RESUMEN
The human serotonin transporter (5-HTT) gene is one of the most extensively studied in psychiatry. A functional polymorphism in the promoter region of the 5-HTT gene (5-HTTLPR) has been associated with several psychiatric disorders as well as anxiety-related personality traits. In search of a mechanistic understanding of the functional implications of 5-HTTLPR, the influence of this polymorphism on regional 5-HT1A receptor density has previously been examined in two positron emission tomography (PET) studies in humans, yielding, however, contradictory results. In the present study, 54 control subjects were examined with [11C]WAY 100635 PET and a battery of cognitive tests. Regional binding potential (BP) of [11C]WAY 100635 to 5-HT1A receptor was calculated for the dorsal raphe nuclei, the hippocampus, the anterior cingulate, the insula, the temporal cortex and the frontal cortex. The influence of 5-HTTLPR genotype on regional 5-HT1A BP and cognitive performance was investigated. No differences in 5-HT1A receptor density between carriers and non-carriers of the S allele were found. Thus, we could not replicate any of the previously reported associations between 5-HTTLPR and 5-HT1A density. There was, however, a highly significant association between 5-HTTLPR genotype and performance in Wisconsin Card Sorting Test; carriers of the S allele had a superior performance compared to the LL carriers. These observations suggest that functional implications of the 5-HTTLPR polymorphism are not likely to be mediated by differences in 5-HT1A expression levels and that other biomarkers must be considered for future investigations at phenotype level.
Asunto(s)
Cognición/fisiología , Polimorfismo Genético , Receptor de Serotonina 5-HT1A/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Adulto , Análisis de Varianza , Encéfalo/anatomía & histología , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Mapeo Encefálico , Femenino , Genotipo , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Piperazinas/metabolismo , Tomografía de Emisión de Positrones/métodos , Unión Proteica/fisiología , Piridinas/metabolismo , Factores Sexuales , Estadística como Asunto , Tritio/metabolismo , Adulto JovenRESUMEN
The efficacy of serotonin reuptake inhibitors in depression and anxiety disorders suggests the gene coding for the serotonin transporter (5-HTT), SLC6A4, as a candidate of importance for these conditions. Positive findings regarding associations between polymorphisms in SLC6A4 have been reported, indicating that these polymorphisms may influence anxiety-related personality traits, as well as the risk of developing depression and suicidality. Serotonin 5-HTT availability was assessed with single photon emission computed tomography (SPECT), using (123)I-beta-CIT as ligand, in a population of unmedicated male suicide attempters (n=9) and in matched controls (n=9). Two polymorphisms in SLC6A4 were assessed, including the 5-HTTLPR located in the promoter region and a variable number of tandem repeats (VNTR) polymorphism in intron 2 (STin2). In suicide attempters, but not in controls, low 5-HTT availability was associated with the S allele of 5-HTTLPR and with the 12 repeat allele of STin2. Data suggest that polymorphisms in SLC6A4 may influence the expression of the brain serotonin transporter in suicide attempters.
Asunto(s)
Encéfalo/metabolismo , Conducta Autodestructiva/genética , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Intento de Suicidio/psicología , Adulto , Alelos , Expresión Génica/genética , Frecuencia de los Genes , Humanos , Intrones/genética , Masculino , Repeticiones de Minisatélite/genética , Polimorfismo Genético/genética , Regiones Promotoras Genéticas , Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
Receptors of the 5-HT2C subtype are assumed to be involved in the influence of serotonin on food intake. A polymorphism in the coding region of the gene for this receptor, resulting in a cysteine to serine substitution, has been reported. Fifty-seven somatically healthy teenage girls displaying weight loss and 91 normal-weight girls of the same age, all recruited by means of a population-based screening study, were compared with respect to this polymorphism. Subjects in the weight loss group displayed a higher frequency of the serine allele than those in the comparison group (23.7% vs. 7.7%, p =.0001). Seventy-two percent of the weight loss girls fulfilled the diagnostic criteria of anorexia nervosa, whereas 28% did not; when these two groups were separately analyzed, both differed significantly from controls with respect to serine allele frequency. The results support the notion that the studied gene may be involved in the regulation of food intake in young women.
Asunto(s)
Adolescente/fisiología , Polimorfismo Genético/genética , Receptores de Serotonina/genética , Pérdida de Peso/genética , Distribución de Chi-Cuadrado , Conducta Alimentaria/fisiología , Femenino , Humanos , Receptor de Serotonina 5-HT2CRESUMEN
BACKGROUND: Concentrations of monoamine metabolites in human cerebrospinal fluid (CSF) have been used extensively as indirect estimates of monoamine turnover in the brain. CSF monoamine metabolite concentrations are partly determined by genetic influences. METHODS: We investigated possible relationships between DNA polymorphisms in the serotonin 2C receptor (HTR2C), the serotonin 3A receptor (HTR3A), the dopamine D4 receptor (DRD4), and the dopamine beta-hydroxylase (DBH) genes and CSF concentrations of 5-hydroxyindolacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) in healthy volunteers (n = 90). RESULTS: The HTR3A 178 C/T variant was associated with 5-HIAA levels (p = 0.02). The DBH-1021 heterozygote genotype was associated with 5-HIAA (p = 0.0005) and HVA (p = 0.009) concentrations. Neither the HTR2C Cys23Ser variant, nor the DRD4 -521 C/T variant were significantly associated with any of the monoamine metabolites. CONCLUSIONS: The present results suggest that the HTR3A and DBH genes may participate in the regulation of dopamine and serotonin turnover rates in the central nervous system.
Asunto(s)
Encéfalo/metabolismo , Dopamina/metabolismo , Genotipo , Ácido Homovanílico/líquido cefalorraquídeo , Ácido Hidroxiindolacético/líquido cefalorraquídeo , Metoxihidroxifenilglicol/líquido cefalorraquídeo , Polimorfismo Genético , Serotonina/metabolismo , Adulto , Dopamina beta-Hidroxilasa/genética , Dopamina beta-Hidroxilasa/metabolismo , Femenino , Frecuencia de los Genes , Variación Genética , Ácido Homovanílico/metabolismo , Humanos , Ácido Hidroxiindolacético/metabolismo , Estudios Longitudinales , Masculino , Metoxihidroxifenilglicol/metabolismo , Persona de Mediana Edad , Escalas de Valoración Psiquiátrica , Receptor de Serotonina 5-HT2C/genética , Receptores de Dopamina D2/genética , Receptores de Dopamina D4 , Receptores de Serotonina 5-HT3/genéticaRESUMEN
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 associations 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. It will be important to confirm these findings in additional panic disorder patient groups.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Ghrelina/genética , Trastorno de Pánico/genética , Polimorfismo de Nucleótido Simple/genética , Adolescente , Adulto , Anciano , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Mutación Missense/genética , Adulto JovenRESUMEN
Receptors of the 5-HT2C subtype are of importance for the influence of serotonin on food intake, and 2 single nucleotide polymorphisms in this gene (HTR2C)--Cys23Ser (rs6318) and -759C>T (rs3813929)--have been reported to be associated with weight and/or antipsychotic-induced weight gain. The present study aimed to replicate these associations; in addition, the 5-HTTLPR polymorphism in the promoter region of the serotonin transporter gene (SLC6A4) was assessed. The polymorphisms were genotyped in subjects recruited from the normal population (n = 510), and possible associations between genotype and body mass index (BMI) were assessed. The Ser23 allele was more common in underweight subjects (BMI <20) than in normal- and overweight (BMI > or =20) subjects (P = .006). The T allele of the -759C/T polymorphism was less common in the overweight group (BMI > or =25) (P = .007). Homozygosity for the short allele of 5-HTTLPR was more frequent in underweight subjects (P = .015). Our results are in agreement with previous studies, suggesting polymorphisms in HTR2C to be associated with body weight, particularly in women; and they also suggest that 5-HTTLPR may influence this phenotype. Further studies on the importance of the investigated genes for eating disorders and drug-induced weight gain are warranted.
Asunto(s)
Peso Corporal , Polimorfismo Genético , Receptor de Serotonina 5-HT2C/genética , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Adulto , Índice de Masa Corporal , Femenino , Genotipo , Humanos , Masculino , Regiones Promotoras GenéticasRESUMEN
BACKGROUND: The serotonergic system, including the serotonin transporter (5-HTT), which is the target of many antidepressants, seems to be influenced by brain-derived neurotrophic factor (BDNF). METHODS: Positron emission tomography (PET) was used to address, in 25 and 53 healthy volunteers, respectively, the possible association between six polymorphisms in the gene encoding BDNF and the availability of two proteins expressed by serotonergic neurons: the 5-HTT, measured with the radioligand [(11)C]MADAM, and the serotonin-1A (5-HT1A) receptor, measured with [(11)C]WAY-100635. RESULTS: Several single nucleotide polymorphisms were associated with [(11)C]MADAM binding potential (BP) in most brain regions, male carriers of the valine/valine genotype of the Val66Met polymorphism displaying higher availability. Effect sizes ranged from a 50% to a threefold increase. In contrast, there was no association for [(11)C]WAY-100635 BP. The observation that BDNF polymorphisms were associated with 5-HTT availability could be partly replicated in an independent population comprising nine male suicide attempters and nine matched control subjects, in which transporter availability had been measured with single photon emission computed tomography with (123)I-beta-CIT as ligand. CONCLUSIONS: Our results suggest that genetic variation in BDNF influences 5-HTT but not 5-HT1A receptor density in the human brain.