Associations between serotonin transporter gene promoter region (5-HTTLPR) polymorphism and gaze bias for emotional information.

The serotonin transporter promoter region polymorphism (5-HTTLPR) is associated with neural response to negative images in brain regions involved in the experience of emotion. However, the behavioral implications of this sensitivity have been studied far less extensively. The current study used eye-tracking methodology to examine how individuals genotyped for the 5-HTTLPR, including the single nucleotide polymorphism (SNP) rs25531, allocated attention during prolonged (30-s) exposure to face stimuli depicting positive and negative emotion. Short 5-HTTLPR allele carriers and carriers of the long allele with guanine at the sixth nucleotide (S/LG) displayed a stronger gaze bias (total fixation time, number of fixations, mean fixation length) for positive than for sad, threat, or neutral stimuli. In contrast, those homozygous for the long 5-HTTLPR allele with adenine at the sixth nucleotide (LA) viewed the emotion stimuli in an unbiased fashion. Time course analyses indicated no initial 5-HTTLPR group differences; however, S/LG 5-HTTLPR allele carriers were more likely than LA 5-HTTLPR homozygotes to direct gaze toward happy than toward sad stimuli over time. This bias toward positive stimuli during the later stages of information processing likely reflects a strategic effort to downregulate heightened reactivity to negative stimuli among 5-HTTLPR S/LG allele carriers. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Association between the serotonin transporter promoter polymorphism (5-HTTLPR) and adult unresolved attachment.

Research on antecedents of organized attachment has focused on the quality of caregiving received during childhood. In recent years, research has begun to examine the influence of genetic factors on quality of infant attachment. However, no published studies report on the association between specific genetic factors and adult attachment. This study examined the link between the 5-HTTLPR promoter polymorphism of the serotonin transporter gene and adult unresolved attachment assessed with the Adult Attachment Interview. Genetic material and information on attachment-related loss or trauma were available for 86 participants. Multivariate regression analyses showed an association between the short 5-HTTLPR allele and increased risk for unresolved attachment. Temperament traits and psychological symptoms did not affect the association between 5-HTTLPR and unresolved attachment. The authors hypothesize that the increased susceptibility to unresolved attachment among carriers of the short allele of 5-HTTLPR is consistent with the role of serotonin in modulation of frontal-amygdala circuitry. The findings challenge current thinking by demonstrating significant genetic influences on a phenomenon previously thought to be largely environmentally driven. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Serotonin transporter genetic variation and biased attention for emotional word stimuli among psychiatric inpatients.

The short allele in a variable repeat sequence of the promoter region of the serotonin transporter gene (5-HTTLPR) has been associated with stronger activation in brain regions critical for processing emotional stimuli. The authors examined whether variants of the 5-HTTLPR promoter polymorphism were also associated with individual differences in attentional biases for emotional stimuli. Words related to anxious and dysphoric emotional states were presented to psychiatric inpatients in a standard dot-probe reaction time task. Compared with participants with two long alleles, carriers of the short 5-HTTLPR allele exhibited a stronger attentional bias for anxious word stimuli. No genetic group difference was observed for dysphoric word stimuli. Findings from this preliminary study highlight the potential for integrating genetic and cognitive models of psychopathology. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The serotonin transporter promoter polymorphism and childhood positive and negative emotionality.

Association studies of the serotonin transporter promoter polymorphism (5-HTTLPR) and negative emotionality (NE) are inconclusive. However, emerging evidence suggests that the association between this polymorphism and NE may be influenced by levels of another temperament trait, positive emotionality (PE). Therefore, this study examined whether the association between the 5-HTTLPR and NE was moderated by PE. A community sample of 413 three-year-old children completed a standardized battery of laboratory tasks designed to tap temperamental emotionality. Children were also genotyped for the 5-HTTLPR. No direct association between 5-HTTLPR genotype and NE was found. However, the interaction of child PE and NE predicted 5-HTTLPR genotype. Furthermore, children with a short allele who were also low in PE had significantly greater NE than children without a short allele or children with high PE. Our findings suggest that the short allele of the 5-HTTLPR is associated with NE only in the context of low PE. Inconsistent links between NE and this gene in previous research may stem from the failure to consider other temperament traits that moderate associations. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Variation in the serotonin transporter gene modulates selective attention to threat.

The 5-HTTLPR is an insertion/deletion polymorphism in the promoter region of the serotonin transporter gene. Prior research has revealed associations between the short-allele variant of this polymorphism, enhanced self-reported negative emotionality, and hypersensitivity of fear relevant neural circuits. In a sample of 50 healthy women we examined the role of 5-HTTLPR for cognitive-affective processing of phylogenetical fear-relevant stimuli (spiders) in a dot probe task. In contrast to homozygote long-allele carriers (ll), participants carrying at least 1 short allele (ss and sl) selectively shifted attention toward pictures of spiders, when these were presented for a duration of 2,000 ms. These results argue for an involvement of 5-HTTLPR in cognitive processing of threatening stimuli and thus, underpin its general role for individual differences in negative affect. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The BDNF Val66Met polymorphism is associated with rumination in healthy adults.

This study examined associations between the tendency to ruminate and 2 polymorphisms: the Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene and 5-HTTLPR polymorphism in the serotonin transporter gene (SLC6A4). Participants were a homogeneous group of healthy, unmedicated, never depressed individuals with few current symptoms of depression (N = 71). Results indicated that met heterozygotes of the BDNF allele were significantly more likely to ruminate than individuals homozygous for the val BDNF allele. There was no association between rumination and the 5-HTTLPR polymorphism. Furthermore, the interaction between the 5-HTTLPR and BDNF polymorphisms did not predict rumination. Results suggest that variation in the BDNF gene may contribute to the tendency to ruminate. Because this association exists in healthy adults, it may represent a susceptibility factor for affective disorders. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Covariance structure of neuroticism and agreeableness: A twin and molecular genetic analysis of the role of the serotonin transporter gene.

The Revised NEO Personality Inventory domains of Neuroticism and Agreeableness are considered factorially distinct despite several intercorrelations between these domains. The genetic correlation, an index of the degree to which these intercorrelations are caused by genetic influences, was estimated using data from 913 monozygotic and 562 dizygotic volunteer twin pairs from Canada, Germany, and Japan. The serotonin transporter gene, 5-HTTLPR, was assayed in a sample of 388 nontwin sibling pairs from the US to determine the contribution of the serotonin transporter locus to the covariation between the Neuroticism and Agreeableness scales. In all four samples, genetic influences contributed to the covariance of Neuroticism and Agreeableness, with the serotonin transporter gene accounting for 10% of the relationship between these domains. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Biased processing of emotional information in girls at risk for depression.

Researchers have documented that children of depressed mothers are at elevated risk for developing a depressive disorder themselves. There is currently little understanding, however, of what factors place these children at elevated risk. In the present study, the authors investigated whether never-disordered daughters whose mothers have experienced recurrent episodes of depression during their daughters' lifetime are characterized by biased processing of emotional information. Following a negative mood induction, participants completed an emotional-faces dot-probe task. Daughters at elevated risk for depression, but not control daughters of never-disordered mothers, selectively attended to negative facial expressions. In contrast, only control daughters selectively attended to positive facial expressions. These results provide support for cognitive vulnerability models of depression. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Interaction effect of D4 dopamine receptor gene and serotonin transporter promoter polymorphism on the cortisol stress response.

Genetic variation of the serotonin transporter (SCL6A4, 5-HTT) has been associated with fear- and anxiety-related behaviors, while a polymorphism in exon III of the D4 dopamine receptor gene (DRD4) has been linked to novelty seeking. The dopaminergic and the serotonergic neurotransmitter system have been found to modulate the amygdala-connected circuitries that are crucial in emotional modulation and response to fearful stimuli. Additionally, reactivity of amygdala-innervated effector systems is also essential for our understanding of anxiety-related behaviors. Here, we used the stress-induced activation of the hypothalamic-pituitary-adrenal axis to investigate the impact of 5-HTTLPR and DRD4 on the cortisol stress response in 84 healthy adults. Saliva cortisol was measured during and after the Trier Social Stress Test. We found a significant main effect of DRD4: Carriers of the 7R allele exhibited lower cortisol responses. Additionally, a DRD4 by 5-HTTLPR interaction emerged: 5-HTTLPR LA/LA homozygotes showed a lower cortisol response than did S or LG allele carriers but only if they possessed at least one copy of the DRD4 7R allele. The results point to independent and joint effects of these polymorphisms on stress responsivity. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

5-HTTLPR status moderates the effect of early adolescent substance use on risky sexual behavior.

Objective: A longitudinal, prospective design was used to investigate a moderation effect in the association between early adolescent substance use and risky sexual behavior 2 years later. A genetic vulnerability factor, a variable nucleotide repeat polymorphism (VNTR) in the promoter region of the serotonin transporter gene SLC6A4, known as 5-HTTLPR, was hypothesized to moderate the link between substance use at age 14 and risky sexual behavior at age 16. This VNTR has been associated with risk-taking behavior. Design: African American youths in rural Georgia (N = 185) provided 2 waves of data on their substance use and sexual behavior. Genetic data were obtained via saliva samples. Main Outcome Measures: Substance use and sexual risk behavior were assessed using youth self-report items developed for this investigation. Results: Multiple regression analyses indicated that the presence of 1 or 2 copies of the short allele of the VNTR interacted with substance use to predict sexual behavior. Substance use had little effect on sexual behavior for youths without the short allele; this effect was greatly increased for youths with the short allele. Conclusion: Genetic vulnerability affected the implications of early onset substance use for later sexual behavior. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Selective attention to affective stimuli and clinical depression among youths: Role of anxiety and specificity of emotion.

Cognitive models of psychopathology posit that the content or focus of information-processing biases (e.g., attentional biases) is disorder specific: Depression is hypothesized to be characterized by attentional biases specifically for depression-relevant stimuli (e.g., sad facial expressions), whereas anxiety should relate particularly to attentional biases to threat-relevant stimuli (e.g., angry faces). However, little research has investigated this specificity hypothesis and none with a sample of youths. The present study examined attentional biases to emotional faces (sad, angry, and happy compared with neutral) in groups of pure depressed, pure anxious, comorbid depressed and anxious, and control youths (ages 9–17 years; N = 161). Consistent with cognitive models, pure depressed and pure anxious youths exhibited attentional biases specifically to sad and angry faces, respectively, whereas comorbid youths exhibited attentional biases to both facial expressions. In addition, control youths exhibited attentional avoidance of sad faces, and comorbid boys avoided happy faces. Overall, findings suggest that cognitive biases and processing of particular emotional information are specific to pure clinical depression and anxiety, and results inform etiological models of potentially specific processes that are associated with internalizing disorders among youths. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Interactions between early parenting and a polymorphism of the child's dopamine transporter gene in predicting future child conduct disorder symptoms.

Mounting evidence suggests that genetic risks for mental disorders often interact with the social environment, but most studies still ignore environmental moderation of genetic influences. The authors tested interactions between maternal parenting and the variable number tandem repeat (VNTR) polymorphism in the 3′ untranslated region of the dopamine transporter gene in the child to increase understanding of gene–environment interactions involving early parenting. Participants were part of a 9-year longitudinal study of 4- to 6-year-old children who met criteria for attention-deficit/hyperactivity disorder (ADHD) and demographically matched controls. Maternal parenting was observed during standard mother–child interactions in Wave 1. The child's conduct disorder (CD) symptoms 5–8 years later were measured using separate structured diagnostic interviews of the mother and youth. Controlling for ADHD symptoms and child disruptive behavior during the mother–child interaction, there was a significant inverse relation between levels of both positive and negative parenting at 4–6 years and the number of later CD symptoms, but primarily among children with 2 copies of the 9-repeat allele of the VNTR. The significant interaction with negative parenting was replicated in parent and youth reports of CD symptoms separately. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Genetic polymorphism of the 3' VNTR region of the human dopaminergic function gene DAT1 (human dopamine transporter gene) in the Mongolian population

The hypervariable region of the dopamine transporter gene (DAT1) was amplified from samples in the Mongolian population. This region includes a variable number of tandem repeats of a 40-bp core unit in the 3' untranslated region of DAT1. Vandenbergh et al. (1992) reported variability in the number of repeats of this 3' flanking region ranging from 3 to 11 times in white and black populations. We examined polymorphism at the DAT1 locus in 78 native Mongolian subjects. We found alleles with 7 to 13 repeats, which is different from the findings of Vandenbergh et al. (1992). The allele distribution of the Mongolian population is similar to that in the Japanese population, reported previously by Nakatome et al. (1995). Chi-square analysis showed a significant lack of homogeneity between our findings in Mongolian subjects and those reported previously in white and black populations. The DAT1 locus was estimated to have a heterozygosity index of 14.1%, and the polymorphic information content was calculated to be 0.16.     

Cloning and characterization of the 5'' flanking sequences (promoter region) of the human GLP-1 receptor gene

We have investigated in rat brain slices the effects of the volatile anaesthetics enflurane, isoflurane and halothane on spontaneous discharge patterns and mean firing rates of cerebellar Purkinje cells. In the absence of these anaesthetics, Purkinje cells fired bursts of action potentials separated by quiescent periods lasting less than 2 s. Mean discharge rates were 10.8 (SEM 0.4) Hz at 23 +/- 1 degrees C and 25.6 (1.2) Hz at 35 +/- 1 degrees C. The agents exhibited qualitatively different effects when applied at concentrations corresponding to 1-3 MAC. Enflurane markedly lengthened burst and inter-burst durations. Isoflurane acted in a similar manner, but effects were less pronounced. In contrast with isoflurane and enflurane, halothane shortened burst durations. At concentrations corresponding to 1-1.5 MAC, halothane, isoflurane and enflurane significantly depressed action potential firing by 15-30% (P < 0.05). Enflurane 1.2 mmol litre-1 (2.0 MAC), isoflurane 0.9 mmol litre-1 (2.8 MAC) and halothane 0.9 mmol litre-1 (3.8 MAC) depressed spontaneous spike rates by 50%. The changes in discharge patterns and the concentration-dependent decrease in the firing rates were similar at 23 +/- 1 degrees C and 35 +/- 1 degrees C. In summary, we observed that neither the anaesthetic-induced alterations in spontaneous discharge patterns nor the EC50 values of the concentration-dependent depression of the mean firing rates were in accordance with the Meyer-Overton rule. However, at clinically relevant concentrations, depression of average spike rates did not differ significantly between the anaesthetics and thus followed the rule. Our results suggest that anaesthetic actions, which are in accordance with the rule, are frequently masked by several side effects.     

Enhancing brain adenosine signaling with the nucleoside transport blocker NBTI (S-(4-nitrobenzyl)-6-theoinosine) mimics the effects of inescapable shock on later shuttle-escape performance in rats.

Experience with unsignaled, inescapable shock represents a profound challenge to brain metabolic function and physiology. The authors have argued that behavioral impairment following this traumatic stress is a consequence of enhanced brain adenosine signaling, which promotes metabolic recovery by profoundly inhibiting neural activation. The authors tested this hypothesis by artificially increasing extracellular brain adenosine concentration by blocking uptake transport with NBTI in rats given only restraint stress in five experiments. NBTI impaired shuttle-escape performance in the manner of inescapable shock in a dose-dependent manner and acted synergistically with an ineffective number of inescapable shocks to maximally impair test performance. These deficits produced by inescapable shock and NBTI were reversed by the nonselective adenosine receptor antagonist caffeine, and the highly selective A2A receptor antagonist CSC (8-(3-chloro-styrl)caffeine). The highly selective A? receptor antagonist DPCPX (8-Cyclopentyl-1,3-Dipropylxanthine) failed to improve performance in rats preexposed to inescapable shock or pretreated with NBTI. These data suggest that enhanced adenosine signaling at a brain A2A receptor impairs escape performance following inescapable shock in the learned helplessness paradigm. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A novel polymorphism in the promoter region for the human osteocalcin gene: the possibility of a correlation with bone mineral density in postmenopausal Japanese women

We present a polymorphism of the human osteocalcin gene (also known as BGP, for bone Gla protein) due to a 1 base pair (bp) substitution from cytosine to thymine at position 298 nucleotides (nt), which is at position 198 nt upstream from the BGP exon 1. This mutation was detected by single-strand conformation polymorphism analysis after polymerase chain reaction for the osteocalcin gene fragment (326 bp) and sequencing analysis. The cytosine/thymine polymorphism can be defined by restriction fragment length polymorphism analysis using a modified primer pair and the restriction endonuclease HindIII. The osteocalcin genotype was determined in 160 postmenopausal Japanese women (age 48-80 years). Osteocalcin alleles were designated according to the absence (H) or presence (h) of the HindIII restriction site. There were 12 HH, 49 Hh, and 99 hh individuals, and the allele frequencies were 22.8% for H and 77.2% for h. To determine if genetic variation influences bone mineral density (BMD) and thus can be a determinant of susceptibility to osteoporosis in older women, we examined the association of BMD with the osteocalcin genotypes found in the present study. The subjects with genotype HH had the smallest BMD and those with hh had the greatest BMD among subjects, but these differences did not reach statistical significance. The HindIII genotype showed a significant effect on the prevalence of osteopenia in the subjects, that is, women with genotype HH had a 5.74 times greater risk for osteopenia (p < 0.05) and those with genotype Hh had a 1.59 times greater risk than women with genotype hh. We identified the osteocalcin gene polymorphism, detected with the HindIII genotype, which was suggested to influence bone density and is a possible genetic marker for bone metabolism.     

Diabetic retinopathy, promoter (4G/5G) polymorphism of PAI-1 gene, and PAI-1 activity in Pima Indians with type 2 diabetes

OBJECTIVE: To examine the relationship between plasma plasminogen activator inhibitor 1 (PAI-1) activity and PAI-1 gene (4G/5G) polymorphism and diabetic retinopathy in Pima Indians with type 2 diabetes. RESEARCH DESIGN AND METHODS: We studied 171 Pima Indians with type 2 diabetes between the ages of 30-70 years in a population-based epidemiological survey. Plasma PAI-1 activity was measured by a spectrophotometric assay and PAI-1 4G/5G promoter genotype by the polymerase chain reaction (PCR) using allele-specific primers. Retinopathy was assessed by ophthalmoscopy after pupillary dilation and classified as any retinopathy or as nonproliferative and proliferative. RESULTS: Retinopathy was present in 70 (41%) subjects, and 4 (2.3%) subjects had proliferative retinopathy. Plasma PAI-1 activity was not significantly different among subjects with and without retinopathy (17.1 +/- vs. 19.7 +/- 9.1 arbitrary units (AU)/ml, P = 0.09). PAI-1 activity was negatively correlated with duration of diabetes (rs = -0.18, P = 0.02). In a logistic regression analysis controlled for age, sex, BMI, and duration of diabetes, any retinopathy was significantly associated with fasting plasma glucose concentrations (P < 0.05), 2-h postload glucose (P = 0.02), and HbA1c (P = 0.008), but not with PAI-1 activity (P = 0.48). The prevalence of retinopathy in the three genotype groups differed significantly (4G/4G, 4G/5G, and 5G/5G were 44, 49, and 24%, respectively; chi 2 = 8.22, df = 2, P = 0.016) and remained significant after controlling for age, sex, BMI, duration of diabetes, glycated hemoglobin, and urine albumin-to-creatine ratio in a logistic regression analysis. The odds ratios for retinopathy in subjects with 4G/4G and 4G/5G, compared with the 5G/5G genotype, were 2.0 and 3.1, respectively. CONCLUSIONS: Although diabetic retinopathy in Pima Indians with type 2 diabetes is not associated with PAI-1 activity, subjects with the 4G/4G and 4G/5G genotype had a higher prevalence of retinopathy compared with 5G/5G PAI-1genotype. These preliminary findings indicate that in Pima Indians with type 2 diabetes, presence of the 4G allele of the PAI-1 gene was associated with a higher risk of diabetic retinopathy.