Gene Polymorphism 5-HTTLPR Research Articles

837 5-Httlpr Gene Polymorphism Modulates Activity and Connectivity Within An Emotional Arousal Network of Healthy Control Subjects During Visceral Pain

Background and Aims: Variants of the function polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) have been implicated in the vulnerability for affective disorders and in IBS pathophysiology. We hypothesized that 5-HTTLPR genotype would moderate: 1) a significant pattern of brain activity discriminating pain from non-pain conditions and 2) the effective connectivity in an emotional arousal network, previously shown to be involved in central pain amplification. Methods: Regional cerebral blood flow (rCBF) of 21 healthy controls (Ctrls; 5 females and 16 males) was assessed using PET (H15O) during an intense (40 mm Hg) colorectal balloon inflation (INF) or during no INF (0 mm Hg). Polymerase chain reaction was used to determine the genetic polymorphism of the 5-HTTLPR (10 short (s/s) and 11 long (l) (included 9 l/s, 2 l/l). Task partial least squares (PLS) tested for distributed patterns of brain activity discriminating the INF conditions and interacting with genotype. Structural equation modeling (SEM) tested for group differences in the effective connectivity of an emotional arousal network during INF. Results: PLS revealed a significant network of regions (p<.01, 59% cross-covariance matrix variance) differentiating INF from non-INF. Compared to s/s, l carriers showed greater engagement of this network, which comprised regions of activation (including thalamus, insula, sACC, pons) and deactivation (including medial orbital frontal cortex, amygdala, and infragenual ACC) during INF. SEM showed genotype differences in the effective connectivity within the emotional arousal network. That is, s/s showed strong positive connectivity from sACC to amygdala (lack of feedback inhibition of amygdala), while l carriers showed the expected negative connectivity (sACC to AMYG [.46, -.40, χ2∆=7.7]). Conclusions: In healthy Ctrls, s/s genotype is associated with altered connectivity within an emotional arousal network activated by visceral pain. The resultant disinhibition of the amygdala may play a role in central pain amplification, and represent a vulnerability factor for the development of IBS. Support Contributed By: K08 DK 071626 (JSL) NR04881, P50 DK64539, R24 AT002681, DK 64539

Bipolar affective disorders and temperaments

Since ancient times has there been knowledge of affective temperaments with descriptions ranging from Hippokrates and Galenus to Kraepelin and Kretschmer (in the early 20th century). Whilst temperament can be broadly defined as “an individual's characteristic or habitual inclination or mode of emotional response”, there are three different underlying concepts of temperament, which are based on (1) psychopathology (e.g. Kretschmer or Akiskal), (2) neurobiology (e.g. Eysenck or Gray) or (3) developmental observations (e.g. Chess or Kagan). Despite some undisputable overlap, it is noteworthy that “temperament” differs significantly from “character” or “personality”. Recent research has confirmed that there is a genetic basis to temperament. For example, links to the serotonin transporter gene 5HTTLPR polymorphism have been made. In regards to temperament other neurobiological systems including the HPA axis have been studied as well as issues of gender, ethnicity and psychosocial factors

The association of 5-HTTLPR and DRD4 VNTR polymorphisms with affective temperamental traits in healthy volunteers

Background There has been growing evidence that temperamental traits, including affective temperaments, are heritable and associated with genetic polymorphisms. The purpose of the present study was to investigate the possible relationship between affective temperaments and the triallelic serotonin transporter gene-linked polymorphic region (5-HTTLPR) and dopamine receptor D4 (DRD4) polymorphisms in healthy Korean subjects. Methods Three hundred thirty-five healthy college students were recruited, and 290 participants with a complete data set (172 males, 118 females) were included in the data analysis. The DNA of the subjects was isolated from whole blood cells, and the 5-HTTLPR and DRD4 variable number of tandem repeats polymorphisms were genotyped using polymerase chain reaction. Participants performed the 110-item version of the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego auto-questionnaire (TEMPS-A) measuring five affective temperamental traits. Results A significant association was found between the DRD4 polymorphism and the cyclothymic and irritable temperaments in male subjects. No significant association was shown between the 5-HTTLPR gene polymorphisms and affective temperaments. Limitation Our data were collected from a specific group of college students and cannot be generalized easily to other non-clinical populations. In addition, Korean version of the TEMPS-A used in this study has not yet been validated in Korean population. Conclusions This study showed a possible association between the DRD4 polymorphism and certain affective temperaments in the Korean male population. The clarification of the biological basis of predisposing temperaments such as cyclothymic temperament might help to understand the pathophysiology and mechanisms of mood disorders.

P.3.13 Lithium therapy reverses the influence of 5-HTTLPR gene polymorphism on anti-depressant response to sleep deprivation

P.3.13 Lithium therapy reverses the influence of 5-HTTLPR gene polymorphism on anti-depressant response to sleep deprivation

Association analyses of the serotonin transporter gene with lifetime depression and alcohol dependence in the Collaborative Study on the Genetics of Alcoholism (COGA) sample

The objective of this study was to analyze association of the serotonin transporter gene 5-HTTLPR polymorphism on lifetime depression and alcohol dependence in the Collaborative Study on the Genetics of Alcoholism sample. We conducted family-based association analyses in 1913 Caucasians genotyped for the 5-HTTLPR polymorphism. We found evidence for association of the short allele with depression, but no evidence of association with alcohol dependence. On the basis of the evidence that the effect of this polymorphism may be moderated by stressful life events, we classified individuals for the presence and/or absence of stress, as defined by unemployment, relationship problems, or poor health. The evidence for the association with lifetime depression was limited to the group of individuals who had experienced stress, paralleling the direction of effects originally reported by Caspi and colleagues. No evidence was found for the association with alcohol dependence in either the stress or the no-stress groups.

High anxiety and migraine are associated with the s allele of the 5HTTLPR gene polymorphism

The 5HTTLPR polymorphism of the serotonin transporter gene has been associated with anxiety disorders and also migraine, suggesting a common etiological background of these disorders. This association is further supported by the high comorbidity of these disorders. In our study Spielberger's State-Trait Anxiety Inventory and the 5HTTLPR genotype were investigated in a cohort of 97 psychiatrically healthy females also including 45 migraineurs. Higher state anxiety scores were significantly associated with the s allele either in the whole sample or when the group was separated into migraineurs and non-migraineurs. Migraineurs also had a significantly higher frequency of the s allele. Our results indicate that even in a healthy population the s allele is associated with a high anxiety endophenotype. The association of migraine with anxiety may be explained by the higher rate of individuals carrying the s allele among migraineurs.

A Family Based Linkage Analysis of HLA and 5-HTTLPR Gene Polymorphisms in Sardinian Children with Autism Spectrum Disorder

Autism spectrum disorders (ASD) are characterized by a broad range in clinical presentation. Although a definite genetic cause has not yet been fully demonstrated, family based studies suggest that a multigenic pattern may be responsible for susceptibility, but most results are conflicting and have yet to be replicated. The purpose of this investigation was to analyze the linkage of the human leukocyte antigen (HLA) and the human serotonin transporter coding (5-HTTLPR) genes with ASD in a group of 37 families of Sardinian ethnicity in insular Italy. In 50% of these families, ASD is linked to HLA, and in the other 50% it is linked to 5-HTTLPR polymorphic genes; in other words, linkage to one or the other was evident in all cases. Despite a very homogenous genetic pattern being generally reported for Sardinians, the linkage observed with HLA and 5-HTTLPR genetic regions indicated a statistically defined heterogeneity ( p = 0.002). No allelic HLA or 5-HTTLPR polymorphisms were specifically associated with ASD, suggesting these loci as markers of other genes mapped in their close proximity that may be more directly involved and thus may merit further analytical studies.

Gene–environment interaction in psychiatric disorders as indicated by season of birth variations in tryptophan hydroxylase (TPH), serotonin transporter (5-HTTLPR) and dopamine receptor (DRD4) gene polymorphisms

Genetic and environmental factors, as well as their interactions, are likely to be involved in psychiatric disorders. Considerable progress has been made in association and linkage studies with various candidate genes, at times with conflicting or ambiguous results. An environmental factor that has persistently shown associations with several psychiatric and neurological disorders is the season of birth. If it is the interaction of a specific gene allele with a specific season of birth that constitutes an increased (or decreased) risk for a disorder, then the individuals with this disorder are likely to have a season of birth variation in this gene allele. We investigated the variations in TPH, 5-HTTLPR and DRD4 gene polymorphisms according to seasonality of birth in 954 patients with unipolar affective disorder, bipolar affective disorder, and schizophrenia, respectively, and in 395 controls. We first analyzed season of birth variations in the gene alleles with one cycle or two cycles per year, and then compared specified birth seasons with each other. We found season of birth variations in these gene alleles that were different for different psychiatric disorders. Significant differences between cases and controls could be obtained when restricting the analysis within certain birth seasons but not within others. Our results thus suggest an interaction between the seasons of birth and the expression of the candidate genes, and that season of birth is a confounding variable when investigating the role of the candidate genes in susceptibility to psychiatric disorders.