Dual antiplatelet therapy reduces ischemic events in cardiovascular disease, but it increases bleeding risk. Thrombin receptors PAR1 and PAR4 are drug targets, but the role of thrombin in platelet aggregation remains largely unexplored in large populations. We performed a genome-wide association study (GWAS) of platelet aggregation in response to full-length thrombin, followed by clinical association analyses, Mendelian randomization, and functional characterization including iPSC-derived megakaryocyte and platelet experiments. We identified a single sentinel variant in the GRK5 locus (rs10886430-G, p = 3.0 × 10⁻⁴²) associated with increased thrombin-induced platelet aggregation (β = 0.70, SE = 0.05). We show that disruption of platelet GRK5 expression by rs10886430-G is associated with enhanced platelet reactivity. The proposed mechanism of a GATA1-driven megakaryocyte enhancer is confirmed in allele-specific experiments. Utilizing further data, we demonstrate that the allelic effect is highly platelet- and thrombin-specific and not likely due to effects on thrombin levels. The variant is associated with increased risk of cardiovascular disease outcomes in UK BioBank, most strongly with pulmonary embolism. The variant associates with increased risk of stroke in the MEGASTROKE, UK BioBank, and FinnGen studies. Mendelian randomization analyses in independent samples support a causal role for rs10886430-G in increasing risk for stroke, pulmonary embolism, and venous thromboembolism through its effect on thrombin-induced platelet reactivity. We demonstrate that G protein-coupled receptor kinase 5 (GRK5) promotes platelet activation specifically via PAR4 receptor signaling. GRK5 inhibitors in development for the treatment of heart failure and cancer could have platelet off-target deleterious effects. Common variants in GRK5 may modify clinical outcomes with PAR4 inhibitors, and upregulation of GRK5 activity or signaling in platelets may have therapeutic benefits.

双重抗血小板治疗可减少心血管疾病的缺血事件，但会增加出血风险。凝血酶受体PAR1和PAR4是药物的靶标，但是凝血酶在血小板聚集中的作用在大多数人群中仍未得到充分探索。我们针对全长凝血酶进行了血小板聚集的全基因组关联研究（GWAS），然后进行了临床关联分析，孟德尔随机化和功能表征，包括iPSC衍生的巨核细胞和血小板实验。我们在GRK5基因座（rs10886430-G，p = 3.0×10 ^-42）中鉴定出一个单一的前哨变体，与凝血酶诱导的血小板聚集增加有关（β= 0.70，SE = 0.05）。我们证明了血小板GRK5的破坏rs10886430-G的表达与血小板反应性增强有关。GATA1驱动的巨核细胞增强子的拟议机制在等位基因特异性实验中得到证实。利用进一步的数据，我们证明等位基因效应是高度血小板和凝血酶特异性的，不太可能是由于对凝血酶水平的影响。该变体与UK BioBank中心血管疾病预后增加的风险相关，最强烈的是肺栓塞。在MEGASTROKE，UK BioBank和FinnGen研究中，该变异与中风风险增加有关。独立样本中的孟德尔随机化分析通过影响凝血酶诱导的血小板反应性，支持rs10886430-G在增加中风，肺栓塞和静脉血栓栓塞风险中起因果作用。我们证明，G蛋白偶联受体激酶5（GRK5）促进血小板活化特别是通过PAR4受体信号传导。正在开发用于治疗心力衰竭和癌症的GRK5抑制剂可能具有血小板脱离靶标的有害作用。中的常见变体GRK5可能会通过PAR4抑制剂改变临床结局，而血小板中GRK5活性或信号转导的上调可能具有治疗益处。