Model-based gene selection shows engrailed 1 is associated with antipsychotic response

Area of Science:

• Genetics
• Psychiatry
• Pharmacogenomics

Background:

• Schizophrenia is a highly heritable disorder with variable treatment responses to antipsychotics.
• Limited understanding of genetic factors contributing to treatment variability necessitates broader gene investigation.
• Current candidate gene selection methods often rely on intuitive, potentially biased, data integration.

Purpose of the Study:

• To develop a less biased method for selecting candidate genes influencing schizophrenia treatment response.
• To identify novel genes associated with antipsychotic treatment efficacy using integrated data sources.

Main Methods:

• A novel method was developed to select candidate genes for schizophrenia liability and treatment response by integrating multiple datasets.
• The method identified DTNBP1 as a strong candidate and subsequently evaluated engrailed 1 (EN1) and secretin receptor (SCTR).
• Single nucleotide polymorphisms in EN1 and SCTR were genotyped in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) sample, assessing symptom and neurocognitive outcomes.

Main Results:

• Several single nucleotide polymorphisms in the EN1 gene showed significant associations with schizophrenia symptoms (P=0.0061) and antipsychotic drug response (P=2.4x10⁻¹⁰).
• The false discovery rates were estimated at 0.14 for symptom association and 0.0012 for drug response association.
• These results suggest a potential role for EN1 in modulating treatment outcomes.

Conclusions:

• The engrailed 1 (EN1) gene may play a role in individual variability of response to antipsychotic medications.
• Model-based integration of diverse schizophrenia-related data enhances the probability of identifying genes affecting antipsychotic response.
• This approach offers a more objective strategy for prioritizing genes for future pharmacogenomic studies in schizophrenia.