Rare variants in long non-coding RNAs are associated with blood lipid levels in the TOPMed whole-genome sequencing study
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Dokumenter
- Fulltext
Indsendt manuskript, 781 KB, PDF-dokument
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.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | American Journal of Human Genetics |
| Vol/bind | 110 |
| Udgave nummer | 10 |
| Sider (fra-til) | 1704-1717 |
| Antal sider | 14 |
| ISSN | 0002-9297 |
| DOI | |
| Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:
Whole-genome sequencing (WGS) for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung, and Blood Institute (NHLBI). G.M.P. is supported by NIH grants R01HL142711 and R01HL127564 . P.N. is supported by grants from the National Heart, Lung, and Blood Institute ( R01HL142711 , R01HL148050 , R01HL151283 , R01HL148565 , R01HL135242 , and R01HL151152 ), Fondation Leducq ( TNE-18CVD04 ), and Massachusetts General Hospital (Paul and Phyllis Fireman Endowed Chair in Vascular Medicine). X. Lin is supported by grants R35-CA197449, U19-CA203654, R01-HL113338, and U01-HG009088. We would like to acknowledge all the grants that supported this study: R01 HL121007, U01 HL072515, R01 AG18728, X01HL134588, HL 046389, HL113338, and 1R35HL135818, K01 HL135405, R03 HL154284, U01HL072507, R01HL087263, R01HL090682, P01HL045522, R01MH078143, R01MH078111, R01MH083824, U01DK085524, R01HL113323, R01HL093093, R01HL133040, R01HL140570, R01HL142711, R01HL127564, R01HL148050, R01HL148565, HL105756, and Leducq TNE-18CVD04 . The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services. We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed and UK Biobank. The full study-specific acknowledgments and NHLBI TOPMed Fellowship acknowledgment are detailed in Supplementary Notes.
Funding Information:
P.N. reports research grants from Allelica, Apple, Amgen, Boston Scientific, Genentech/Roche, and Novartis; personal fees from Allelica, Apple, AstraZeneca, Blackstone Life Sciences, Eli Lilly & Co, Foresite Labs, Genentech/Roche, GV, HeartFlow, Magnet Biomedicine, and Novartis; scientific advisory board membership of Esperion Therapeutics, Preciseli, and TenSixteen Bio; scientific co-founder of TenSixteen Bio; equity in MyOme, Preciseli, and TenSixteen Bio; and spousal employment at Vertex Pharmaceuticals, all unrelated to the present work. B.M.P. serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. L.M.R., S.S.R., and R.M. are consultants for the TOPMed Administrative Coordinating Center (through Westat). M.E.M. receives funding from Regeneron Pharmaceutical Inc. unrelated to this work. X. Lin is a consultant of AbbVie Pharmaceuticals and Verily Life Sciences. P.T.E. receives sponsored research support from Bayer AG, IBM Research, Bristol Myers Squibb, Pfizer, and Novo Nordisk; he has also served on advisory boards or consulted for Bayer AG, MyoKardia, and Novartis. A.P.C. previously received investigator-initiated grant support from Amgen, Inc. unrelated to the present work.
Publisher Copyright:
© 2023 American Society of Human Genetics
ID: 372823537