Clinical and Biomedical Sciences, University of Exeter, Exeter, UK.
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Nat Commun. 2024 Oct 3;15(1):8549. doi: 10.1038/s41467-024-52579-w.
The role of rare non-coding variation in complex human phenotypes is still largely unknown. To elucidate the impact of rare variants in regulatory elements, we performed a whole-genome sequencing association analysis for height using 333,100 individuals from three datasets: UK Biobank (N = 200,003), TOPMed (N = 87,652) and All of Us (N = 45,445). We performed rare ( < 0.1% minor-allele-frequency) single-variant and aggregate testing of non-coding variants in regulatory regions based on proximal-regulatory, intergenic-regulatory and deep-intronic annotation. We observed 29 independent variants associated with height at P < after conditioning on previously reported variants, with effect sizes ranging from -7cm to +4.7 cm. We also identified and replicated non-coding aggregate-based associations proximal to HMGA1 containing variants associated with a 5 cm taller height and of highly-conserved variants in MIR497HG on chromosome 17. We have developed an approach for identifying non-coding rare variants in regulatory regions with large effects from whole-genome sequencing data associated with complex traits.
稀有非编码变异在复杂人类表型中的作用在很大程度上仍然未知。为了阐明调控元件中稀有变异的影响，我们使用来自三个数据集的 333,100 个人进行了全基因组测序关联分析，这些数据集是：英国生物银行（N=200,003）、TOPMed（N=87,652）和 All of Us（N=45,445）。我们基于近端调控、基因间调控和深内含子注释，对调控区域内的稀有（ < 0.1% 次要等位基因频率）单变体和非编码变异进行了汇总测试。在对先前报道的变异进行条件处理后，我们观察到 29 个与身高相关的独立变异，其效应大小范围从-7cm 到+4.7cm。我们还鉴定并复制了 HMGA1 附近与 5cm 更高身高相关的包含变异的非编码聚集相关性，以及 17 号染色体上 MIR497HG 中高度保守的变异。我们已经开发了一种从与复杂性状相关的全基因组测序数据中识别具有大效应的调控区域内稀有非编码变异的方法。
