Rheumatoid arthritis (RA) has an estimated heritability of nearly 50%, which is particularly high in seropositive RA. HLA alleles account for a large proportion of this heritability, in addition to many common single-nucleotide polymorphisms with smaller individual effects. Low-frequency and rare variants, such as those captured by next-generation sequencing, can also have a large role in heritability in some individuals. Rare variant discovery has informed the development of drugs such as inhibitors of PCSK9 and Janus kinases. Some 34 low-frequency and rare variants are currently associated with RA risk. One variant (19:10352442G>C in TYK2) was identified in five separate studies, and might therefore represent a promising therapeutic target. Following a set of best practices in future studies, including studying diverse populations, using large sample sizes, validating RA and serostatus, replicating findings, adjusting for other variants and performing functional assessment, could help to ensure the relevance of identified variants. Exciting opportunities are now on the horizon for genetics in RA, including larger datasets and consortia, whole-genome sequencing and direct applications of findings in the management, and especially treatment, of RA.

类风湿性关节炎 (RA) 的遗传力估计接近 50%，在血清阳性 RA 中尤其高。除了许多个体效应较小的常见单核苷酸多态性之外，HLA等位基因在这种遗传性中占很大比例。低频和罕见的变异，例如通过下一代测序捕获的变异，也可以在某些个体的遗传力中发挥重要作用。罕见变异的发现为 PCSK9 和 Janus 激酶抑制剂等药物的开发提供了信息。目前约有 34 种低频和罕见变异与 RA 风险相关。五项独立研究中鉴定出一种变异（TYK2中的 19:10352442G>C），因此可能代表一个有希望的治疗靶点。在未来的研究中遵循一系列最佳实践，包括研究不同人群、使用大样本、验证 RA 和血清状态、重复研究结果、调整其他变异以及进行功能评估，可能有助于确保已识别变异的相关性。 RA 遗传学现在面临着令人兴奋的机遇，包括更大的数据集和联盟、全基因组测序以及研究结果在 RA 管理（尤其是治疗）中的直接应用。