Background:The availability of whole-genome sequencing data in large studies has enabled the assessment of coding and noncoding variants across the allele frequency spectrum for their associations with blood pressure.Methods:We conducted a multiancestry whole-genome sequencing analysis of blood pressure among 51 456 Trans-Omics for Precision Medicine and Centers for Common Disease Genomics program participants (stage-1). Stage-2 analyses leveraged array data from UK Biobank (N=383 145), Million Veteran Program (N=318 891), and Reasons for Geographic and Racial Differences in Stroke (N=10 643) participants, along with whole-exome sequencing data from UK Biobank (N=199 631) participants.Results:Two blood pressure signals achieved genome-wide significance in meta-analyses of stage-1 and stage-2 single variant findings (P<5×10^-8). Among them, a rare intergenic variant at novel locus, LOC100506274, was associated with lower systolic blood pressure in stage-1 (beta [SE]=−32.6 [6.0]; P=4.99×10^-8) but not stage-2 analysis (P=0.11). Furthermore, a novel common variant at the known INSR locus was suggestively associated with diastolic blood pressure in stage-1 (beta [SE]=−0.36 [0.07]; P=4.18×10^-7) and attained genome-wide significance in stage-2 (beta [SE]=−0.29 [0.03]; P=7.28×10^-23). Nineteen additional signals suggestively associated with blood pressure in meta-analysis of single and aggregate rare variant findings (P<1×10^-6 and P<1×10^-4, respectively).Discussion:We report one promising but unconfirmed rare variant for blood pressure and, more importantly, contribute insights for future blood pressure sequencing studies. Our findings suggest promise of aggregate analyses to complement single variant analysis strategies and the need for larger, diverse samples, and family studies to enable robust rare variant identification.

中文翻译：

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收缩压、舒张压和高血压的大规模全基因组测序研究的见解


背景：大型研究中全基因组测序数据的可用性使得能够评估等位基因频谱上的编码和非编码变异与血压的关系。方法：我们对 51 名受试者的血压进行了多祖先全基因组测序分析。 456 名精准医学跨组学和常见疾病基因组学中心计划参与者（第一阶段）。第 2 阶段分析了来自英国生物银行 (N=383 145)、百万退伍军人计划 (N=318 891) 和中风地理和种族差异原因 (N=10 643) 参与者的杠杆阵列数据，以及全外显子组测序来自英国生物银行 (N=199 631) 参与者的数据。结果：在第 1 阶段和第 2 阶段单变异结果的荟萃分析中，两个血压信号实现了全基因组显着性 ( P <5×10 ^-8 )。其中，新位点的罕见基因间变异LOC100506274与第 1 阶段较低的收缩压相关（β [SE]=−32.6 [6.0]； P =4.99×10 ^-8 ），但与第 2 阶段分析无关（ P =0.11）。此外，已知INSR位点上的一个新的常见变异与第 1 阶段的舒张压相关（β [SE]=−0.36 [0.07]； P =4.18×10 ^-7 ），并在第 1 阶段获得了全基因组显着性。 -2(β[SE]=−0.29[0.03]； P =7.28×10 ^-23 )。在对单一和聚合罕见变异结果的荟萃分析中，有 19 个其他信号暗示与血压相关（分别为P <1×10 ^-6和P <1×10 ^-4 ）。讨论：我们报告了一种有前景但未经证实的罕见血压变异，更重要的是，为未来的血压测序研究提供了见解。我们的研究结果表明，聚合分析有望补充单变异分析策略，并且需要更大、多样化的样本和家族研究来实现可靠的罕见变异识别。