Clock genes and body composition in patients with schizophrenia under treatment with antipsychotic drugs

Context: In the healthy population, several pathways are known to exert an effect on basal metabolic factors. Previous studies have found associations between single nucleotide polymorphisms in clock genes or downstream hormone receptors such as the leptin receptor (LEPR) or glucocorticoid receptor (NR3C1) and obesity in the healthy population, but this association remains to be examined in patients with schizophrenia treated with antipsychotics. Objective: To assess anthropomorphic parameters in patients taking second-generation antipsychotics (SGA) as a function of nine polymorphisms in three core genes of the clock pathway, and two genes of downstream hormone receptors. Methods: Clinical parameters were evaluated in 261 patients with schizophrenia spectrum disorder. Polymorphisms in LEPR, MC3R, NR3C1, PER2 and SDC3 were genotyped. In order to control for multiple testing, permutation tests were used to generate corrected empirical p-values using the Max(T) procedure in PLINK. Results: A significant effect of the rs6196 polymorphism in the NR3C1 on weight (beta= -4.18; SE= 2.02; p = 0.018), BMI (beta= -1.88; SE = 0.64; p = 0.004), waist (beta= -5.77; SE= 1.75; p = 0.001) and waist/hip ratio (beta= -0.03; SE= 0.012; p = 0.009) was found. Permutation tests confirmed the findings for BMI (p=0.037) and waist (p= 0.024). Carriers of the G allele consistently displayed better parameters than patients with the wild type allele. A weak effect of rs4949184 in SDC3 on BMI was found, but this did not sustain permutation testing (beta= -1.27; SE = 0.58; p = 0.030, p = 0.270 after permutations). Conclusion: Variations in genes implicated in circadian regulation or its related downstream pathways may be important in the regulation of antropomorphic parameters in patients with schizophrenia during long-term treatment with SGA.