Department of Experimental & Clinical Pharmacology, University of Minnesota College of Pharmacy, Minneapolis, MN 55455, USA.
Medigenics Consulting LLC, Minneapolis, MN 55407, USA.
Pharmacogenomics. 2019 Mar;20(4):291-306. doi: 10.2217/pgs-2018-0163. Epub 2019 Mar 18.
Clinical symptom response to antipsychotic medications is highly variable. Genome-wide association studies (GWAS) provide a 'hypothesis-free' method of interrogating the genome for biomarkers of antipsychotic response. We performed a systematic review of GWAS findings for antipsychotic efficacy or effectiveness. 14 studies met our inclusion criteria, ten of which examined antipsychotic response using quantitative rating scales to measure symptom improvement. 15 genome-wide significant loci were identified, seven of which were replicated in other antipsychotic GWAS publications: CNTNAP5, GRID2, GRM7, 8q24 (KCNK9), PCDH7, SLC1A1 and TNIK. Notably, four replicated loci are involved in glutamatergic pathways. Additional validation and evaluation of the biological significance of these markers is warranted. These markers should also be evaluated for clinical utility, especially in the context of other validated pharmacogenomic variants (e.g., CYP450 genes). These findings may generate new avenues for development of novel antipsychotic treatments.
抗精神病药物的临床症状反应具有高度可变性。全基因组关联研究（GWAS）为研究抗精神病药物反应的生物标志物提供了一种“无假设”的基因组分析方法。我们对抗精神病疗效或有效性的 GWAS 研究结果进行了系统评价。符合纳入标准的研究有 14 项，其中 10 项使用定量评分量表来衡量症状改善，以此来评估抗精神病药物的反应。确定了 15 个全基因组显著位点，其中 7 个在其他抗精神病 GWAS 出版物中得到了复制：CNTNAP5、GRID2、GRM7、8q24（KCNK9）、PCDH7、SLC1A1 和 TNIK。值得注意的是，四个复制的位点与谷氨酸能途径有关。这些标记物的进一步验证和生物学意义的评估是必要的。这些标记物也应该评估其临床实用性，特别是在其他经过验证的药物基因组学变异（如 CYP450 基因）的背景下。这些发现可能为开发新的抗精神病治疗方法开辟新途径。
