Article

Association of a Polyadenylation Polymorphism in the Serotonin Transporter and Panic Disorder

Department of Psychiatry, Weill Medical College of Cornell University, New York, New York, USA.
Biological psychiatry (Impact Factor: 9.47). 12/2009; 67(4):331-8. DOI: 10.1016/j.biopsych.2009.10.015
Source: PubMed

ABSTRACT Genetic markers in the serotonin transporter are associated with panic disorder (PD). The associated polymorphisms do not include the serotonin transporter-linked polymorphic region and display no obvious functional attributes. A common polymorphism (rs3813034) occurs in one of the two reported polyadenylation signals for the serotonin transporter and is in linkage disequilibrium with the PD-associated markers. If functional, rs3813034 might be the risk factor that explains the association of the serotonin transporter and PD.
Quantitative polymerase chain reaction on human brain samples (n = 65) and lymphoblast cultures (n = 71) was used to test rs3813034 for effects on expression of the polyadenylation forms of the serotonin transporter. rs3813034 was also tested for association in a sample of PD cases (n = 307) and a control sample (n = 542) that has similar population structure.
The balance of the two polyadenylation forms of the serotonin transporter is associated with rs3813034 in brain (p < .001) and lymphoblasts (p < .001). The balance of the polyadenylation forms is also associated with gender in brain only (p < .05). Association testing of rs3813034 in PD identified a significant association (p = .0068) with a relative risk of 1.56 and 1.81 for the heterozygous and homozygous variant genotypes, respectively.
rs3813034 is a functional polymorphism in the serotonin transporter that alters the balance of the two polyadenylation forms of the serotonin transporter. rs3813034 is a putative risk factor for PD and other behavioral disorders that involve dysregulation of serotonergic neurotransmission.

Download full-text

Full-text

Available from: Myrna M Weissman, Jul 18, 2014
0 Followers
 · 
154 Views
  • Source
    • "Total brain RNA was prepared with a Trizol protocol and reverse transcribed using Moloney Murine Leukemia virus reverse transcriptase and oligo dT primer (New England Biolabs). Total SERT, distal SERT, and control gene (glyceraldehyde 3-phosphate dehydrogenase, Beta-glucuronidase , hypoxanthine phosphoribosyltransferase 1, and TATA binding protein) mRNA levels were measured in separate reactions via an ABI 7900HT real time-PCR thermal cycler using SYBR green detection of amplified fragments (Gyawali et al, 2010). Samples were reverse transcribed twice and each cDNA sample analyzed in quadruplicate. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Fear extinction learning, the ability to reassess a learned cue of danger as safe when it no longer predicts aversive events, is often dysregulated in anxiety disorders. Selective serotonin reuptake inhibitors (SSRI's) enhance neural plasticity and their ability to enhance fear extinction learning may explain their anxiolytic properties. Caloric restriction (CR) has SSRI-like effects on neural plasticity and anxiety-related behavior. We implemented CR in mice to determine its effects on conditioned fear responses. Wild type and serotonin transporter (SERT) knockout mice underwent CR for seven days leading to significant weight loss. Mice were then tested for cued fear learning and anxiety-related behavior. CR markedly enhanced fear extinction learning and its retention in adolescent female mice and adults of both sexes. These effects of CR were absent in SERT knockout mice. Moreover, CR phenocopied behavioral and molecular effects of chronic fluoxetine but there was no additive effect of CR in fluoxetine-treated mice. These results demonstrate that CR enhances fear extinction learning through a SERT-dependent mechanism. These results may have implications for eating disorders such as anorexia nervosa (AN), in which there is a high prevalence of anxiety prior to the onset of dietary restriction and support proposals that in AN CR is a motivated effort to control dysregulated fear responses and elevated anxiety.Neuropsychopharmacology accepted article preview online, 3 January 2013; doi:10.1038/npp.2012.268.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 01/2013; 38(6). DOI:10.1038/npp.2012.268 · 7.83 Impact Factor
  • Source
    • "The serotonin system is probably the most studied candidate, partly because selective serotonin reuptake inhibitors (SSRIs) are first choice treatment for the disease. Accordingly, a polymorphism in the serotonin transporter gene has been shown to be associated with panic disorder (Gyawali et al., 2010). Several serotonergic receptors have also been studied in relation to panic disorder, including, for example, the serotonin receptor 1A, which is involved in regulating the release of serotonin (Barnes and Sharp, 1999) and has also been implicated in anxiety (Akimova et al., 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The aim of the study was to investigate whether polymorphisms in the preproghrelin gene are associated with anxiety disorders, such as panic disorder, in humans. Panic disorder is a severe anxiety disorder, characterized by sudden attacks of intense fear or anxiety in combination with somatic symptoms. The preproghrelin gene codes for two gut-derived circulating peptides that have been linked to anxiety-like behaviour in rodents: ghrelin (an orexigenic, pro-obesity hormone) and obestatin. In the present study, we genotyped three missense mutations in the preproghrelin gene in 215 patients suffering from panic disorder and in 451 controls. The A allele of the rs4684677 polymorphism was significantly associated with panic disorder, while there were no significant association with the two other polymorphisms studied. We conclude that the rs4684677 (Gln90Leu) polymorphism in the preproghrelin gene may be associated with increased risk of panic disorder and it will be important to confirm these findings in additional panic disorder patient groups.
    10/2012; 206(1). DOI:10.1016/j.psychres.2012.09.051
  • Source
    • "The serotonin system is probably the most studied candidate, partly because selective serotonin reuptake inhibitors (SSRIs) are first choice treatment for the disease. Accordingly, a polymorphism in the serotonin transporter gene has been shown to be associated with panic disorder (Gyawali et al., 2010). Several serotonergic receptors have also been studied in relation to panic disorder, including, for example, the serotonin receptor 1A, which is involved in regulating the release of serotonin (Barnes and Sharp, 1999) and has also been implicated in anxiety (Akimova et al., 2009). "
    European Neuropsychopharmacology 09/2011; 21. DOI:10.1016/S0924-977X(11)70366-2 · 5.40 Impact Factor
Show more