Division of Psychiatry Research, The Zucker Hillside Hospital, Glen Oaks, NY, USA.
Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Neuropsychopharmacology. 2021 Sep;46(10):1788-1801. doi: 10.1038/s41386-021-01023-4. Epub 2021 May 25.
Broad-based cognitive deficits are an enduring and disabling symptom for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. While novel drug targets for schizophrenia and depression have emerged from recent large-scale genome-wide association studies (GWAS) of these psychiatric disorders, GWAS of general cognitive ability can suggest potential targets for nootropic drug repurposing. Here, we (1) meta-analyze results from two recent cognitive GWAS to further enhance power for locus discovery; (2) employ several complementary transcriptomic methods to identify genes in these loci that are credibly associated with cognition; and (3) further annotate the resulting genes using multiple chemoinformatic databases to identify "druggable" targets. Using our meta-analytic data set (N = 373,617), we identified 241 independent cognition-associated loci (29 novel), and 76 genes were identified by 2 or more methods of gene identification. Actin and chromatin binding gene sets were identified as novel pathways that could be targeted via drug repurposing. Leveraging our transcriptomic and chemoinformatic databases, we identified 16 putative genes targeted by existing drugs potentially available for cognitive repurposing.
广泛存在的认知缺陷是许多严重精神疾病患者的持久和致残症状，而目前的药物治疗并不能充分解决这些问题。虽然最近对这些精神疾病的大规模全基因组关联研究（GWAS）为精神分裂症和抑郁症的新型药物靶点提供了依据，但一般认知能力的 GWAS 可以为益智药再利用提供潜在的靶点。在这里，我们（1）对两项最近的认知 GWAS 结果进行荟萃分析，以进一步提高发现基因座的能力；（2）采用几种互补的转录组学方法来鉴定这些基因座中与认知有可信关联的基因；（3）使用多个化学信息数据库进一步注释产生的基因，以确定“可药用”的靶点。使用我们的荟萃分析数据集（N=373617），我们确定了 241 个独立的认知相关基因座（29 个是新的），并且有 76 个基因被 2 种或更多的基因识别方法所识别。肌动蛋白和染色质结合基因集被确定为可以通过药物再利用靶向的新途径。利用我们的转录组学和化学信息数据库，我们确定了 16 个可能被现有药物靶向的潜在基因，这些药物可能适用于认知再利用。
