Human Genetics Publications and Presentations
Document Type
Article
Publication Date
9-2025
Abstract
Background: Rare genetic variation provided by whole genome sequence datasets has been relatively less explored for its contributions to human traits. Meta-analysis of sequencing data offers advantages by integrating larger sample sizes from diverse cohorts, thereby increasing the likelihood of discovering novel insights into complex traits. Furthermore, emerging methods in genome-wide rare variant association testing further improve power and interpretability.
Results: Here, we conduct the largest meta-analysis of whole genome sequencing for low-density lipoprotein cholesterol (LDL-C), a therapeutic target for coronary artery disease, analyzing data from 246 K participants and integrating 1.23B variants from the UK Biobank and the Trans-Omics for Precision Medicine (TOPMed) program. We identify numerous rare coding and non-coding gene associations related to LDL-C, with replication across 86 K participants in All of Us. Our findings are based on single-variant analyses, rare coding and non-coding variant aggregation tests, and sliding window approaches. Through this comprehensive analysis, we identify 704 novel single-variant associations, 25 novel rare coding variant aggregates, 28 novel rare non-coding variant aggregates, and one novel sliding window aggregate.
Conclusions: This study provides a meta-analysis framework for large-scale whole genome sequence association analyses from diverse population groups, yielding novel rare non-coding variant associations.
Recommended Citation
Selvaraj, M. S., Li, X., Li, Z., Van Buren, E., Haidermota, S., Postupaka, D., Hornsby, W., Bis, J. C., Brody, J. A., Cade, B. E., Chung, R. H., Curran, J. E., Damrauer, S. M., de Las Fuentes, L., de Vries, P. S., Duggirala, R., Freedman, B. I., Graff, M., Guo, X., Hidalgo, B. A., … Natarajan, P. (2025). Whole genome sequence analysis of low-density lipoprotein cholesterol across 246 K individuals. Genome biology, 26(1), 273. https://doi.org/10.1186/s13059-025-03698-0
Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 4.0 International License.
Publication Title
Genome Biology
DOI
10.1186/s13059-025-03698-0
Comments
© 2025 The Author(s). This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material.