Abstract
Obesity development during psychotropic treatments represents a major health issue in psychiatry. Melanin-concentrating hormone receptor 2 (MCHR2) is a central receptor involved in energy homeostasis. MCHR2 shares its promoter region with MCHR2-AS1, a long antisense non-coding RNA. The aim of this study was to determine whether tagging single nucleotide polymorphisms (tSNPs) of MCHR2 and MCHR2-AS1 are associated with the body mass index (BMI) in the psychiatric and in the general population. The influence of MCHR2 and MCHR2-AS1 tSNPs on BMI was firstly investigated in a discovery psychiatric sample (n1 = 474). Positive results were tested for replication in two other psychiatric samples (n2 = 164, n3 = 178) and in two population-based samples (CoLaus, n4 = 5409; GIANT, n5 = 113809). In the discovery sample, TT carriers of rs7754794C>T had 1.08 kg/m2 (p = 0.04) lower BMI as compared to C-allele carriers. This observation was replicated in an independent psychiatric sample (-2.18 kg/m2; p = 0.009). The association of rs7754794C>T and BMI seemed stronger in subjects younger than 45 years (median of age). In the population-based sample, a moderate association was observed (-0.17 kg/m2; p = 0.02) among younger individuals (<45y). Interestingly, this association was totally driven by patients meeting lifetime criteria for atypical depression, i.e. major depressive episodes characterized by symptoms such as an increased appetite. Indeed, patients with atypical depression carrying rs7754794-TT had 1.17 kg/m2 (p = 0.04) lower BMI values as compared to C-allele carriers, the effect being stronger in younger individuals (-2.50 kg/m2; p = 0.03; interaction between rs7754794 and age: p-value = 0.08). This study provides new insights on the possible influence of MCHR2 and/or MCHR2-AS1 on obesity in psychiatric patients and on the pathophysiology of atypical depression.
Highlights
Compared to the general population, patients with chronic severe mental disorders have an estimated shorter life expectancy of 15 to 25 years due to the psychiatric disorder and/or physical comorbidities (i.e obesity or other metabolic disorders) and in the use of psychotropic treatments[1]
Because of the high prevalence of obesity, of metabolic abnormalities and of mortality rate within the psychiatric population, the probable involvement of Melanin-concentrating hormone receptor 2 (MCHR2) in the phenotype of obesity and the absence of studies examining the possible influence of genetic polymorphisms of MCHR2 on body mass index (BMI) in psychiatric patients, we examined associations between tagging single nucleotide polymorphisms (SNPs) of MCHR2 and of MCHR2-AS1 with BMI in three independent psychiatric samples treated with psychotropic drugs that were likely to induce weight (i.e clozapine, olanzapine, quetiapine, risperidone, lithium, valproate, mirtazapine, aripiprazole and/or amisulpride)
The present results suggest a contribution of MCHR2 and/or MCHR2-AS1 in the regulation of human body weight, which is consistent with the proposed role of melanin-concentrating hormone (MCH) and MCHR2 pathway in the literature[9] and with the only other genetic study on MCHR2 which reported an association of MCHR2 genetic polymorphism with obesity in the general population[13]
Summary
Compared to the general population, patients with chronic severe mental disorders have an estimated shorter life expectancy of 15 to 25 years due to the psychiatric disorder and/or physical comorbidities (i.e obesity or other metabolic disorders) and in the use of psychotropic treatments[1]. The variability of weight gain observed in patients sharing similar clinical risk factors (i.e gender, age and psychotropic treatment)[3], together with the heritability of weight regulation observed in twin, adoption and family studies[4] support the key role of genetic factors in the development of obesity. The identification of new genetic predictors for the development of obesity in psychiatric patients is of great interest for a better understanding of the mechanisms underlying excessive weight increase, and for the future personalized prescription of psychotropic drugs
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