rs1000940 (RABEP1): fasting glucose and psychotropics

Key takeaways

• Carriers of the G allele at rs1000940 showed lower fasting glucose levels in psychiatric patients taking psychotropic medications, by approximately 0.16 to 0.77 mmol/l compared to non-G-allele carriers.
• The AA genotype is linked to greater fasting glucose elevations than the AG or GG genotypes in patients treated with at least 10 common psychotropic drugs.
• GTEx data indicate that the alternate allele reduces RABEP1 expression across multiple tissues, including subcutaneous and visceral adipose tissue.
• The overall evidence base is small and preliminary, coming from two cohorts totaling fewer than 500 Caucasian psychiatric patients, with no large-scale general-population replication reported.
• This variant sits near both the RABEP1 (Rab GTPase-binding effector protein 1) and NUP88 (nucleoporin 88 kDa) genes; the primary pharmacogenomic signal has been attributed to RABEP1.

What the research says G-allele carriers of RABEP1 rs1000940A>G had significantly lower fasting glucose levels compared to non-carriers in a study of Caucasian psychiatric patients on weight-gain-inducing psychotropic drugs, with a difference of -0.16 mmol/l (p<0.001) in a discovery sample of 357 patients and -0.77 mmol/l (p=0.03) in an independent replication sample of 140 patients PMID 28132883. The authors described this as the first reported observation of this association in human subjects and noted that psychiatric patients receiving psychotropic treatments represent a high-risk group for metabolic disturbances including dyslipidemia and dysglycemia PMID 28132883. The same study also found that a variant in the nearby SH2B1 gene was independently associated with LDL-cholesterol levels, suggesting that this genomic region may be broadly relevant to cardiometabolic regulation in this population PMID 28132883.

Reported associations

• Fasting glucose levels (psychotropic drug context): G-allele carriers of rs1000940 had lower fasting glucose in psychiatric patients receiving psychotropic medications (-0.16 mmol/l, p<0.001 in discovery sample n=357; -0.77 mmol/l, p=0.03 in replication sample n=140) PMID 28132883
• Fasting glucose response by genotype - AA: Patients with bipolar, depressive, psychotic, or schizoaffective disorders and the AA genotype may have greater elevations of fasting glucose concentrations compared to patients with the AG or GG genotypes when administered amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, paliperidone, risperidone, lithium, valproate, or mirtazapine PharmGKB
• Fasting glucose response by genotype - AG: Patients with the AG genotype may have smaller fasting glucose elevations compared to AA carriers on the same psychotropic medications PharmGKB
• Fasting glucose response by genotype - GG: Patients with the GG genotype may have smaller fasting glucose elevations compared to AA carriers on the same psychotropic medications PharmGKB

Evidence quality The primary published evidence for rs1000940 comes from a single pharmacogenomic study conducted in two independent Caucasian psychiatric cohorts (discovery n=357, replication n=140) PMID 28132883. P-values of p<0.001 and p=0.03 met conventional significance thresholds in both samples, providing nominal replication. However, the effect size differed substantially between the two samples (-0.16 vs -0.77 mmol/l), which may reflect winner's curse inflation in the discovery sample, small-sample variability, or population heterogeneity between the cohorts PMID 28132883. The PharmGKB clinical annotation is Level 3, defined as limited evidence. The association was characterized specifically in patients receiving psychotropic drugs, a population with already elevated cardiometabolic risk; generalizability to the broader population is unknown. No large-scale general-population genome-wide association study in the provided literature identifies rs1000940 as a primary signal for glucose regulation. Taken together, the evidence is preliminary and requires replication in larger and more diverse samples.

Drug response by genotype

• AA: Patients with bipolar, depressive, psychotic, or schizoaffective disorders may experience greater elevations of fasting glucose concentrations when administered amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, paliperidone, risperidone, lithium, valproate, or mirtazapine compared to AG or GG genotype carriers; other clinical and genetic factors may also influence this response PharmGKB
• AG: Patients may experience smaller fasting glucose elevations compared to AA carriers on the same set of psychotropic medications; other clinical and genetic factors may also contribute PharmGKB
• GG: Patients may experience smaller fasting glucose elevations compared to AA carriers on the same set of psychotropic medications; other clinical and genetic factors may also contribute PharmGKB

Tissue-specific expression effects

• RABEP1: The alternate allele is associated with reduced expression in testis, pituitary, thyroid, tibial nerve, subcutaneous adipose, visceral (omental) adipose, and lung tissue GTEx Portal
• RPAIN: The alternate allele is associated with reduced expression in testis GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.