MC4R Rs489693 Polymorphism Influences Antipsychotic-Related Weight Gain

Weight gain is a therapy limiting and very frequent adverse effect of many second-generation antipsychotic (SGA) drugs. The human melanocortin four receptor (MC4R) is one of the most important causative genes regarding monogenic obesity. In a recently published report, we found that the rs17782313 polymorphism downstream from MC4R was also associated with SGA-related weight gain. Malhotra et al. identified another polymorphism (rs489693) near the MC4R gene in a genome wide association study and could confirm this association with weight gain in three replication cohorts. We tried to replicate these results in our independent naturalistic study population. From 341 Caucasian inpatients receiving at least one SGA drug, carriers homozygous for the rs489693 A-allele (n = 35) showed a 2.2 times higher weight increase than carriers of the CC-genotype after 4 weeks of treatment (ANCOVA, p = 0.039). We revealed an even stronger effect in a subpopulation without weight gain inducing co-medication (factor 3.1, p = 0.044, (n = 16 of 169)) and in first episode patients (factor 2.7, p = 0.017, (n = 13 of 86)). Comparing both polymorphisms (rs17782313/rs489693), we identified a strong correlation (Cramer V = 0.706, p < 0.001). Our results underline the involvement of these point mutations in SGA-related weight gain and confirm the rs489693 A-allele as a possible risk factor. Nevertheless, further studies are needed to elucidate the clear role and mechanism of these promising polymorphisms.