Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A relationship between genetic makeup and susceptibility to major depressive disorder (MDD) has long been suspected on the basis of family and twin studies. A metaanalysis of reports on the basis of twin studies has estimated MDD's degree of heritability to be 0.33 (confidence interval, 0.26-0.39). Among families exhibiting an increased prevalence of MDD, risk of developing the illness was enhanced in members exposed to a highly stressful environment. Aberrant genes can predispose to depression in a number of ways, for example, by diminishing production of growth factors that act during brain development. An aberrant gene could also increase or decrease a neurotransmitter's release into synapses, its actions, or its duration of activity. The gene products of greatest interest at present are those involved in the synthesis and actions of serotonin; among them, the serotonin-uptake protein localized within the terminals and dendrites of serotonin-releasing neurons. It has been found that the Vmax of platelet serotonin uptake is low in some patients with MDD; also, Vmax is highly correlated in twins. Antidepressant drugs such as the selective serotonin reuptake inhibitors act on this uptake protein. The specific genetic locus causing serotonin uptake to be lower in some patients with major depression involves a polymorphic region (5-HTTLPR) in the promoter region of the gene for the uptake protein. The gene itself exists as several alleles, the short "S" allele and the long "L" allele. The S variant is associated with less, and the L variant with more, of the uptake protein. The effect of stressful life events on depressive symptoms in young adults was found to be significantly stronger among SS or SL subjects than among LL subjects. Neuroimaging studies showed that people with the SS or SL alleles exhibited a greater activation of the amygdala in response to fearful stimuli than those with LL. It has been reported recently that mutations in the gene that controls serotonin synthesis in the human brain (tryptophan hydroxylase) also predispose to mood disturbances. It may be asked whether people who lack a psychiatric history should be advised to avoid stressful environments if they are found to carry the SS or SL alleles.
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PMID:Genes, stress, and depression. 1587 7

Autism is a spectrum of neurodevelopmental disorders with a primarily genetic etiology exhibiting deficits in (1) development of language and (2) social relationships and (3) patterns of repetitive, restricted behaviors or interests and resistance to change. Elevated platelet serotonin (5-HT) in 20%-25% of cases and efficacy of selective 5-HT reuptake inhibitors (SSRIs) in treating anxiety, depression, and repetitive behaviors points to the 5-HT transporter (5-HTT; SERT) as a strong candidate gene. Association studies involving the functional insertion/deletion polymorphism in the promoter (5-HTTLPR) and a polymorphism in intron 2 are inconclusive, possibly because of phenotypic heterogeneity. Nonetheless, mounting evidence for genetic linkage of autism to the chromosome 17q11.2 region that harbors the SERT locus (SLC6A4) supports a genetic effect at or near this gene. We confirm recent reports of sex-biased genetic effects in 17q by showing highly significant linkage driven by families with only affected males. Association with common alleles fails to explain observed linkage; therefore, we hypothesized that preferential transmission of multiple alleles does explain it. From 120 families, most contributing to linkage at 17q11.2, we found four coding substitutions at highly conserved positions and 15 other variants in 5' noncoding and other intronic regions transmitted in families exhibiting increased rigid-compulsive behaviors. In the aggregate, these variants show significant linkage to and association with autism. Our data provide strong support for a collection of multiple, often rare, alleles at SLC6A4 as imposing risk of autism.
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PMID:Allelic heterogeneity at the serotonin transporter locus (SLC6A4) confers susceptibility to autism and rigid-compulsive behaviors. 1599 45

The Hypothesis of Initial Conditions posits that differences in psychotropic drug response result from individual differences in receptor site kinetics, and differences in the sensitivity of downstream receptor-linked responses. This work examines data consistent with the hypothesis, specific to genetic and kinetic differences of the serotonin (5-HT) transporter (SERT), as they may be linked to divergent antidepressant response (ADR). The mechanisms for divergent ADR in association with different initial SERT function are considered within the context of SERT trafficking as sensitive to various different kinase and cytokine signals, some of which are dependent on the 5-HTTLPR polymorphism of the SERT gene. Pilot data suggest that human lymphocytes show kinase changes similar to those found in rat brain with ADT. These studies additionally suggest that ADT prompts a shift in cytokine gene expression toward a greater anti-inflammatory/inflammatory ratio. These latter findings are discussed within the context of a literature suggesting increased inflammatory cytokine levels in depression, and recent observations of increased temperature associated with depression. In sum, the data suggest the opportunity to identify response dependent protein (RDP) expression patterns that may differ with dichotomous ADR, and suggest new insights into understanding the mechanisms of psychotropic drug response through an understanding of initial differences in potential for psychotropic drug target regulation during therapy.
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PMID:Initial conditions of psychotropic drug response: studies of serotonin transporter long promoter region (5-HTTLPR), serotonin transporter efficiency, cytokine and kinase gene expression relevant to depression and antidepressant outcome. 1600 36

Correlations exist between the incidence of depression, irritable bowel syndrome (IBS) and overactive bladder [Masand, P.S., Kaplan, D.S., Gupta, S., Bhandary, A.N., Nasra, G.S., Kline, M.D., Margo, K.L., 1995. Major depression and irritable bowel syndrome: is there a relationship? J. Clin. Psychiatry 56, 363-367.; Cukier, J.M., Cortina-Borja, M., Brading, A.F., 1997. A case-control study to examine any association between idiopathic detrusor instability and gastrointestinal tract disorder, and between irritable bowel syndrome and urinary tract disorder. Br. J. Urol. 79, 865-878.; Monga, A.K., Marrero, J.M., Stanton, S.L., Lemieux, M.C., Maxwell, J.D., 1997. Is there an irritable bladder in the irritable bowel syndrome? Br. J. Obstet. Gynaecol. 104, 1409-1412.; Zorn, B.H., Montgomery, H., Pieper, K., Gray, M., Steers, W.D., 1999. Urinary incontinence and depression. J. Urol. 162, 82-84.]. Furthermore, alterations in serotonergic neurotransmission may play a common role in the etiology of these disorders. Serotonin reuptake transporter knockout mice (5-HTT(-/-)) display phenotypes consistent with clinical features of mood and bowel disorders including anxiety and abnormal gastrointestinal motility [Holmes, A., Murphy, D.L., Crawley, J.N., 2003. Abnormal behavioral phenotypes of serotonin transporter knockout mice: parallels with human anxiety and depression. Biol. Psychiatry 54, 953-959.]. In the present study, we evaluated bladder function in 5-HTT(-/-) mice. We have found that female 5-HTT(-/-) mice exhibit bladder dysfunction, characterized by significant increases in the frequency of spontaneous non-voiding bladder contractions and decreases in void volume compared to control female mice. These differences were not observed in male knockout mice. These studies provide significant supporting data for a mechanistic link between alterations in 5-HT, depression, IBS and overactive bladder in women.
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PMID:Female, but not male, serotonin reuptake transporter (5-HTT) knockout mice exhibit bladder instability. 1602 97

Previous research has demonstrated that a polymorphism in the serotonin transporter gene (5-HTTLPR) and adverse psychosocial circumstances interact to predict depression. The purpose of the present study was to explore the extent to which sex modulates these effects. Eighty-one boys and 119 girls (16-19 years old) were interviewed about psychosocial background variables and genotyped for the 5-HTT promoter polymorphism. There were two main results. First, boys and girls carrying the short 5-HTTLPR allele react to different kinds of environmental factors. Whereas males were affected by living in public housing rather than in own owned homes and by living with separated parents, females were affected by traumatic conflicts within the family. Second, the responses of males and females carrying the short 5-HTTLPR allele to environmental stress factors go in opposite directions. Thus, whereas females tend to develop depressive symptoms, males seem to be protected from depression. The results suggest that both the molecular and the psychosocial mechanisms underlying depression may differ between boys and girls.
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PMID:Development of depression: sex and the interaction between environment and a promoter polymorphism of the serotonin transporter gene. 1621 76

Major depressive disorder (MDD) is common and moderately heritable. Recurrence and early age at onset characterize cases with the greatest familial risk. Major depressive disorder and the neuroticism personality trait have overlapping genetic susceptibilities. Most genetic studies of MDD have considered a small set of functional polymorphisms relevant to monoaminergic neurotransmission. Meta-analyses suggest small positive associations between the polymorphism in the serotonin transporter promoter region (5-HTTLPR) and bipolar disorder, suicidal behavior, and depression-related personality traits but not yet to MDD itself. This polymorphism might also influence traits related to stress vulnerability. Newer hypotheses of depression neurobiology suggest closer study of genes related to neurotoxic and neuroprotective (neurotrophic) processes and to overactivation of the hypothalamic-pituitary axis, with mixed evidence regarding association of MDD with polymorphisms in one such gene (brain-derived neurotrophic factor [BDNF]). Several genome-wide linkage studies of MDD and related traits have been reported or are near completion. There is some evidence for convergence of linkage findings across studies, but more data are needed to permit meta-analysis. Future directions will include more intensive, systematic study of linkage candidate regions and of the whole genome for genetic association; gene expression array studies; and larger-scale studies of gene-environment interactions and of depression-related endophenotypes.
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PMID:The genetics of depression: a review. 1630 Jul 47

A genetic susceptibility to depression in PD, acting via the serotonergic system, has been suggested. We examined the influence of allelic variation (L/S) in a functional polymorphism in the serotonin transporter (5-HTTLPR) gene upon mood in 108 PD patients and 82 controls. Using a logistic regression model we found no evidence for an association between 5-HTTLPR genotypes, or the presence of the S allele, and depression.
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PMID:Allelic variation of a functional polymorphism in the serotonin transporter gene and depression in Parkinson's disease. 1693 46

Clinical reports document that depression as a side effect is more prevalent in hepatic patients given interferon (IFN)-alpha therapy than in those given lamivudine. The mechanisms, however, are poorly understood. Serotonin transporter (5-HTT), via uptake of serotonin (5-HT) into presynaptic serotoninergic neurons, is an initial action site for antidepressants. Real-time polymerase chain reaction (PCR) was used to quantify 5-HTT mRNA expression in immune cells in order to evaluate whether 5-HTT acted as an indicator of depression. Results showed that the 5-HTT mRNA expression was much higher in T-cell and B-cell lines than that in a monocytic cell line. Treatment with either lamivudine or ribavirin reduced the 5-HTT mRNA expression, protein level and 5-HT uptake in T-cell line. Treatment with IFN-alpha, however, increased those levels in the same group. A similar effect was observed in peripheral blood mononuclear cells (PBMC). Mimicking clinical use by treating PBMC with a combination of IFN-alpha and ribavirin increased the 5-HTT mRNA expression level. Our study indicates that these therapeutic drugs regulate 5-HTT expression, which implies that 5-HTT might be a trait marker in IFN-alpha-induced depression after hepatic therapy.
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PMID:Serotonin transporter mRNA expression is decreased by lamivudine and ribavirin and increased by interferon in immune cells. 1647 9

Identifying biological mechanisms through which genes lead to individual differences in emotional behavior is paramount to our understanding of how such differences confer risk for neuropsychiatric illness. The emergence of techniques such as in vivo imaging of brain function in humans and genetic engineering in rodents has provided important new insights into the impact of serotonin (5-HT), a key modulator of emotional behavior, on neural systems subserving anxiety and depression. A major finding has been the discovery of genetic variation in a crucial regulatory molecule within the 5-HT system, the 5HT transporter (5-HTT), and its influence on emotional traits. The study of the 5-HTT provides a new foundation for understanding the neurobiological and genetic basis of emotional regulation and affective illness.
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PMID:Genetics of emotional regulation: the role of the serotonin transporter in neural function. 1653 Apr 63

The serotonin (5-HT) system is implicated in incentive motivational processes. The present study utilized the acute tryptophan depletion (ATD) procedure to investigate the effect of temporarily lowering 5-HT synthesis on motivation in healthy volunteers, stratifying the results by allelic variation at the serotonin transporter gene (5-HTTLPR). ATD resulted in a robust reduction in plasma tryptophan concentration. Consistent with a previous study, ATD attenuated motivationally speeded action on the Cued-Reinforcement Reaction Time task. The present investigation revealed that this effect was restricted to volunteers of the ss genotype, whereas ll volunteers exhibited intact motivationally speeded action following ATD (treatment x reinforcement probability x genotype interaction: F1,26=5.8, p=0.024). Furthermore, tryptophan availability to the brain was correlated positively with motivationally speeded action following ATD in the ss genotype group (rho13=0.71, p=0.006), whereas this correlation was negative in the ll genotype group (rho14=-0.60, p=0.023). This is the first study to suggest that allelic variation at the 5-HTTLPR mediates motivational responses to ATD in healthy volunteers. These data indicate that the s allele at the 5-HTTLPR may confer risk for depression via its effect on incentive motivational processing, and highlight the importance of genetic variation in determining individual responses to pharmacological treatments.
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PMID:Serotonin transporter polymorphism mediates vulnerability to loss of incentive motivation following acute tryptophan depletion. 1654 Oct 86


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