Clonal haematopoiesis involves the expansion of certain blood cell lineages and has been associated with ageing and adverse health outcomes^1,2,3,4,5. Here we use exome sequence data on 628,388 individuals to identify 40,208 carriers of clonal haematopoiesis of indeterminate potential (CHIP). Using genome-wide and exome-wide association analyses, we identify 24 loci (21 of which are novel) where germline genetic variation influences predisposition to CHIP, including missense variants in the lymphocytic antigen coding gene LY75, which are associated with reduced incidence of CHIP. We also identify novel rare variant associations with clonal haematopoiesis and telomere length. Analysis of 5,041 health traits from the UK Biobank (UKB) found relationships between CHIP and severe COVID-19 outcomes, cardiovascular disease, haematologic traits, malignancy, smoking, obesity, infection and all-cause mortality. Longitudinal and Mendelian randomization analyses revealed that CHIP is associated with solid cancers, including non-melanoma skin cancer and lung cancer, and that CHIP linked to DNMT3A is associated with the subsequent development of myeloid but not lymphoid leukaemias. Additionally, contrary to previous findings from the initial 50,000 UKB exomes⁶, our results in the full sample do not support a role for IL-6 inhibition in reducing the risk of cardiovascular disease among CHIP carriers. Our findings demonstrate that CHIP represents a complex set of heterogeneous phenotypes with shared and unique germline genetic causes and varied clinical implications.

克隆造血涉及某些血细胞谱系的扩张，并与衰老和不良健康结果有关^1,2,3,4,5。在这里，我们使用 628,388 个个体的外显子组序列数据来识别 40,208 个不确定潜能克隆性造血 (CHIP) 的携带者。使用全基因组和全外显子组关联分析，我们确定了 24 个位点（其中 21 个是新的），其中种系遗传变异影响 CHIP 的易感性，包括淋巴细胞抗原编码基因 LY75 中的错义变异，这与 CHIP 的发生率降低有关。我们还确定了与克隆造血和端粒长度相关的新型罕见变异。对英国生物银行 (UKB) 的 5,041 项健康特征的分析发现，CHIP 与严重的 COVID-19 结果、心血管疾病、血液学特征、恶性肿瘤、吸烟、肥胖、感染和全因死亡率之间存在关系。纵向和孟德尔随机化分析显示，CHIP 与实体癌相关，包括非黑色素瘤皮肤癌和肺癌，并且与DNMT3A相关的 CHIP与随后发生的骨髓性白血病相关，但与淋巴性白血病无关。此外，与之前对最初的 50,000 个 UKB 外显子组的研究结果相反⁶，我们在完整样本中的结果不支持抑制 IL-6 在降低 CHIP 携带者患心血管疾病风险方面的作用。我们的研究结果表明，CHIP 代表了一组复杂的异质表型，具有共同和独特的种系遗传原因以及不同的临床意义。