A Cys 23-Ser 23 substitution in the 5-HT(2C) receptor gene influences body weight regulation in females with seasonal affective disorder: an Austrian-Canadian collaborative study.
ABSTRACT Most females with seasonal affective disorder (SAD) exhibit atypical vegetative symptoms such as overeating, and weight gain when depressed. The serotonin 2C receptor (5-HT(2C)) plays a key role in control of appetite and satiety. A 5-HT(2C) Cys 23 Ser substitution, coded for by a single nucleotide polymorphism (Cys 23 Ser) within the 5-HT(2C) gene, has been shown to influence 5-HT(2C) function. We hypothesized that Cys 23 Ser influences weight regulation in females with SAD. Two independent samples from Austria (162 females with SAD, 119 controls), and Canada (90 females with SAD, 42 controls) were genotyped for Cys 23 Ser. Influence on weight regulation was analyzed within patients with atypical features. In Austrians, genotype distribution differed between patients and controls (p=0.044) and Cys 23 Ser was associated with weight (p=0.039), body mass index (BMI; p=0.038), and seasonal appetite change (p=0.031). All values were highest in Cys/Cys, intermediate in Cys/Ser, and lowest in Ser/Ser carriers. In Canadian patients, Cys 23 Ser was associated with minimum lifetime BMI (p=0.046), with lowest values in Ser/Ser carriers. Our data provide evidence that Cys 23 Ser mediates severity of weight regulation disturbances in females with SAD, and the gene-dose effect-like differences suggest a direct functional role of Cys 23 Ser in the behavioral regulation of body weight.
- Neuroreport 01/2003; 14(6):781-783. · 1.40 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Substantial evidence supports a role for dysfunction of brain serotonergic (5-HT) systems in the pathogenesis of major affective disorder, both unipolar (recurrent major depression) and bipolar.(1) Modification of serotonergic neurotransmission is pivotally implicated in the mechanism of action of antidepressant drugs(2) and also in the action of mood stabilizing agents, particularly lithium carbonate.(3) Accordingly, genes that code for the multiple subtypes of serotonin receptors that have been cloned and are expressed in brain,(4) are strong candidates for a role in the genetic etiology of affective illness. We examined a structural variant of the serotonin 2C (5-HT2C) receptor gene (HTR2C) that gives rise to a cysteine to serine substitution in the N terminal extracellular domain of the receptor protein (cys23ser),(5) in 513 patients with recurrent major depression (MDD-R), 649 patients with bipolar (BP) affective disorder and 901 normal controls. The subjects were drawn from nine European countries participating in the European Collaborative Project on Affective Disorders. There was significant variation in the frequency of the HT2CR ser23 allele among the 10 population groups included in the sample (from 24.6% in Greek control subjects to 9.2% in Scots, chi(2) = 20.9, df 9, P = 0.01). Logistic regression analysis demonstrated that over and above this inter-population variability, there was a significant excess of HT2CR ser23 allele carriers in patients compared to normal controls that was demonstrable for both the MDD (chi(2) = 7.34, df 1, P = 0.006) and BP (chi(2) = 5.45, df 1, P = 0.02) patients. These findings support a possible role for genetically based structural variation in 5-HT2C receptors in the pathogenesis of major affective disorder.Molecular Psychiatry 10/2001; 6(5):579-85. · 14.90 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: There is significant evidence that altered dopamine activity plays a role in seasonal affective disorder (SAD). The current study examined three separate genetic hypotheses for SAD related to the 7-repeat allele (7R) of the dopamine-4 receptor gene (DRD4), a variant associated with decreased affinity for dopamine. We examined the possible contribution of 7R to the overall expression of SAD, attention deficit disorder (ADD) comorbidity, and body weight regulation. As part of an ongoing genetic study of increased eating behavior and mood in female subjects, 108 women with winter SAD and carbohydrate craving/weight gain were administered the Wender-Utah Rating Scale to measure childhood ADD symptomatology, and a questionnaire to assess maximal lifetime body mass index (BMI). To test for an association between 7R and the categorical diagnosis of SAD, the transmission disequilibrium test (TDT) was used in a subsample of probands providing familial DNA. Standard parametric tests were used to compare childhood ADD symptoms and maximal lifetime BMI across the two genotypic groups defined by the presence or absence of 7R. The TDT found no initial evidence for an association between 7R and the categorical diagnosis of SAD. However, 7R carriers reported significantly greater inattention and dysphoria in childhood (p=0.01 and 0.001, respectively) and a higher maximal lifetime BMI (p=0.007) than did probands without this allele. Furthermore, excluding probands with extreme obesity (maximal BMI >40), a strong correlation was found linking childhood inattentive symptoms and maximal lifetime BMI (r=0.35, p=0.001). In overeating women with SAD, the 7R allele of DRD4 may be associated with a unique developmental trajectory characterized by attentional deficits and dysphoria in childhood and mild to moderate obesity in adulthood. This developmental course may reflect different manifestations of the same underlying vulnerability related to central dopamine dysfunction. Given the possibility of population stratification when studying genotype/phenotype relationships, future use of genomic controls and replication of our findings in other overeating and/or ADD populations are needed to confirm these initial results.Neuropsychopharmacology 01/2004; 29(1):179-86. · 8.68 Impact Factor