Whole genome sequence analysis of low-density lipoprotein cholesterol across 246 K individuals.
Journal
Genome biology
Journal Volume
26
Journal Issue
1
Start Page
Article number 273
ISSN
1474-760X
Date Issued
2025-09-09
Author(s)
Selvaraj, Margaret Sunitha
Li, Xihao
Li, Zilin
Van Buren, Eric
Haidermota, Sara
Postupaka, Darina
Hornsby, Whitney
Bis, Joshua C
Brody, Jennifer A
Cade, Brian E
Chung, Ren-Hua
Curran, Joanne E
Damrauer, Scott M
de Las Fuentes, Lisa
de Vries, Paul S
Duggirala, Ravindranath
Freedman, Barry I
Graff, MariaElisa
Guo, Xiuqing
Hidalgo, Bertha A
Hou, Lifang
Irvin, Ryan
Judy, Renae
Kalyani, Rita R
Kelly, Tanika N
Konigsberg, Iain R
Kral, Brian G
Kwee, Lydia Coulter
Levy, Daniel
Li, Changwei
Manichaikul, Ani W
Martin, Lisa Warsinger
Montasser, May E
Morrison, Alanna C
Naseri, Take
North, Kari E
O'Connell, Jeffrey R
Palmer, Nicholette D
Peyser, Patricia A
Reiner, Alex P
Shah, Svati H
Smit, Roelof A J
Smith, Jennifer A
Taylor, Kent D
Tiwari, Hemant
Tsai, Michael Y
Viali, Satupa'itea
Wang, Zhe
Wang, Yuxuan
Zhao, Wei
Arnett, Donna K
Blangero, John
Boerwinkle, Eric
Bowden, Donald W
Carlson, Jenna C
Chen, Yii-Der Ida
Ellinor, Patrick T
Fornage, Myriam
He, Jiang
Heard-Costa, Nancy
Kaplan, Robert C
Kardia, Sharon L R
Kooperberg, Charles
Kraus, William E
Lange, Leslie A
Loos, Ruth J F
Mitchell, Braxton D
Psaty, Bruce M
Rader, Daniel J
Redline, Susan
Rich, Stephen S
Yanek, Lisa R
Gibbs, Richard
Gabriel, Stacey
Viaud-Martinez, Karine A
Dutcher, Susan K
Germer, Soren
Kim, Ryan
Rotter, Jerome I
Lin, Xihong
Peloso, Gina M
Natarajan, Pradeep
et al.
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.
Publisher
BioMed Central Ltd
Type
journal article