Rare variants in long non-coding RNAs are associated with blood lipid levels in the TOPMed Whole Genome Sequencing Study
Author:
Wang YuxuanORCID, Selvaraj Margaret SunithaORCID, Li XihaoORCID, Li ZilinORCID, Holdcraft Jacob A., Arnett Donna K.ORCID, Bis Joshua C.ORCID, Blangero JohnORCID, Boerwinkle Eric, Bowden Donald W.ORCID, Cade Brian E.ORCID, Carlson Jenna C.ORCID, Carson April P.ORCID, Chen Yii-Der IdaORCID, Curran Joanne E.ORCID, de Vries Paul S., Dutcher Susan K.ORCID, Ellinor Patrick T.ORCID, Floyd James S.ORCID, Fornage MyriamORCID, Freedman Barry I.ORCID, Gabriel Stacey, Germer Soren, Gibbs Richard A., Guo XiuqingORCID, He JiangORCID, Heard-Costa NancyORCID, Hildalgo Bertha, Hou Lifang, Irvin Marguerite R., Joehanes Roby, Kaplan Robert C.ORCID, Kardia Sharon LR., Kelly Tanika N.ORCID, Kim Ryan, Kooperberg Charles, Kral Brian G., Levy Daniel, Li Changwei, Liu ChunyuORCID, Lloyd-Jone Don, Loos Ruth JF., Mahaney Michael C., Martin Lisa W., Mathias Rasika A.ORCID, Minster Ryan L., Mitchell Braxton D.ORCID, Montasser May E.ORCID, Morrison Alanna C.ORCID, Murabito Joanne M., Naseri TakeORCID, O’Connell Jeffrey R., Palmer Nicholette D.ORCID, Preuss Michael H., Psaty Bruce M.ORCID, Raffield Laura M.ORCID, Rao Dabeeru C., Redline Susan, Reiner Alexander P., Rich Stephen S., Ruepena Muagututi’a SefuivaORCID, Sheu Wayne H-H., Smith Jennifer A.ORCID, Smith AlbertORCID, Tiwari Hemant K., Tsai Michael Y., Viaud-Martinez Karine A.ORCID, Wang ZheORCID, Yanek Lisa R.ORCID, Zhao Wei, Rotter Jerome I.ORCID, Lin XihongORCID, Natarajan PradeepORCID, Peloso Gina M.ORCID,
Abstract
AbstractLong non-coding RNAs (lncRNAs) are known to perform important regulatory functions. Large-scale whole genome sequencing (WGS) studies and new statistical methods for variant set tests now provide an opportunity to assess the 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 blood lipid levels (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 variations and rare protein coding variations 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 lncRNA, implicating new therapeutic opportunities.
Publisher
Cold Spring Harbor Laboratory
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