Patterns of Variation Influencing Antipsychotic Treatment Outcomes in South African First-Episode Schizophrenia Patients

Abstract

Aim: Many antipsychotic pharmacogenetics studies have been performed examining candidate genes or known variation; however, our understanding of the genetic factors involved in antipsychotic pharmacogenetic traits remains limited. Materials & methods: A well-characterized cohort of first-episode schizophrenia (FES) patients was used to identify a subset of nonresponders and responders to antipsychotic treatment for exome sequencing (n = 11). The variation observed in the responders and nonresponders was subsequently compared and a prioritization strategy was employed to identify variants for genotyping in the entire FES cohort (n = 103) as well as an additional Xhosa schizophrenia cohort (n = 222). Results: Examination of coding variation revealed a potential role for rare loss-of-function variants in treatment response outcomes. One variant, rs11368509, was found to be weakly associated with better treatment outcomes in the FES cohort (p = 0.057) and the Xhosa schizophrenia cohort (p = 0.016). In addition, the majority of the loss-of-function variation that was considered likely to be involved in antipsychotic treatment response was either novel or rare in Asian and European populations. Conclusion: This pilot study has highlighted the importance of exome sequencing for antipsychotic pharmacogenomics studies, particularly in African individuals. Furthermore, the results emphasize once again the complexity of antipsychotic pharmacogenomics and the need for future research.

Original submitted 8 July 2013; Revision submitted 24 October 2013

KEYWORDS::

• antipsychotic treatment
• exome
• genome
• rare variants
• schizophrenia
• South Africa
• UPP2

Disclaimer

The opinions expressed and conclusions arrived at, are those of the authors and are not necessarily attributed to the funding sources.

Financial & competing interests disclosure

The work reported here was supported by grants to the following authors: BI Drögemöller is the recipient of a National Research Foundation (NRF) research bursary and the L‘Oréal-UNESCO for Women in Science in sub-Saharan Africa Fellowship; DJH Niehaus is the recipient of a South African Medical Research Council (MRC) operating research grant; B Chiliza is the recipient of a South African MRC and Hamilton Naki Clinical Research Fellowship; AK Malhotra acts as a consultant for Genomind Inc. and has received a grant from AbbVie; R Emsley has participated in speakers/advisory boards and received honoraria from AstraZeneca, Bristol-Myers Squibb, Janssen, Lilly, Lundbeck, Organon, Pfizer, Servier, Otsuka and Wyeth. He has also received research funding from Janssen, Lundbeck and AstraZeneca; L Warnich is the recipient of a NRF operating research grant. This study was supported by a New Partnership for Africa‘s Development (NEPAD) grant, through the Department of Science and Technology of South Africa. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

The work reported here was supported by grants to the following authors: BI Drögemöller is the recipient of a National Research Foundation (NRF) research bursary and the L‘Oréal-UNESCO for Women in Science in sub-Saharan Africa Fellowship; DJH Niehaus is the recipient of a South African Medical Research Council (MRC) operating research grant; B Chiliza is the recipient of a South African MRC and Hamilton Naki Clinical Research Fellowship; AK Malhotra acts as a consultant for Genomind Inc. and has received a grant from AbbVie; R Emsley has participated in speakers/advisory boards and received honoraria from AstraZeneca, Bristol-Myers Squibb, Janssen, Lilly, Lundbeck, Organon, Pfizer, Servier, Otsuka and Wyeth. He has also received research funding from Janssen, Lundbeck and AstraZeneca; L Warnich is the recipient of a NRF operating research grant. This study was supported by a New Partnership for Africa‘s Development (NEPAD) grant, through the Department of Science and Technology of South Africa. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.