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期刊来源：Nat Med

原文链接：https://doi.org/10.1038/s41591-024-02839-5

摘要内容如下：

慢性疼痛是一种常见的问题，超过五分之一的美国成年人每天或在大多数日子里都会感到疼痛。它对生活质量产生不利影响，并造成巨大的个人和经济代价。使用阿片类药物治疗慢性疼痛的努力在加速阿片类药物危机中发挥了核心作用。尽管估计的遗传率为25-50%，但慢性疼痛的遗传结构并没有得到很好的描述，部分原因是研究主要局限于欧洲血统的样本。为了帮助填补这一知识空白，我们对“百万退伍军人计划”（Million Veteran Program）的598，339名参与者进行了跨家系疼痛强度的荟萃分析，确定了126个独立的基因位点，其中69个是新的。疼痛强度与其他疼痛表型、物质使用水平和物质使用障碍、其他精神特征、教育水平和认知特征存在遗传相关性。全基因组关联研究结果与功能基因组学数据的整合显示，在脑组织中，特别是在GABA能神经元中，假定的因果基因（n=142）和蛋白质（n=14）表达富集。药物再利用分析发现，除其他药物外，抗惊厥药、β-受体阻滞剂和钙通道阻滞剂具有潜在的镇痛作用。我们的研究结果提供了对疼痛体验的关键分子贡献者的见解，并突出了有吸引力的药物靶点。

英文原文如下：

Abstracts

Chronic pain is a common problem, with more than one-fifth of adult Americans reporting pain daily or on most days. It adversely affects the quality of life and imposes substantial personal and economic costs. Efforts to treat chronic pain using opioids had a central role in precipitating the opioid crisis. Despite an estimated heritability of 25-50%, the genetic architecture of chronic pain is not well-characterized, in part because studies have largely been limited to samples of European ancestry. To help address this knowledge gap, we conducted a cross-ancestry meta-analysis of pain intensity in 598,339 participants in the Million Veteran Program, which identified 126 independent genetic loci, 69 of which are new. Pain intensity was genetically correlated with other pain phenotypes, level of substance use and substance use disorders, other psychiatric traits, education level and cognitive traits. Integration of the genome-wide association studies findings with functional genomics data shows enrichment for putatively causal genes (n = 142) and proteins (n = 14) expressed in brain tissues, specifically in GABAergic neurons. Drug repurposing analysis identified anticonvulsants, β-blockers and calcium-channel blockers, among other drug groups, as having potential analgesic effects. Our results provide insights into key molecular contributors to the experience of pain and highlight attractive drug targets.

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