Collaborative Cross recombinant inbred inter-crosses (RIX) for the study of antipsychotic pharmacogenomics (2015)

Undergraduates: Daniela DeCristo, P Giusti-Rodr¿¿guez, JJ Crowley, RJ Nonneman, A Ryan, DR Miller, GS Shaw, V Zhabotynsky, W Sun, PF Sullivan, and F Pardo-Manuel de Villena

Faculty Advisor: Patrick Sullivan
Department: Biology

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Schizophrenia is a chronic, severe, and disabling brain disorder affecting ~1% of the global population. Antipsychotics are the mainstay of schizophrenia treatment, but the majority of patients discontinue assigned treatments due to intolerable side effects and/or inefficacy over short periods of time. Currently, there are no compelling algorithms to predict adverse drug reactions (ADRs) or efficacy by the genetic makeup of a patient, an ability that would make drug treatment of schizophrenia safer and more effective.

Human genetic studies of ADRs are difficult to perform. The laboratory mouse can instead be used as a proxy to study some human pharmacogenetic phenotypes. For example, chronic treatment with the typical antipsychotic haloperidol causes the ADR tardive dyskinesia in ~30% of patients, effectively modeled in rodents by means of vacuous chewing movements. A major goal of the UNC Center of Excellence is to harness the genetic diversity of Collaborative Cross recombinant inbred inter-crosses (RIX) to elucidate the genetic basis of antipsychotic side effects.

RIX mice treated with haloperidol have been subjected to a panel of behavioral assessments to monitor side effect development. Here we present our preliminary findings of the behavioral characterization of RIX mice. We aim to correlate these phenotypes with strain genotypes and RNA-seq data to understand how genetic variation, gene expression, and epigenetic features act and interact to impact these phenotypes.