Triallelic 5-HTTLPR Polymorphism Research Articles

Unraveling the Contribution of Serotonergic Polymorphisms, Prefrontal Alpha Asymmetry, and Individual Alpha Peak Frequency to the Emotion-Related Impulsivity Endophenotype

The unique contribution of the serotonin transporter-linked polymorphic region (5-HTTLPR), intronic region 2 (STin2), and monoamine oxidase A (MAO-A) genes to individual differences in personality traits has been widely explored, and research has shown that certain forms of these polymorphisms relate to impulsivity and impulsivity-related disorders. Humans showing these traits are also described as having an asymmetrical prefrontal cortical activity when compared to others. In this explorative study, we examine the relationship between serotonergic neurotransmission polymorphisms, cortical activity features (prefrontal alpha asymmetry, individual alpha peak frequency [iAPF]), emotion-related and non-emotion-related impulsivity in humans. 5-HTTLPR, MAO-A, and STin2 polymorphisms were assessed in blood taken from 91 participants with high emotion-related impulsivity levels. Sixty-seven participants completed resting electroencephalography and a more comprehensive impulsivity index. In univariate analyses, iAPF correlated with both forms of emotion-related impulsivity. In multiple linear regression models, 5-HTTLPR polymorphism (model 1, adj. R2 = 15.2%) and iAPF were significant interacting predictors of emotion-related impulsivity, explaining a large share of the results’ variance (model 2, adj. R2 = 21.2%). Carriers of the low transcriptional activity 5-HTTPLR and MAO-A phenotypes obtained higher emotion-related impulsivity scores than others did. No significant results were detected for non-emotion-related impulsivity or for a form of emotion-related impulsivity involving cognitive/motivational reactivity to emotion. Our findings support an endophenotypic approach to impulsivity, showing that tri-allelic 5-HTTLPR polymorphism, iAPF, and their interaction are relevant predictors of one form of emotion-related impulsivity.

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.

Sex-specific pathways among tri-allelic serotonin transporter polymorphism, trait neuroticism and generalized anxiety disorder.

Neuroticism personality trait is recognized as an important endophenotypic predictor of generalized anxiety disorder (GAD). Furthermore, endophenotype-based pathway approaches have recently been shown to have greater advantages for gene-finding strategies than traditional case-control studies. In the present study, in addition to conventional case-control methods, we used pathway analyses to test whether the tri-allelic serotonin transporter promoter polymorphism (combining 5-HTTLPR and rs25531) is associated with risk of GAD through its effects on trait neuroticism. We included 2236 Han Chinese adults in this study, including 736 patients with GAD and 1500 healthy participants. We genotyped the 5-HTTLPR and rs25531 polymorphisms using the polymerase chain reaction restriction fragment length polymorphism method. We used the Neuroticism scale of the Maudsley Personality Inventory (MPI) short version (MPI-Neuroticism) to measure participants' tendency toward neuroticism. Using endophenotype-based path analyses, we found significant indirect effects of the tri-allelic genotype on risk of GAD, mediated by MPI-Neuroticism in both men and women. Compared to women carrying the S'S' genotype, women carrying the L' allele had higher levels of MPI-Neuroticism, which in turn were associated with higher risk of GAD. Men, however, showed the opposite pattern. Using traditional case-control comparisons, we observed that the effect of tri-allelic genotype on GAD was significant, but only in women. Participants were restricted to Han Chinese, and we used only 1 questionnaire to assess neuroticism. These findings are the first to show that the triallelic 5-HTTLPR polymorphism is associated with elevated risk of GAD, and that this effect is mediated via increased trait neuroticism, a sex-dependent risk pathway.

AB081. Biallelic and triallelic 5-HTTLPR polymorphisms and their relationship with lifelong premature ejaculation: a case-control study from a Chinese population

BackgroundThe study aimed to explore the relationship between premature ejaculation (PE) and the serotonin transporter gene-linked polymorphic region (5-HTTLPR) with respect to the biallelic and triallelic classifications.MethodsA total of 115 outpatients who complained of ejaculating prematurely and were diagnosed as lifelong premature ejaculation (LPE) and 101 controls without PE complaint were recruited. All subjects completed a detailed questionnaire and were genotyped for 5-HTTLPR polymorphism using PCR-based technology. Associations between 5-HTTLPR allelic and genotypic frequencies and their association with LPE, and the intravaginal ejaculation latency time (IELT) of different 5-HTTLPR genotypes among LPE patients were evaluated.ResultsThe patients and controls didn’t differ significantly in terms of any characteristic except age. The results showed no significant difference regarding the biallelic 5-HTTLPR. According to the triallelic classification, no significant difference was found comparing the genotypic distribution (P=0.091). However, the distribution of the S, LG and LA alleles in the cases was significantly different from the controls (P=0.018). We found a significantly lower frequency of LA allele and higher frequency of LG allele in patients. Based on another classification by expression, we found a significantly lower frequency of the L/L genotype (OR =0.37; 95% CI: 0.15–0.91, P=0.025) in patients with LPE. No significant association was detected between IELT of LPE and different genotypes.ConclusionsContrary to the general classification based on S/L alleles, triallelic 5-HTTLPR was associated with LPE. Triallelic 5-HTTLPR may be a promising field for genetic research of PE to avoid false negative results in future studies.

AB090. Biallelic and triallelic 5-HTTLPR polymorphisms and their relationship with lifelong premature ejaculation: a case-control study from a Chinese population

ObjectiveThe study aimed to explore the relationship between premature ejaculation (PE) and the serotonin transporter gene-linked polymorphic region (5-HTTLPR) with respect to the biallelic and triallelic classifications.MethodsA total of 115 outpatients who complained of ejaculating prematurely and were diagnosed as LPE and 101 controls without PE complaint were recruited. All subjects completed a detailed questionnaire and were genotyped for 5-HTTLPR polymorphism using PCR-based technology. Associations between 5-HTTLPR allelic and genotypic frequencies and their association with LPE, and the intravaginal ejaculation latency time (IELT) of different 5-HTTLPR genotypes among LPE patients were evaluated.ResultsThe patients and controls didn’t differ significantly in terms of any characteristic except age. The results showed no significant difference regarding the biallelic 5-HTTLPR. According to the triallelic classification, no significant difference was found comparing the genotypic distribution (P=0.091). However, the distribution of the S, LG and LA alleles in the cases was significantly different from the controls (P=0.018). We found a significantly lower frequency of LA allele and higher frequency of LG allele in patients. Based on another classification by expression, we found a significantly lower frequency of the L’L’ genotype (OR =0.37; 95% CI =0.15–0.91, P=0.025) in patients with LPE. No significant association was detected between IELT of LPE and different genotypes.ConclusionsContrary to the general classification based on S/L alleles, triallelic 5-HTTLPR was associated with LPE. Triallelic 5-HTTLPR may be a promising field for genetic research of PE to avoid false negative results in future studies.

The serotonin transporter gene (triallelic 5-HTTLPR polymorphism) may associate with male depression in Han Chinese population

Background: Pharmacological, neurobehavioral, and therapeutic evidence have implicated serotonin in the pathogenesis of depression. There are conflicting reports on the association of genetic variants of serotonin transporter gene (5-HTTLPR) with major depressive disorder. The 5-HTTLPR is thought to have three primary allelic variants (rs25531): LA, LG, and S. The present study examined whether major depression was associated with tri-allelic 5-HTTLPR polymorphisms in a Han Chinese population. Materials and Methods: Bi-allelic and tri-allelic 5-HTTLPR polymorphisms were assessed in 305 patients with major depressive disorder (MD) and 313 unrelated healthy control subjects. In addition, to reduce clinical heterogeneity, subtype analyses were performed for clinically important variables, including family history of major affective disorder, age at onset, and severity of MD. Results: The bi-allelic 5-HTTLPR polymorphism was not associated with MD and its clinical subgroups. However, the tri-allelic 5-HTTLPR polymorphism was associated with major depression and with specific subgroups. In particular, in male subjects, patients with a low expressing genotype ( S'/S' ) were at higher risk for MD than those with high expressing genotypes ( S'/L' and L'/L' ). This positive association was only observed in the subgroups of late-onset and moderate severity MD. Conclusions: The present study suggests that the tri-allelic 5-HTTLPR polymorphism might be a risk factor for susceptibility to either MD or its clinical subtypes in the Han Chinese male population but not in the female population. However, these results should be validated in a larger patient population that includes different ethnic samples or subdiagnosis groups.

5-HTTLPR moderates naltrexone and psychosocial treatment responses in heavy drinking men who have sex with men.

A functional polymorphism (5-HTTLPR) in the promoter region of the serotonin transporter gene has been widely studied as a risk factor and moderator of treatment for a variety of psychopathologic conditions. To evaluate whether 5-HTTLPR moderates the effects of treatment to reduce heavy drinking, we studied 112 high-functioning European-American men who have sex with men (MSM). Subjects participated in a randomized clinical trial of naltrexone (NTX) and cognitive behavioral therapy (CBT) for problem drinking. Subjects were treated for 12 weeks with 100 mg/d of oral NTX or placebo (PBO). All participants received medical management with adjusted brief behavioral compliance enhancement treatment (BBCET) alone or in combination with modified behavioral self-control therapy (MBSCT; an amalgam of motivational interviewing and CBT). Participants were genotyped for the tri-allelic 5-HTTLPR polymorphism (i.e., low-activity S' or high-activity L' alleles). During treatment, the number of weekly heavy drinking days (HDD; defined as 5 or more standard drinks per day) was significantly lower in subjects with the L'L' (N = 26, p = 0.015) or L'S' (N = 52, p = 0.016) genotype than those with the S'S' (N = 34) genotype regardless of treatment type. There was a significant interaction of genotype with treatment: For subjects with the S'S' genotype, the effects of MBSCT or NTX on HDD were significantly greater than the minimal intervention (i.e., BBCET or PBO, p = 0.007 and p = 0.049, respectively). In contrast, for subjects with 1 or 2 L' alleles, the effects of the more intensive psychosocial treatment (MBSCT) or NTX did not significantly differ from BBCET or PBO. These preliminary findings support the utility of the 5-HTTLPR polymorphism for personalizing treatment selection in problem drinkers.

Bi-allelic and tri-allelic 5-HTTLPR polymorphisms and triptan non-response in cluster headache.

BackgroundTriptans are only effective in terminating cluster headache (CH) attacks in 70-80% of patients. Pharmacogenetic aspects of the serotonin metabolism, specifically variation in the 5-HTTLPR may be involved.MethodsGenetic association study in a well-defined cohort of 148 CH patients with information on drug response to triptans. CH was diagnosed according to the criteria of the International Headache Society. Genotypes of the 43-bp insdel (rs4795541) and A > G (rs25531) polymorphisms in the 5-HTTLPR promoter region were detected by restriction fragment length polymorphism analysis. We used logistic regression analysis to investigate the association between bi-allelic and tri-allelic genotypes and triptan non-response with genotype models.ResultsMean age at study entry among patients was 44.6 ± 10.5 years, 77.7% were men. The genotype distribution both for the bi-allelic and the tri-allelic polymorphism was in Hardy-Weinberg equilibrium. We did not find an association of the bi-allelic polymorphism with triptan non-response. While the effect estimates for the S variant of the tri-allelic polymorphisms suggested increased odds of triptan non-response in CH patients (multivariable-adjusted odds ratio [95% confidence interval]: L*L* genotype—reference; L*S* genotype—1.33 [0.53-3.32]; S*S* genotype—1.46 [0.54-3.98]), the results were not statistically significant.ConclusionsData from our study do not indicate a role of bi-allelic and tri-allelic genotypes of the 5-HTTLPR polymorphism in triptan non-response in CH.

Topiramate for alcoholism treatment: novel pharmacogenetic evidence for the journey to personalized medicine?

The small number of medications approved for the treatment of alcoholism is, by itself, an important justification for the significant efforts directed towards medication development. Perhaps an even more important issue is why a medication (approved or used off-label) does not always reproduce the same results across randomized clinical trials (RCTs). Indeed, even clinical trials that find effects report that there are both treatment responders and non-responders, and the ability to identify responders and non-responders could help explain variation across clinical trials. This variation forms the foundation of ‘personalized medicine’ approaches, and highlights the need to identify patient sub-types that respond better to a certain medication. Although typologies (Leggio et al., 2009) provide phenotypic traits that may be applied in RCTs, pharmacogenetics (Heilig et al., 2011) represents an even more compelling approach, as it is more reproducible, biologically-based and mechanistic. Although in its infancy, the alcoholism pharmacotherapy literature has already shown the potential value of pharmacogenetics as a way to develop personalized medicine. The functional OPRM1 polymorphism A118G plays an important role in the effects of naltrexone on alcohol consumption, with G-allele carriers responding more positively to treatment than A-allele homozygotes (Oslin et al., 2003; Anton et al., 2008; Barr et al., 2010; Kranzler et al., 2013). A functional polymorphism in the promoter region of the serotonin transporter gene, SLC6A4 , known as 5-HTTLPR, results in a long (L) and a short (S) allele. Alcoholic patients who were L homozygotes had significant reductions in alcohol use when treated with ondansetron, as compared to S carriers (Kenna et al., 2009b, 2014; Johnson et al., 2011, 2013). It has also been shown that the tri-allelic 5-HTTLPR polymorphism moderated the effects of sertraline and age at onset of alcohol dependence on the frequency of drinking and heavy drinking …

Study of the association of serotonin transporter triallelic 5-HTTLPR and STin2 VNTR polymorphisms with lithium prophylaxis response in bipolar disorder

The 5-hydroxy tryptamine transporter (5-HTT) gene has been previously implicated in lithium response, but the roles of the triallelic 5-HTT linked promoter region (5-HTTLPR) and variable number tandem repeats in the second intron [serotonin transporter intron 2 (STin2)] have not been reported. We examined these polymorphisms in 122 patients with bipolar I disorder, among which 49 patients were classified as good responders, 49 as nonresponders, and 24 as partial responders to lithium prophylaxis. We observed significant variation in the genotype frequencies of STin2 polymorphism among the response groups (P=0.02). There was also a significant association of haplotype consisting of the S allele of 5-HTTLPR and 10 repeat allele of STin2 with lithium response (P=0.01) and no such relationship was found with 5-HTTLPR variants. Our data support preliminary information of a possible association of STin2 and its combined effect with 5-HTTLPR variants with lithium response and also suggest that lithium is likely to be more effective for patients carrying 5-HTT polymorphisms associated with reduced transcriptional activity.

Independent effects of 5′ and 3′ functional variants in the serotonin transporter gene on suicidal behavior in the context of childhood trauma

The serotonin transporter, encoded by the SLC6A4 gene, influences the synaptic actions of serotonin and is responsive to stress hormones. We hypothesized that 5-HTTLPR, a functional SLC6A4 promoter polymorphism, and two tightly-linked, putatively functional 3′ UTR SNPs (rs3813034, rs1042173) might have independent effects on suicidal behavior in the context of childhood trauma (CT).DNA and Childhood Trauma Questionnaire scores were available for a total of 474 African Americans, including 112 suicide attempters and 362 non-suicide attempters. Genotyping was performed for the triallelic 5-HTTLPR polymorphism, 14 SLC6A4 haplotype-tagging SNPs, and 186 ancestry informative markers.There were independent G × E interactive effects of 5-HTTLPR (p = 0.017) and the rs3813034–rs1042173 diplotype (p = 0.011) on suicidal behavior. In individuals exposed to high CT the risk of suicide attempt was 0.52 in carriers of the low activity 5-HTTLPR variant and 0.32 in medium/high activity variant carriers. Likewise, CT exposed carriers of the major rs3813034–rs1042173 ATAT diplotype had an increased risk of suicidal behavior relative to the ATCG/CGCG diplotype carriers (0.40 vs 0.31). Neither the 5′ nor the 3′ functional variants had an effect in individuals without CT: suicide attempt risk = 0.12–0.22. In individuals exposed to high CT the prevalence of suicide attempt was 0.56 in carriers of both 5′ and 3′ risk variants, 0.39 in carriers of one risk variant and 0.25 in individuals without either risk variant.Our findings suggest that the 5′ and 3′SLC6A4 functional variants have independent effects on the risk for suicidal behavior in CT exposed individuals.

Short Sleep as an Environmental Exposure: A Preliminary Study Associating 5-HTTLPR Genotype to Self-Reported Sleep Duration and Depressed Mood in First-Year University Students

This study examined whether the 5-HTTLPR polymorphism in the SLC6A4 gene is associated with self-reported symptoms of depressed mood in first-year university students with a persistent pattern of short sleep. Students provided DNA samples and completed on-line sleep diaries and a mood scale during the first semester. A priori phenotypes for nocturnal sleep and mood scores were compared for the distribution of genotypes. Brown University, Providence, Rhode Island. A sample of 135 first-year students, 54 male, 71 Caucasian, mean age 18.1 (± 0.5) yr. None. Students completed on-line sleep diaries daily across the first term (21-64 days; mean = 51 days ± 11) and Center for Epidemiologic Studies-Depression (CES-D) mood scale after 8 wk. DNA was genotyped for the triallelic 5-HTTLPR polymorphism. Low-expressing S and L(G)polymorphisms were designated S', and high-expressing L(A) was designated L'. Phenotype groups were identified from a combination of CES-D (median split: high > 12; low < 13) and mean nocturnal total sleep time (TST) from diaries: (shorter ≤ 7 hr; longer ≥ 7.5 hr). Three genotypes were identified (S'S', S'L', L'L'); the S'S' genotype was present in a higher proportion of Asian than non-Asian students. FOUR PHENOTYPE GROUPS WERE COMPARED: 40 students with shorter TST/high CES-D; 34 with shorter TST/low CES-D; 29 with longer TST/high CES-D; 32 with longer TST/low CES-D. Female:male distribution did not vary across phenotype groups (chi-square = 1.39; df = 3; P = 0.71). S'S' participants (n = 23) were overrepresented in the shorter TST/high CES-D group (chi- square = 15.04; df = 6; P < 0.02). This association was sustained after removing participants with preexisting evidence of depressed mood (chi-square = 12.90; df = 6; P = 0.045). These data indicate that young adults who reported shorter nocturnal sleep and higher depressed mood are more likely than others to carry a variant of the SLC6A4 gene associated with low expression of the serotonin transporter.

The 5‐HTTLPR polymorphism moderates the effect of stressful life events on drinking behavior in college students of African descent

Covault et al. [Covault et al. (2007); Biol Psychiatry 61(5): 609-616] reported that the common functional polymorphism, 5-HTTLPR, in the serotonin transporter gene moderated the association between past-year stressful events and daily reports of drinking in a sample of European-American (EA) college students. We examined this effect in college students of African descent. Students recruited at a Historically Black University (n = 564) completed web-based measures of past-year stressful life experiences and daily reports of drinking and heavy drinking over a 30-day period. Participants were genotyped for the tri-allelic 5-HTTLPR polymorphism and dichotomized as low-activity S' allele carriers or high-activity L' homozygotes. Generalized linear models were used to examine the effects of life stress, genotype, and their interaction on the two drinking measures. In students who completed 15 or more daily surveys (n = 393), there was a significant interaction of past-year stressful events, 5-HTTLPR genotype, and gender on the number of drinking days (P = 0.002). Similar findings were obtained in relation to heavy drinking days (P = 0.007). Men showed a main effect of past-year stressful events on both drinking outcomes (P's < 0.001), but no main or moderator effects of genotype. In women, the S' allele moderated the impact of past-year life stressors on the frequency of drinking and heavy drinking days (P's < 0.001). In college students of African descent, past-year stressful events were associated with more frequent drinking and heavy drinking, an effect that was moderated by the 5-HTTLPR polymorphism. However, in contrast to the findings in EA students, in the current sample, 5-HTTLPR moderated the association only among women.

Association between suicide attempt and a tri-allelic functional polymorphism in serotonin transporter gene promoter in Chinese patients with schizophrenia

Mounting evidence supports the association between a polymorphism in the serotonin transporter gene promoter region (5-HTTLPR) and suicidal behaviour. Recently, a novel variant of the 5-HTTLPR L allele was identified. The previously unknown L G allele produced similar levels of gene expression to the S allele and might have been misclassified as a “high-expression” allele in previous association studies. In this study, we aimed to compare the genotype distribution of the tri-allelic 5-HTTLPR polymorphism in 168 Chinese patients with schizophrenia, including 60 suicide attempters and 108 non-suicide attempters. In our analysis, which used the L A dominant model, it was found that the L A allele carriers were significantly more likely to have attempted suicide ( p = 0.035). Further analysis showed this association existed only in male patients ( p = 0.012). A similar association between the L A allele and violent suicide attempt was also found ( p = 0.028). In addition, logistic regression confirmed our findings that male L A allele carriers were at a higher risk of suicide, although the lack of a significant association in females may reflect insufficient power due to small sample size. However, no association was found when we examined the traditional bi-allelic 5-HTTLPR. These findings differ from those reported in Caucasian subjects, where no associations have been reported. Different genetic backgrounds may give rise to different allelic distribution, causing differential effects on the expression of endophenotypes of suicide behaviours. Although the potential influence of multiple comparisons might weaken our findings, our study provides preliminary evidence for a potentially gender-specific role of a “high-expression” 5-HTTLPR polymorphism in susceptibility to suicide in Chinese patients with schizophrenia.

Variation in the gene encoding the serotonin transporter is associated with a measure of sociopathy in alcoholics

The present study examined the association between a measure of sociopathy and 5-HTTLPR genotype in a sample of individuals from Project MATCH, a multi-center alcohol treatment trial. 5-HTTLPR, an insertion-deletion polymorphism in SLC6A4, the gene encoding the serotonin transporter protein, results in functionally distinct long (L) and short (S) alleles. The S allele has been associated with a variety of psychiatric disorders and symptoms including alcohol dependence, but it is unknown whether 5-HTTLPR increases the risk for co-morbid sociopathy among those with alcohol dependence. Eight hundred sixty-two subjects diagnosed with alcohol dependence completed the California Psychological Inventory, a psychological assessment that includes a measure of socialization, which was used as a proxy measure of sociopathy. Subjects were genotyped for the insertion-deletion polymorphism, as well as a single nucleotide polymorphism (A→G) that is located in the inserted region. Regression analysis revealed that after controlling for age, which was negatively related to socialization score, 5-HTTLPR genotype interacted with sex to determine socialization score (P < 0.001). Males with the L'L' genotype (i.e. those homozygous for the L(A) allele) had lower socialization scores (i.e. greater sociopathy) than males who were carriers of the S' allele (P = 0.03). In contrast, women with the S'S' genotype had lower socialization scores than women with two L' alleles (P = 0.002) and tended to have lower Socialization Index of the California Psychological Inventory scores than women with one copy of the L' allele (P = 0.07). Among individuals with alcohol use disorders, the tri-allelic 5-HTTLPR polymorphism had opposite effects on socialization scores in men than women. The basis for this finding is unknown, but it may have implications for sub-typing alcoholics.

The 5-HTTLPR polymorphism of the serotonin transporter gene and short term behavioral response to methylphenidate in children with ADHD

BackgroundAnimal models of ADHD suggest that the paradoxical calming effect of methylphenidate on motor activity could be mediated through its action on serotonin transmission. In this study, we have investigated the relationship between the 5-HTTLPR polymorphism in the serotonin transporter gene (SLC6A4) and the response of ADHD relevant behaviors with methylphenidate treatment.MethodsPatients between ages 6-12 (n = 157) were assessed with regard to their behavioral response to methylphenidate (0.5 mg/kg/day) using a 2-week prospective within-subject, placebo-controlled (crossover) trial. The children were then genotyped with regard to the triallelic 5-HTTLPR polymorphism in the SLC6A4 gene. Main outcome measure: Conners' Global Index for parents (CGI-Parents) and teachers (CGI-Teachers) at baseline and at the end of each week of treatment with placebo and methylphenidate. For both outcome measurements, we used a mixed model analysis of variance to determine gene, treatment and gene × treatment interaction effects.ResultsMixed model analysis of variance revealed a gene × treatment interaction for CGI-Parents but not for CGI-Teachers. Children homozygous for the lower expressing alleles (s+lG = s') responded well to placebo and did not derive additional improvement with methylphenidate compared to children carrying a higher expressing allele (lA). No genotype main effects on either CGI-Parents or CGI-teachers were observed.ConclusionsA double blind placebo-controlled design was used to assess the behavioral effects of methylphenidate in relation to the triallelic 5-HTTLPR polymorphism of the SLC6A4 gene in children with ADHD. This polymorphism appears to modulate the behavioral response to methylphenidate in children with ADHD as assessed in the home environment by parents. Further investigation is needed to assess the clinical implications of this finding.Trial RegistrationClinicalTrials.gov NCT00483106

The symptomatic profile of panic disorder is shaped by the 5-HTTLPR polymorphism

The short allele of a functional polymorphism (5-HTTLPR) in the serotonin transporter (5-HTT) promoter is associated with reduced serotonin transporter expression, lower in vivo 5-HTT binding, higher neuroticism and amygdala reactivity as well as facilitated fear conditioning and is a candidate variant for panic disorder. However, case–control studies have consistently failed to show an association between 5-HTTLPR and panic disorder. As psychiatric disorders are broadly defined phenotypes merging different symptoms to syndromes, they may not be very well suited for genetic association studies. An alternative approach is to measure symptoms along continuous symptom dimensions which may more appropriately reflect their biological underpinnings and may reveal subpopulations within clinical diagnostic groups. We recorded the symptomatic profile in 73 in panic disorder patients using observer-rated instruments (Panic Disorder Severity Scale, PDSS; Montgomery–Åsberg Depression Rating Scale, MADRS) and hypothesized more severe symptoms in patients carrying the 5-HTTLPR s-allele. We observed a strong association between bi- and triallelic 5-HTTLPR polymorphisms and the symptomatic profile. Carriers of the 5-HTTLPR s-allele suffered from most severe panic and depressive symptoms. Our data highlight the importance of defining appropriate phenotypes for psychiatric genetic studies and demonstrate that the 5-HTTLPR genotype may be related to the symptomatic profiles rather than to the vulnerability to develop panic disorder.

Differential Effects of Tri-Allelic 5-HTTLPR Polymorphisms in Healthy Subjects on Mood and Stress Performance After Tryptophan Challenge

Earlier data suggest that a polymorphism at the serotonin (5-HT) transporter gene (5-HTTLPR) may affect depression particularly in the face of stress due to interactions between 5-HT vulnerability and stress exposure. However, this interaction between 5-HT transporter-linked transcriptional promoter region (5-HTTLPR), 5-HT vulnerability and the affective effects of stress exposure has not yet been investigated. As participants with short-allele 5-HTTLPR genotypes may exhibit enhanced 5-HT vulnerability, this study examines the effects of tryptophan challenge on stress reactivity and performance in healthy participants with S'/S' vs L'/L' genotypes. Sixteen healthy subjects with homozygotic short alleles (S'/S'=S/L(G,) L(G)/L(G)) and 14 subjects with homozygotic long alleles (L'/L'=L(A)/L(A)) of the 5-HTTLPR were tested in a double-blind placebo-controlled design under acute stress exposure following tryptophan challenge or placebo. Although there were no 5-HTTLPR-related differences in stress responses, significant beneficial effects of tryptophan challenge on mood and stress performance were exclusively found in participants with S'/S' genotypes. These findings suggest greater brain 5-HT vulnerability to tryptophan manipulations in participants with S'/S' as compared with L'/L' 5-HTTLPR genotypes. This apparent genetic 5-HT vulnerability may become a meaningful risk factor for depression when brain 5-HT falls below functional need in the face of real severe stressful life events.

GENETIC STUDY: Tryptophan hydroxylase 2 gene and alcohol use among college students

Genes that regulate serotonin activity are regarded as promising predictors of heavy alcohol use. Tryptophan hydroxylase (TPH2) plays an important role in serotonergic neurotransmission by serving as the rate-limiting enzyme for serotonin biosynthesis in the midbrain and serotonergic neurons. Despite the link between TPH2 and serotonergic function, TPH2's role in the pathogenesis of alcohol-use disorders remains unclear. The goal of this study was to examine whether a variation in the TPH2 gene is associated with risky alcohol consumption. Specifically, this study examined whether the TPH2 G-703T polymorphism predicted alcohol consumption among college students. In two successive years, 351 undergraduates were asked to record their alcohol use each day for 30 days using an Internet-based electronic diary. Participants' DNA was collected and polymerase chain reaction genotyping was performed. Results show that alcohol consumption was not associated with the TPH2 G-703T polymorphism alone, or the interaction of TPH2 with two other candidate polymorphisms (TPH1 C218A and the SLC6A4 tri-allelic 5-HTTLPR), or negative life events. In conclusion, this study supports recent null findings relating TPH2 to drinking outcomes. It also extends these findings by showing null interactions with the TPH1 C218A polymorphism, the SLC6A4 tri-allelic 5-HTTLPR polymorphism and environmental stressors in predicting sub-clinical alcohol use among Caucasian American young adults.

Analysis of association of clinical correlates and 5‐HTTLPR polymorphism with suicidal behavior among Chinese methamphetamine abusers

Substance use disorders are familial, and genetic factors explain a substantial degree of their familial aggregation. Methamphetamine (MAP) abusers are commonly noted as having psychosis, depression and suicidal behavior. The goals of the present study were (i) to investigate relations of clinical correlates, such as gender, drug use behavior, psychiatric comorbidity and psychiatry family history, with suicidal behavior among Chinese MAP abusers; and (ii) to investigate whether there is an association between a polymorphism in the promotor region of the serotonin transporter gene (5-HTTLPR) and suicidal behavior among Chinese MAP abusers. A total of 439 MAP abusers from a hospital and detention center in Taipei were interviewed with the Diagnostic Interview for Genetic Study and the Family Interview for Genetic Study. The 5-HTTLPR polymorphism was compared between 94 MAP abusers with suicide attempts and 294 MAP abusers without suicide attempts, for whom DNA data were available. The results of the present study indicate that among MAP abusers in Taiwan, suicide attempts were significantly related to female gender, history of MAP-induced psychotic disorder, history of MAP-induced depressive disorder, and family history of psychotic disorders. Among suicide attempters, the attempters with moderate to severe lethality used higher MAP doses than those with minimal to mild lethality. In the present sample the triallelic 5-HTTLPR polymorphism (S, L(G), L(A)) was not associated with MAP-induced depressive disorder, MAP-induced psychotic disorder or suicidal behavior, but studies with larger sample sizes are warranted before excluding the role of the 5-HTTLPR polymorphisms in suicidal behavior among MAP abusers.