Drogemöller Britt I, Niehaus Dana J H, Chiliza Bonginkosi, van der Merwe Lize, Asmal Laila, Malhotra Anil K, Wright Galen E B, Emsley Robin, Warnich Louise
Department of Genetics, Stellenbosch University, Private Bag XI, Matieland, 7602, Western Cape, South Africa.
Pharmacogenomics. 2014 Feb;15(2):189-99. doi: 10.2217/pgs.13.218.
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).
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.
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.
已经开展了许多抗精神病药物遗传学研究来检测候选基因或已知变异；然而，我们对抗精神病药物遗传学特征所涉及的遗传因素的了解仍然有限。
使用一组特征明确的首发精神分裂症（FES）患者来确定对抗精神病治疗无反应者和有反应者的一个子集，用于外显子组测序（n = 11）。随后比较在有反应者和无反应者中观察到的变异，并采用一种优先排序策略来确定在整个FES队列（n = 103）以及另一个科萨精神分裂症队列（n = 222）中进行基因分型的变异。
对编码变异的检测揭示了罕见的功能丧失变异在治疗反应结果中的潜在作用。发现一个变异rs11368509与FES队列（p = 0.057）和科萨精神分裂症队列（p = 0.016）中较好的治疗结果弱相关。此外，大多数被认为可能参与抗精神病治疗反应的功能丧失变异在亚洲和欧洲人群中要么是新出现的，要么是罕见的。
这项初步研究突出了外显子组测序在抗精神病药物基因组学研究中的重要性，特别是在非洲个体中。此外，结果再次强调了抗精神病药物基因组学的复杂性以及未来研究的必要性。
