@article{80cce35f34d64f22b671af55b0f217aa,
title = "Rare variants in long non-coding RNAs are associated with blood lipid levels in the TOPMed whole-genome sequencing study",
abstract = "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.",
keywords = "association, blood lipid, cholesterol, lncRNA, rare variants, whole-genome sequencing",
author = "{NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium} and Yuxuan Wang and Selvaraj, {Margaret Sunitha} and Xihao Li and Zilin Li and Holdcraft, {Jacob A.} and Arnett, {Donna K.} and Bis, {Joshua C.} and John Blangero and Eric Boerwinkle and Bowden, {Donald W.} and Cade, {Brian E.} and Carlson, {Jenna C.} and Carson, {April P.} and Chen, {Yii Der Ida} and Curran, {Joanne E.} and {de Vries}, {Paul S.} and Dutcher, {Susan K.} and Ellinor, {Patrick T.} and Floyd, {James S.} and Myriam Fornage and Freedman, {Barry I.} and Stacey Gabriel and Soren Germer and Gibbs, {Richard A.} and Xiuqing Guo and Jiang He and Nancy Heard-Costa and Bertha Hildalgo and Lifang Hou and Irvin, {Marguerite R.} and Roby Joehanes and Kaplan, {Robert C.} and Kardia, {Sharon LR} and Kelly, {Tanika N.} and Ryan Kim and Charles Kooperberg and Kral, {Brian G.} and Daniel Levy and Changwei Li and Chunyu Liu and Don Lloyd-Jone and Loos, {Ruth JF} and Mahaney, {Michael C.} and Martin, {Lisa W.} and Mathias, {Rasika A.} and Minster, {Ryan L.} and Mitchell, {Braxton D.} and Montasser, {May E.} and Morrison, {Alanna C.} and Murabito, {Joanne M.} and Take Naseri and O'Connell, {Jeffrey R.} and Palmer, {Nicholette D.} and Preuss, {Michael H.} and Psaty, {Bruce M.} and Raffield, {Laura M.} and Rao, {Dabeeru C.} and Susan Redline and Reiner, {Alexander P.} and Rich, {Stephen S.} and Ruepena, {Muagututi'a Sefuiva} and Sheu, {Wayne H.H.} and Smith, {Jennifer A.} and Albert Smith and Tiwari, {Hemant K.} and Tsai, {Michael Y.} and Viaud-Martinez, {Karine A.} and Zhe Wang and Yanek, {Lisa R.} and Wei Zhao and Rotter, {Jerome I.} and Xihong Lin and Pradeep Natarajan and Peloso, {Gina M.}",
note = "Publisher Copyright: {\textcopyright} 2023 American Society of Human Genetics",
year = "2023",
month = oct,
day = "5",
doi = "10.1016/j.ajhg.2023.09.003",
language = "English",
volume = "110",
pages = "1704--1717",
journal = "American journal of human genetics",
issn = "0002-9297",
number = "10",
}