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The identification of novel genetic variants associated with antipsychotic treatment response outcomes in first-episode schizophrenia patients

Drögemöller, Britt I.; Emsley, Robin; Chiliza, Bonginkosi; van der Merwe, Lize; Wright, Galen E.B.; Daya, Michelle; Hoal, Eileen; Malhotra, Anil K.; Lencz, Todd; Robinson, Delbert G.; Zhang, Jian-Ping; Asmal, Laila; Niehaus, Dana J.H.; Warnich, Louise

Pharmacogenetics and Genomics: May 2016 - Volume 26 - Issue 5 - p 235–242
doi: 10.1097/FPC.0000000000000213
Original Articles

Background: Although antipsychotics are integral to the treatment of schizophrenia, drug efficacy varies between patients. Although it has been shown that antipsychotic treatment response outcomes are heritable, our understanding of the genetic factors that are involved remains incomplete. Therefore, this study aims to use an unbiased scan of the genome to identify the genetic variants contributing toward antipsychotic treatment response outcomes.

Materials and methods: This study utilized whole-exome sequencing of patients on extreme ends of the treatment response spectrum (n=11) in combination with results from previous antipsychotic studies to design a panel of variants that were genotyped in two well-characterized first-episode schizophrenia cohorts (n=103 and 87). Association analyses were carried out to determine whether these variants were significantly associated with antipsychotic treatment response outcomes.

Results: Association analyses in the discovery cohort identified two nonsynonymous variants that were significantly associated with antipsychotic treatment response outcomes (P<2.7×10–5), which were also significantly associated with the corresponding treatment response outcome in an independent replication cohort. Computational approaches showed that both of these nonsynonymous variants – rs13025959 in MYO7B (E1647D) and rs10380 in MTRR (H622Y) – were predicted to impair the functioning of their corresponding protein products.

Conclusion: The use of whole-exome sequencing in a subset of patients from a well-characterized cohort of first-episode schizophrenia patients, for whom longitudinal depot treatment response data were available, allowed for (i) the removal of confounding factors related to treatment progression and compliance and (ii) the identification of two genetic variants that have not been associated previously with antipsychotic treatment response outcomes and whose results were applicable across different classes of antipsychotics. Although the genes that are affected by these variants are involved in pathways that have been related previously to antipsychotic treatment outcomes, the identification of these novel genes will play an important role in improving our understanding of the specific variants involved in antipsychotic treatment response outcomes.

aDepartment of Genetics, Stellenbosch University, Stellenbosch

Departments of bPsychiatry

cMolecular Biology and Human Genetics, Stellenbosch University, Cape Town

dDepartment of Statistics, University of the Western Cape, Bellville, South Africa

eDepartment of Psychiatry, Zucker Hillside Hospital, North Shore-Long Island Jewish Health System, New York, New York, USA

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Correspondence to Louise Warnich, PhD, Department of Genetics, Stellenbosch University, Private Bag XI, Matieland 7602, South Africa Tel: +27 218 085 888; fax: +27 218 085 833; e-mail: lw@sun.ac.za

Received May 25, 2015

Accepted February 5, 2016

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