Are novel treatments for brain disorders hiding in plain sight?
Are novel treatments for brain disorders hiding in plain sight?
复制标题
脑部疾病的新疗法是否隐藏在众目睽睽之下？
DOI：
10.1038/s41386-023-01636-x
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Deisseroth,Karl
中科院分区：
文献类型：
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作者：
Duncan,Laramie;Deisseroth,Karl
精神疾病受到遗传学的强烈影响，但基因指导的治疗发展缓慢，精确的分子机制仍然是个谜。虽然基因组中的单个位点往往不会对精神疾病的发病率产生重大影响，但全基因组关联研究（GWAS）现已成功地将数百个特定的遗传位点与精神疾病联系起来[，-]。在这里，基于与精神病学相关的四种表型的强大GWAS的结果，我们激发了一个探索性的工作流程，从GWAS筛选，通过使用光遗传学等方法在动物模型中进行因果测试，到人类的新疗法。我们专注于精神分裂症和多巴胺D2受体（DRD 2），潮热和神经激肽B受体（TACR 3），吸烟和尼古丁结合的受体（CHRNA 5，CHRNA 3，CHRNB 4），以及酒精使用和有助于分解酒精的酶（ADH 1 B，ADH 1C，ADH 7）。单个基因组基因座可能无法在群体水平上有力地决定疾病，但相同的基因座仍然可能代表适用于全群体治疗方法的有效治疗靶点。
Psychiatric diseases are strongly influenced by genetics, but genetically guided treatments have been slow to develop, and precise molecular mechanisms remain mysterious. Although individual locations in the genome tend to not contribute powerfully to psychiatric disease incidence, genome-wide association studies (GWAS) have now successfully linked hundreds of specific genetic loci to psychiatric disorders [, –]. Here, building upon results from well-powered GWAS of four phenotypes relevant to psychiatry, we motivate an exploratory workflow leading from GWAS screening, through causal testing in animal models using methods such as optogenetics, to new therapies in human beings. We focus on schizophrenia and the dopamine D2 receptor (DRD2), hot flashes and the neurokinin B receptor (TACR3), cigarette smoking and receptors bound by nicotine (CHRNA5,CHRNA3,CHRNB4), and alcohol use and enzymes that help to break down alcohol (ADH1B,ADH1C,ADH7). A single genomic locus may not powerfully determine disease at the level of the population, but the same locus may nevertheless represent a potent treatment target suitable for population-wide therapeutic approaches.