Large-scale biobanks can yield unprecedented insights into our health and provide discoveries of new and potentially targetable biomarkers. Several protective loss-of-function alleles have been identified, including variants that protect against cardiovascular disease, obesity, type 2 diabetes, and asthma and allergic diseases. These alleles serve as indicators of efficacy, mimicking the effects of drugs and suggesting that inhibiting these genes could provide therapeutic benefit, as has been observed for PCSK9. We provide a context for these findings through a multifaceted review covering the use of genetics in drug discovery efforts through genome-wide and phenome-wide association studies, linking deep mutation scanning data to molecular function and highlighting some additional tools that might help in the interpretation of newly discovered variants.

中文翻译：

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利用生物库和人类遗传学进行目标发现。

大规模的生物库可以对我们的健康产生空前的见识，并提供新的和可能具有针对性的生物标志物的发现。已经鉴定出几种保护性功能丧失的等位基因，包括可以预防心血管疾病，肥胖，2型糖尿病以及哮喘和过敏性疾病的变体。这些等位基因可作为功效的指标，模仿药物的作用，并暗示抑制这些基因可以提供治疗益处，正如PCSK9所观察到的那样。我们通过多方面的综述为这些发现提供了背景，该综述涵盖了通过基因组范围和全基因组关联研究在药物发现工作中使用遗传学的方法，