A Cys23-Ser23 substitution in the 5-HT2C receptor gene influences body weight regulation in females with seasonal affective disorder: An Austrian-Canadian collaborative study

Most females with seasonal affective disorder (SAD) exhibit atypical vegetative symptoms such as overeating, and weight gain when depressed. The serotonin 2C receptor (5-HT2C) plays a key role in control of appetite and satiety. A 5-HT2C Cys23Ser substitution, coded for by a single nucleotide polymorphism (Cys23Ser) within the 5-HT2C gene, has been shown to influence 5-HT2C function. We hypothesized that Cys23Ser 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 Cys23Ser. Influence on weight regulation was analyzed within patients with atypical features. In Austrians, genotype distribution differed between patients and controls (p = 0.044) and Cys23Ser 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, Cys23Ser was associated with minimum lifetime BMI (p = 0.046), with lowest values in Ser/Ser carriers. Our data provide evidence that Cys23Ser mediates severity of weight regulation disturbances in females with SAD, and the gene-dose effect-like differences suggest a direct functional role of Cys23Ser in the behavioral regulation of body weight.