Computational Biology, GSK R&D, Collegeville, PA, USA.
Computational Biology, GSK R&D, Collegeville, PA, USA.
Drug Discov Today. 2019 Jun;24(6):1232-1236. doi: 10.1016/j.drudis.2019.03.024. Epub 2019 Mar 29.
Genome-wide association studies (GWAS) have made considerable progress and there is emerging evidence that genetics-based targets can lead to 28% more launched drugs. We analyzed 1589 GWAS across 1456 pathways to translate these often imprecise genetic loci into therapeutic hypotheses for 182 diseases. These pathway-based genetic targets were validated by testing whether current drug targets were enriched in the pathway space for the same indication. Remarkably, 30% of diseases had significantly more targets in these pathways than expected by chance; the comparable number for GWAS alone (without pathway analysis) was zero. This study shows that a systematic global pathway analysis can translate genetic findings into therapeutic hypotheses for both new drug discovery and repositioning opportunities for current drugs.
全基因组关联研究（GWAS）已经取得了相当大的进展，有新的证据表明，基于遗传学的靶点可以使新上市药物增加 28%。我们分析了 1456 条途径中的 1589 个 GWAS，将这些通常不精确的遗传基因座转化为 182 种疾病的治疗假说。通过测试当前药物靶点是否在相同适应症的途径空间中富集，验证了基于途径的遗传靶点。值得注意的是，30%的疾病在这些途径中有比预期更多的靶点；仅 GWAS（不进行途径分析）的相应数字为零。这项研究表明，系统的全球途径分析可以将遗传发现转化为治疗假说，既为新药发现提供了机会，也为现有药物的重新定位提供了机会。
