Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10⁻⁸), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.

迄今为止，血压（BP）的遗传学研究主要分析了常见变异（次要等位基因频率> 0.05）。在一项对约 130 万名参与者进行的荟萃分析中，我们发现了 106 个新的 BP 相关基因组区域和 87 个罕见（次要等位基因频率 ≤ 0.01）变异 BP 关联 ( P < 5 × 10 ^-8 )，其中 32 个位于新的 BP 相关基因座和 55 个是已知 BP 相关区域内独立的 BP 相关单核苷酸变异。罕见变异（44% 编码）的平均效应比常见变异效应大约 8 倍，表明新的和已知的基因座（例如GATA5和PLCB3 ）上存在潜在的候选因果基因。血压相关变异（包括罕见和常见）在胎儿组织的活性染色质区域富集，可能将胎儿发育与以后的血压调节联系起来。多变量孟德尔随机化表明，收缩压和舒张压升高可能对大动脉卒中产生反向影响。我们的研究证明了稀有变异分析在识别候选基因方面的实用性，结果突出了潜在的治疗靶点。