Abstract WMP90: Homozygous Short Variation Allele Genotype of the Serotonin-Transporter-Linked Polymporphic Region (5-HTTLPR) is Associated Post-Sstroke Depression- A Meta-analysis

Aim: Polymorphisms of the genes for encoding serotonin transporter, specifically, the length variation in the serotonin-transporter-linked polymorphic region (5-HTTLPR), a single nucleotide polymorphisms, in the 5-HTTLPR (RS25531), and variable number of tandem repeats (VNTR) in the second intron 2 (STin2) have been implicated in the development of post-stroke depression (PSD). We aimed at evaluating this association in the published literature. Methods: Random-effects meta-analyses were conducted among studies examining the relations between the polymorphisms of the genes encoding serotonin transporter and the risk of developing PSD. Meta-regression identified patient- and study-related factors that may contribute to heterogeneity. Results: Five studies consisting of patients suffering from PSD and stroke patients without PSD were included. Our analyses showed statistically significant evidence of the positive association between the homozygous short (S) variation allele genotype of the 5-HTTLPR (SS) and PSD (random-effects pooled odds ratio (OR) = 2.05, 95% Confidence Interval (CI) = 1.41-2.98, Z =3.79, p&lt; 0.001 ). Our analyses also showed significant evidence of a negative association between the homozygous long (L) variation alleles of the 5-HTTLPR (LL) and PSD (random-effects OR = 0.52, 95% CI = 0.27-0.97, Z =- 2.07, p= 0.039). No statistically significant association of PSD with either heterozygous Short and Long allele genotype for the 5-HTTLPR or other polymorphisms with the RS25531 and the STin2 VNTR were found. Conclusion: Our meta-analysis suggests that the 5-HTTLPR SS genotype may be a risk factor for PSD while the 5-HTTLPR LL genotype may be a candidate protective factor against PSD

A human laboratory pilot study with baclofen in alcoholic individuals

Preclinical and clinical studies show that the GABAB receptor agonist baclofen may represent a pharmacotherapy for alcohol dependence (AD). However, the mechanisms by which baclofen affects drinking are not well characterized; thus this pilot study investigated possible baclofen's biobehavioral mechanisms. The design was a double-blind controlled randomized human laboratory pilot study. Fourteen non-treatment seeking alcohol-dependent heavy drinking subjects received either baclofen 10mg t.i.d. or an active placebo (cyproheptadine 2mg t.i.d., to control for sedation) for a 7-day period. At day 8, participants performed an alcohol cue-reactivity (CR) followed by an alcohol self-administration (ASA). Additionally, we explored possible moderators that might guide future larger studies, i.e. anxiety, family history and onset of alcoholism, and D4 dopamine receptor (DRD4) and 5-HTTLPR polymorphisms. The main results were a significant effect of baclofen for increasing stimulation (p=.001) and sedation (p<.01). Furthermore, when drinking during the ASA and the 2days before was analyzed as a composite variable, there was a significant effect of baclofen to reduce alcohol consumption (p<.01). As for the exploratory analyses, baclofen's effects to increase alcohol sedation and to reduce alcohol consumption were limited to those individuals with DRD4 ≥7 repeats (DRD4L). Yet, baclofen's effects on alcohol consumption were also moderated by 5-HTTLPR LL genotype. In conclusion, baclofen's ability to reduce alcohol drinking may be related to its effects on the biphasic effects of alcohol, but larger studies are needed to confirm these preliminary findings.

Polymorphisms of the serotonin transporter gene and post-stroke depression: a meta-analysis

BackgroundPolymorphisms of the gene encoding the serotonin transporter—specifically, length variation in the serotonin-transporter-linked polymorphic region (5-HTTLPR), a single-nucleotide polymorphism in the 5-HTTLPR (rs25531), and variable number of tandem repeats (VNTR)...

Serotonin receptor 3A polymorphism c.-42C &gt; T is associated with severe dyspepsia

BackgroundThe association between anxiety and depression related traits and dyspepsia may reflect a common genetic predisposition. Furthermore, genetic factors may contribute to the risk of having increased visceral sensitivity, which has been implicated in dyspeptic symptom generation. Serotonin (5-HT) modulates visceral sensitivity by its action on 5-HT3 receptors. Interestingly, a functional polymorphism in HTR3A, encoding the 5-HT3 receptor A subunit, has been reported to be associated with depression and anxiety related traits. A functional polymorphism in the serotonin transporter (5-HTT), which terminates serotonergic signalling, was also found associated with these psychiatric comorbidities and increased visceral sensitivity in irritable bowel syndrome, which coexistence is associated with higher dyspeptic symptom severity. We investigated the association between these functional polymorphisms and dyspeptic symptom severity.MethodsData from 592 unrelated, Caucasian, primary care patients with dyspepsia participating in a randomised clinical trial comparing step-up and step-down antacid drug treatment (The DIAMOND trial) were analysed. Patients were genotyped for HTR3A c.-42C > T SNP and the 44 bp insertion/deletion polymorphism in the 5-HTT promoter (5-HTTLPR). Intensity of 8 dyspeptic symptoms at baseline was assessed using a validated questionnaire (0 = none; 6 = very severe). Sum score ≥20 was defined severe dyspepsia.ResultsHTR3A c.-42T allele carriers were more prevalent in patients with severe dyspepsia (OR 1.50, 95% CI 1.06-2.20). This association appeared to be stronger in females (OR 2.05, 95% CI 1.25-3.39) and patients homozygous for the long (L) variant of the 5-HTTLPR genotype (OR 2.00, 95% CI 1.01-3.94). Females with 5-HTTLPR LL genotype showed the strongest association (OR = 3.50, 95% CI = 1.37-8.90).ConclusionsThe HTR3A c.-42T allele is associated with severe dyspeptic symptoms. The stronger association among patients carrying the 5-HTTLPR L allele suggests an additive effect of the two polymorphisms. These results support the hypothesis that diminished 5-HT3 mediated antinociception predisposes to increased visceral sensitivity of the gastrointestinal tract. Moreover, the HTR3A c.-42C > T and 5-HTTLPR polymorphisms likely represent predisposing genetic variants in common to psychiatric morbidity and dyspepsia.

Interaction of chronic stress with serotonin transporter and catechol-O -methyltransferase polymorphisms in predicting youth depression

Investigations of gene-environment interaction (GxE) in depression have implicated a polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) as a moderator of the stress-depression relationship. However, recent evidence for 5-HTTLPR GxE in depression has been inconsistent. This study examined the moderating effect of the val158met polymorphism in the catechol-O-methyltransferase (COMT) gene on the strength of 5-HTTLPR GxE. A community sample of youth (n=384) was genotyped for 5-HTTLPR and COMT. A multi-method, multi-informant index of chronic family stress was derived from interviews and questionnaires administered at youth age 15. GxGxE was examined in relation to depression diagnoses between ages 15 and 20 and depressive symptoms at age 20. Significant three-way interactions were observed for both depressive symptoms and diagnoses, such that 5-HTTLPR GxE occurred only in the context of COMT val158 allele homozygosity. For val158 homozygotes, the 5-HTTLPR LL genotype exerted a protective effect in the face of stress. No genetic main effect or two-way GxE was found for 5-HTTLPR. Inconsistent 5-HTTLPR GxE findings to date may be partly attributable to unmeasured epistatic effects between 5-HTTLPR and COMT val158met. Identifying the conditions under which 5-HTTLPR GxE is most likely to operate may allow depression prevention and treatment efforts to target youth at highest risk.

The serotonin transporter promoter polymorphism (5-HTTLPR) is associated with type 2 diabetes

Background The serotonergic system contributes substantially to the regulation of glucose homeostasis and feeding. 5-HTTLPR is a serotonin transporter (5-HTT) gene-linked polymorphic region that regulates the transcriptional activity of 5-HTT. Our aim was to investigate the possible association of 5-HTTLPR polymorphism with type 2 diabetes mellitus and obesity. Methods Study population consisted of 252 subjects diagnosed with Type 2 DM and 211 non-diabetic subjects, all Caucasians of Greek ethnic origin. Genomic DNA was extracted from peripheral blood and analyzed for 5-HTTLPR polymorphism with a novel PCR protocol. Results The frequency of SS and SL genotypes of HTTLPR was significantly higher in the diabetic group (77.0%) than in the non-diabetic group (61.6%) ( P < 0.001). The genetic risk of Type 2 DM for subjects carrying at least one S allele was increased compared to non-diabetic subjects (OR = 2.08, 95% CI = 1.39–3.12). When subjects were divided according to BMI status, the frequency of S allele carriers was similar in obese and non-obese subjects. Conclusions The S allele of 5-HTTLPR is strongly associated with the presence of Type 2 DM. This association appears to be direct and not dependent on obesity status. Therefore, 5-HTTLPR LL genotype might be protective for development of Type 2 DM.

Association of serotonin transporter gene linked polymorphic region polymorphism with early onset myocardial infarction and platelet membrane glycoprotein I b

To investigate the association of serotonin transporter gene linked polymorphic region (5-HTTLPR) insertion/deletion polymorphism with early onset myocardial infarction(MI) and platelet membrane glycoprotein I b(GP I b) in Northern Han population of China. A total of 150 patients with early onset MI and 150 age- and sex-matched controls with negative coronary arteriography were genotyped for the 5-HTTLPR polymorphism by using a polymerase chain reaction-based technique. The percentage of positive platelet membrane GP I b and the average fluorescence intensity were quantified by flow cytometry. The genotype frequencies of LL, LS and SS in the 5-HTTLPR were 32%, 47% and 21% in the MI patients, 17%, 43% and 39% in the controls respectively(P<0.01). The L allele frequency in the MI patients was significantly higher than that of the control group (56% vs 39%, P<0.01). The percentage of positive platelet membrane GP I b and the fluorescence intensity in subjects with LL homozygote were markedly lower than that of LS and SS genotypes in the MI and control groups (all P<0.01). Multivariate logistic regression analysis showed that the 5-HTTLPR LL genotype was independently related to the occurrence of early onset MI(OR was 1.961, P was 0.037). The LL genotype of the 5-HTTLPR might be associated with the susceptibility to developing early MI in Northern Han population of China. The platelet activation is increased in individuals of LL genotype.

Interaction between the 5-HTTLPR serotonin transporter polymorphism and environmental adversity for mood and anxiety psychopathology: evidence from a high-risk community sample of young adults

Previous research examining gene-environment interaction (GxE) with regard to vulnerability to depression and anxiety has yielded conflicting results. The present study was designed to further investigate GxE between 5-HTTLPR and exposure to environmental adversity, using different phenotypic and genotypic characterizations as well as different types of adversity within a prospective study design. Data were available from an ongoing epidemiological cohort study following the outcome of early risk factors from birth to adulthood. At age 19 yr, 309 participants (142 males, 167 females) were characterized on measures of depression and anxiety through interview and questionnaire (DSM-IV diagnosis, Beck Depression Inventory, Harm Avoidance). Environmental adversity was assessed at birth (family adversity), and at age 19 yr (stressful life events). Bi- and tri-allelic 5-HTTLPR genotypes were obtained from genomic DNA. Results indicated that depression and anxiety in 19-yr-olds were strongly associated with both family adversity and stressful life events. Individuals with the LL genotype of 5-HTTLPR who were exposed to high family adversity displayed significantly higher rates of depressive or anxiety disorders and had more depressive symptoms than those without either condition. This GxE replicates recent findings from an epidemiological cohort study of adolescents but is in contrast to many previous reports suggesting an interaction with the S allele. No evidence for GxE was obtained with regard to current stressful life events and trait anxiety. One possible source for the conflicting findings might be attributed to heterogeneity in depression phenotypes and environmental adversity.

A functional serotonin transporter promoter gene polymorphism increases ADHD symptoms in delinquents: Interaction with adverse childhood environment

Although attention-deficit/hyperactivity disorder (ADHD) is highly heritable, environmental conditions play an important role in its manifestation during childhood development. Here, we report the results of an investigation on the interaction of adverse childhood environment with a functional polymorphism of the serotonin transporter promoter gene (5-HTTLPR) and its impact on ADHD psychopathology in young adult delinquents. Standardized instruments were used to assess childhood and current ADHD and adverse childhood environment in 184 male delinquents. Each subject was genotyped for 5-HTTLPR long (L) and small (S) alleles. Logistic regression analysis revealed independent effects of high childhood environmental adversity and the 5-HTTLPR LL-genotype on self-reported childhood ADHD and on persistent ADHD. In addition, a significant gene by environment interaction was found, indicating that carriers of at least one 5-HTTLPR short allele are more sensitive to childhood environment adversity than carriers of the LL-genotype. The results support prior findings of association between ADHD and 5-HTTLPR LL-genotype and adverse childhood environment, and they underline the need for further investigation of gene by environment interaction with respect to ADHD.

Serotonin transporter polymorphism (5-HTTLPR) association with melancholic depression: a female specific effect?

Earlier studies yielded inconsistent results on the association between variation in the serotonin transporter (5-HTT) gene and depression, with evidence for a differential effect of the 5-HTTLPR on melancholic versus atypical depression. To further delineate the impact of 5-HTT gene variation on psychopathology in depression, in this analysis the influence of the 5-HTTLPR and the functionally closely related 5-HTT rs25531 was investigated in 340 Caucasian patients with a major depressive episode (DSM-IV) with particular attention to the subtype of depression (melancholic depression versus atypical depression) applying logistic regression models adjusted for age and gender. The homozygous, more active 5-HTTLPR LL genotype was significantly associated with melancholic depression (odds ratio, OR, 1.7; 95% confidence interval, CI, 1.1-2.6; P=0.04), with the effect originating in the female subgroup of patients (OR 1.9; 95%CI 1.0-3.4; P=0.05). Also, the more active 5-HTTLPR/5-HTT rs25531 haplotype L(A)L(A) conveyed a significant risk for melancholic depression (OR 2.0; 95%CI 1.3-3.1; P=0.001), again only in the female subsample of patients (OR 2.1; 95%CI 1.1-4.1; P=0.02). The present results provide further support for an association of genetic variation increasing serotonin transporter activity with the melancholic subtype of depression as well as evidence for a potential female-specific mechanism underlying this effect.

52. Reverse pharmacogenetics: a new approach to rapid relapse in schizophrenia?

A significant subgroup of patients with schizophrenia experience rapid exacerbations in clinical symptoms following antipsychotic drug discontinuation. There are limited clinical or biological data with which to predict which patients are at increased risk for rapid relapse. New assessment tools that provide more accurate risk-benefit profiles for individual patients may be of use in determining clinical management strategies of patients at high risk for medication discontinuation. Previously, we have examined the role of a functional polymorphism (5-HTTLPR) in the serotonin transporter gene in antipsychotic drug-free patients participating in a placebo-controlled clinical trial. In this study, the clinical profile of 50 schizophrenia patients was assessed with the Brief Psychiatric Rating Scale (BPRS) after 4 weeks of placebo administration. Analysis by genotype revealed that the 5-HTTLPR ll genotype was markedly over-represented in the group of patients with increased BPRS ratings of positive symptoms (p = 0.0003). Patients with the 5-HTTLPR ll genotype were also observed to experience greater negative symptoms, anxiety and depression BPRS ratings. Although these data are preliminary, they suggest that studies of genetic variation may provide a means to identify schizophrenia patients at high risk for rapid relapse following drug discontinuation. New studies are underway to assess the merits of this reverse pharmacogenetics approach.