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Genetic factors associated with Body Mass Index (BMI) have been widely studied over the last decade. We examined whether genetic variants previously associated with BMI in the general population are associated with cardiometabolic parameter worsening in the psychiatric population receiving psychotropic drugs, a high-risk group for metabolic disturbances. Classification And Regression Trees (CARTs) were used as a tool capable of describing hierarchical associations, to pinpoint genetic variants best predicting worsening of cardiometabolic parameters (i.e total, HDL and LDL-cholesterol, triglycerides, body mass index, waist circumference, fasting glucose, and blood pressure) following prescription of psychotropic drugs inducing weight gain in a discovery sample of 357 Caucasian patients. Significant findings were tested for replication in a second Caucasian psychiatric sample (n = 140). SH2B1 rs3888190C > A was significantly associated with LDL levels in the discovery and in the replication sample, with A-allele carriers having 0.2 mmol/l (p = 0.005) and 0.36 mmol/l (p = 0.007) higher LDL levels compared to others, respectively. G-allele carriers of RABEP1 rs1000940A > G had lower fasting glucose levels compared to others in both samples (− 0.16 mmol/l; p < 0.001 and − 0.77 mmol/l; p = 0.03 respectively). The present study is the first to observe such associations in human subjects, which may in part be explained by a high risk towards dyslipidemia and diabetes in psychiatric patients receiving psychotropic treatments compared to population-based individuals. These results may therefore give new insight into the etiology of LDL-cholesterol and glucose regulation in psychiatric patients under psychotropic drug therapy. [ABSTRACT FROM AUTHOR]