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

Authors

Yuxuan Wang
Margaret Sunitha Selvaraj
Xihao Li
Zilin Li
Jacob A. Holdcraft
Donna K. Arnett
Joshua C. Bis
John Blangero, The University of Texas Rio Grande Valley
Joanne E. Curran, The University of Texas Rio Grande Valley
Michael C. Mahaney, The University of Texas Rio Grande Valley

Document Type

Article

Publication Date

10-5-2023

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.

Comments

Original published version available at https://doi.org/10.1016/j.ajhg.2023.09.003

Recommended Citation

Wang, Y., Selvaraj, M. S., Li, X., Li, Z., Holdcraft, J. A., Arnett, D. K., Bis, J. C., Blangero, J., Boerwinkle, E., Bowden, D. W., Cade, B. E., Carlson, J. C., Carson, A. P., Chen, Y. I., Curran, J. E., de Vries, P. S., Dutcher, S. K., Ellinor, P. T., Floyd, J. S., Fornage, M., … Peloso, G. M. (2023). Rare variants in long non-coding RNAs are associated with blood lipid levels in the TOPMed whole-genome sequencing study. American journal of human genetics, 110(10), 1704–1717. https://doi.org/10.1016/j.ajhg.2023.09.003

Publication Title

American journal of human genetics

DOI

10.1016/j.ajhg.2023.09.003

Academic Level

faculty

Mentor/PI Department

Office of Human Genetics