Rare variants in long non-coding RNAs are associated with blood lipid levels in the TOPMed whole-genome sequencing study

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  • Yuxuan Wang
  • Margaret Sunitha Selvaraj
  • Xihao Li
  • Zilin Li
  • Jacob A. Holdcraft
  • Donna K. Arnett
  • Joshua C. Bis
  • John Blangero
  • Eric Boerwinkle
  • Donald W. Bowden
  • Brian E. Cade
  • Jenna C. Carlson
  • April P. Carson
  • Yii Der Ida Chen
  • Joanne E. Curran
  • Paul S. de Vries
  • Susan K. Dutcher
  • Patrick T. Ellinor
  • James S. Floyd
  • Myriam Fornage
  • Barry I. Freedman
  • Stacey Gabriel
  • Soren Germer
  • Richard A. Gibbs
  • Xiuqing Guo
  • Jiang He
  • Nancy Heard-Costa
  • Bertha Hildalgo
  • Lifang Hou
  • Marguerite R. Irvin
  • Roby Joehanes
  • Robert C. Kaplan
  • Sharon LR Kardia
  • Tanika N. Kelly
  • Ryan Kim
  • Charles Kooperberg
  • Brian G. Kral
  • Daniel Levy
  • Changwei Li
  • Chunyu Liu
  • Don Lloyd-Jone
  • Loos, Ruth
  • Michael C. Mahaney
  • Lisa W. Martin
  • Rasika A. Mathias
  • Ryan L. Minster
  • Braxton D. Mitchell
  • May E. Montasser
  • Alanna C. Morrison
  • Joanne M. Murabito
  • NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium

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.

Original languageEnglish
JournalAmerican Journal of Human Genetics
Volume110
Issue number10
Pages (from-to)1704-1717
Number of pages14
ISSN0002-9297
DOIs
Publication statusPublished - 2023

Bibliographical note

Publisher Copyright:
© 2023 American Society of Human Genetics

    Research areas

  • association, blood lipid, cholesterol, lncRNA, rare variants, whole-genome sequencing

ID: 372823537