Long non-coding RNAs (lncRNAs) are known to perform important regulatory functions in lipid metabolism. Large-scale whole-genome sequencing (WGS) studies and new statistical methods for variant set tests now provide an opportunity to assess more associations between rare variants in lncRNA genes and complex traits across the genome. In this study, we used high-coverage WGS from 66,329 participants of diverse ancestries with measurement of blood lipids and lipoproteins (LDL-C, HDL-C, TC, and TG) in the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) program to investigate the role of lncRNAs in lipid variability. We aggregated rare variants for 165,375 lncRNA genes based on their genomic locations and conducted rare-variant aggregate association tests using the STAAR (variant-set test for association using annotation information) framework. We performed STAAR conditional analysis adjusting for common variants in known lipid GWAS loci and rare-coding variants in nearby protein-coding genes. Our analyses revealed 83 rare lncRNA variant sets significantly associated with blood lipid levels, all of which were located in known lipid GWAS loci (in a ±500-kb window of a Global Lipids Genetics Consortium index variant). Notably, 61 out of 83 signals (73%) were conditionally independent of common regulatory variation and rare protein-coding variation at the same loci. We replicated 34 out of 61 (56%) conditionally independent associations using the independent UK Biobank WGS data. Our results expand the genetic architecture of blood lipids to rare variants in lncRNAs.

已知长链非编码 RNA (lncRNA) 在脂质代谢中发挥重要的调节功能。大规模全基因组测序 (WGS) 研究和用于变异集测试的新统计方法现在提供了一个机会来评估 lncRNA 基因中的罕见变异与整个基因组的复杂性状之间的更多关联。在这项研究中，我们使用了国家心肺血液研究所 (NHLBI) 66,329 名不同血统参与者的高覆盖率全基因组测序 (WGS) 来测量血脂和脂蛋白（LDL-C、HDL-C、TC 和 TG） Trans-Omics for Precision Medicine (TOPMed) 计划旨在研究 lncRNA 在脂质变异中的作用。我们根据基因组位置聚合了 165,375 个 lncRNA 基因的罕见变异，并使用 STAAR（使用注释信息进行关联的变异集测试）框架进行了罕见变异聚合关联测试。我们针对已知脂质GWAS位点的常见变异和附近蛋白质编码基因的稀有编码变异进行了 STAAR 条件分析。我们的分析揭示了 83 个罕见的 lncRNA 变异集与血脂水平显着相关，所有这些变异都位于已知的脂质 GWAS 位点（在全球脂质遗传学联盟索引变异的 ±500 kb 窗口中）。值得注意的是，83 个信号中有 61 个 (73%) 有条件地独立于同一位点的常见调控变异和罕见蛋白质编码变异。我们使用独立的英国生物银行 WGS 数据复制了 61 个有条件独立协会中的 34 个 (56%)。我们的结果将血脂的遗传结构扩展到 lncRNA 的罕见变异。