Biostatistics, Massachusetts General Hospital, Boston, MA, USA.
Department of Biostatistics, Harvard TH Chan School of Public Health, Boston, MA, USA.
J Hum Genet. 2022 May;67(5):307-310. doi: 10.1038/s10038-022-01012-5. Epub 2022 Jan 11.
Many complex disease risk loci map to intergenic regions containing long intergenic noncoding RNAs (lincRNAs). The majority of these is not conserved outside humans, raising the question whether genetically regulated expression of non-conserved and conserved lincRNAs has similar rates of association with complex traits. Here we leveraged data from the Genotype-Tissue Expression (GTEx) project and multiple public genome-wide association study (GWAS) resources. Using an established transcriptome-wide association study (TWAS) tool, FUSION, we interrogated the associations between cis-regulated expression of lincRNAs and multiple cardiometabolic traits. We found that cis-regulated expression of non-conserved lincRNAs had a strikingly similar trend of association with complex cardiometabolic traits as conserved lincRNAs. This finding challenges the conventional notion of conservation that has led to prioritization of conserved loci for functional studies and calls attention to the need to develop comprehensive strategies to study the large number of non-conserved human lincRNAs that may contribute to human disease.
许多复杂疾病风险位点映射到含有长基因间非编码 RNA(lincRNA)的基因间区域。这些 lincRNA 绝大多数在人类之外没有保守性，这就提出了一个问题，即非保守和保守 lincRNA 的遗传调控表达与复杂性状的关联率是否相似。在这里，我们利用了来自基因型-组织表达 (GTEx) 项目和多个公共全基因组关联研究 (GWAS) 资源的数据。使用一种成熟的全转录组关联研究 (TWAS) 工具 FUSION，我们研究了 lincRNA 的顺式调控表达与多种心脏代谢特征之间的关联。我们发现，非保守 lincRNA 的顺式调控表达与复杂的心脏代谢特征之间的关联趋势与保守 lincRNA 非常相似。这一发现挑战了保守性的传统观念，这种观念导致了对保守基因座进行功能研究的优先级排序，并引起了人们的关注，需要制定全面的策略来研究大量可能导致人类疾病的非保守人类 lincRNA。
