Rare variants in long non-coding RNAs are associated with blood lipid levels in the TOPMed Whole Genome Sequencing Study.

TitleRare variants in long non-coding RNAs are associated with blood lipid levels in the TOPMed Whole Genome Sequencing Study.
Publication TypeJournal Article
Year of Publication2023
AuthorsWang, Y, Selvaraj, MSunitha, Li, X, Li, Z, Holdcraft, JA, Arnett, DK, Bis, JC, Blangero, J, Boerwinkle, E, Bowden, DW, Cade, BE, Carlson, JC, Carson, AP, Chen, Y-DIda, Curran, JE, de Vries, PS, Dutcher, SK, Ellinor, PT, Floyd, JS, Fornage, M, Freedman, BI, Gabriel, S, Germer, S, Gibbs, RA, Guo, X, He, J, Heard-Costa, N, Hildalgo, B, Hou, L, Irvin, MR, Joehanes, R, Kaplan, RC, Kardia, SLr, Kelly, TN, Kim, R, Kooperberg, C, Kral, BG, Levy, D, Li, C, Liu, C, Lloyd-Jone, D, Loos, RJf, Mahaney, MC, Martin, LW, Mathias, RA, Minster, RL, Mitchell, BD, Montasser, ME, Morrison, AC, Murabito, JM, Naseri, T, O'Connell, JR, Palmer, ND, Preuss, MH, Psaty, BM, Raffield, LM, Rao, DC, Redline, S, Reiner, AP, Rich, SS, Ruepena, M'aSefuiva, Sheu, WH-H, Smith, JA, Smith, A, Tiwari, HK, Tsai, MY, Viaud-Martinez, KA, Wang, Z, Yanek, LR, Zhao, W, Rotter, JI, Lin, X, Natarajan, P, Peloso, GM
Corporate AuthorsNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
JournalmedRxiv
Date Published2023 Jun 29
Abstract

Long 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.

DOI10.1101/2023.06.28.23291966
Alternate JournalmedRxiv
PubMed ID37425772
PubMed Central IDPMC10327287
Grant ListR01 HL113323 / HL / NHLBI NIH HHS / United States
R35 CA197449 / CA / NCI NIH HHS / United States
R01 HL127564 / HL / NHLBI NIH HHS / United States
R01 MH078111 / MH / NIMH NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
R01 HL140570 / HL / NHLBI NIH HHS / United States
R01 HL151152 / HL / NHLBI NIH HHS / United States
R03 HL154284 / HL / NHLBI NIH HHS / United States
R01 HL135242 / HL / NHLBI NIH HHS / United States
R01 HL090682 / HL / NHLBI NIH HHS / United States
K01 HL135405 / HL / NHLBI NIH HHS / United States
R01 HL121007 / HL / NHLBI NIH HHS / United States
U01 DK085524 / DK / NIDDK NIH HHS / United States
U19 CA203654 / CA / NCI NIH HHS / United States
R01 HL151283 / HL / NHLBI NIH HHS / United States
R01 HL148565 / HL / NHLBI NIH HHS / United States
R01 HL113338 / HL / NHLBI NIH HHS / United States
R01 HL142711 / HL / NHLBI NIH HHS / United States
R35 HL135818 / HL / NHLBI NIH HHS / United States
U01 HL072515 / HL / NHLBI NIH HHS / United States
P01 HL045522 / HL / NHLBI NIH HHS / United States
R01 MH078143 / MH / NIMH NIH HHS / United States
U01 HL072507 / HL / NHLBI NIH HHS / United States
R01 HL093093 / HL / NHLBI NIH HHS / United States
R01 HL087263 / HL / NHLBI NIH HHS / United States
U01 HG009088 / HG / NHGRI NIH HHS / United States
R01 MH083824 / MH / NIMH NIH HHS / United States
R01 HL148050 / HL / NHLBI NIH HHS / United States
R01 AG018728 / AG / NIA NIH HHS / United States