SLCO1B7 – Schizophrenia

SLCO1B7 has been investigated as a pharmacogenetic modifier in schizophrenia patients treated with clozapine but lacks evidence for direct involvement in schizophrenia susceptibility. In a genome‐wide association study of 66 clozapine‐induced neutropenia cases and 5,583 clozapine‐treated controls, followed by meta‐analysis with an additional 163 cases and 7,970 controls from the Clozapine-Induced Agranulocytosis Consortium, rs149104283 intronic to SLCO1B7 was identified with an odds ratio of 4.32 (P=1.79×10⁻⁸) (PMID:27400856). This association is specific to the drug-induced neutropenia phenotype rather than primary schizophrenia risk. No series of unrelated schizophrenia probands or familial segregation data for SLCO1B7 variants have been reported. Moreover, SLCO1B7 has not been implicated in schizophrenia case–control GWAS unrelated to clozapine treatment. Consequently, genetic evidence supporting a role for SLCO1B7 in schizophrenia pathogenesis is limited.

Functional studies reveal that SLCO1B7 contributes to the SLCO1B3–SLCO1B7 readthrough transcript encoding the OATP1B3-1B7 transporter and a splice variant termed LST-3TM12, both of which localise to hepatocyte endoplasmic reticulum and plasma membranes (PMID:29248594). Heterologous expression assays demonstrate transport activity for dehydroepiandrosterone-sulfate and estradiol-17β-glucuronide. Coding polymorphisms within the SLCO1B7 region significantly reduce substrate accumulation without affecting protein expression levels in vitro (PMID:32818652). These findings confirm that SLCO1B7 variants can alter transporter function but do not address neuronal or immunological mechanisms relevant to schizophrenia. No cell or animal models have evaluated the impact of SLCO1B7 disruption on neurodevelopment or synaptic function. Mechanistic evidence linking SLCO1B7 transporter dysfunction to schizophrenia pathophysiology is currently lacking.

References

• Molecular psychiatry • 2017 • Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia. PMID:27400856
• Pharmacological research • 2020 • Genetic variants of SLCO1B7 are of relevance for the transport function of OATP1B3-1B7. PMID:32818652
• Biochemical pharmacology • 2018 • LST-3TM12 is a member of the OATP1B family and a functional transporter. PMID:29248594

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