Methylome-wide association analyses of lipids and modifying effects of behavioral factors in diverse race and ethnicity participants

Circulating lipid concentrations are clinically associated with cardiometabolic diseases. The phenotypic variance explained by identified genetic variants remains limited, highlighting the importance of searching for additional factors beyond genetic sequence variants. DNA methylation has been linked to lipid concentrations in previous studies, although most of the studies harbored moderate sample sizes and exhibited underrepresentation of non-European ancestry populations. In addition, knowledge of nongenetic factors on lipid profiles is extremely limited. In the Population Architecture Using Genomics and Epidemiology (PAGE) Study, we performed methylome-wide association analysis on 9,561 participants from diverse race and ethnicity backgrounds for HDL-c, LDL-c, TC, and TG levels, and also tested interactions between smoking or alcohol intake and methylation in their association with lipid levels. We identified novel CpG sites at 16 loci (P < 1.18E-7) with successful replication on 3,215 participants. One additional novel locus was identified in the self-reported White participants (P = 4.66E-8). Although no additional CpG sites were identified in the genome-wide interaction analysis, 13 reported CpG sites showed significant heterogeneous association across smoking or alcohol intake strata. By mapping novel and reported CpG sites to genes, we identified enriched pathways directly linked to lipid metabolism as well as ones spanning various biological functions. These findings provide new insights into the regulation of lipid concentrations.

Authors

Institutions

Publication Details

Journal
Clinical Epigenetics
Published
2025-04-02
DOI
https://doi.org/10.1186/s13148-025-01859-3
Citations
1
Primary Topic
Genetic Associations and Epidemiology
Type
article
Field-Weighted Citation Impact
1.82

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Methylome-wide association analyses of lipids and modifying effects of behavioral factors in diverse race and ethnicity participants

Charles Kooperberg, Xuzhi Wang, Yesha Patel, Eric A. Whitsel et al.
1 citations
Clinical Epigenetics
Genetic Associations and Epidemiology
1.82
article

Methylome-wide association analyses of lipids and modifying effects of behavioral factors in diverse race and ethnicity participants

Charles Kooperberg, Xuzhi Wang, Yesha Patel, Eric A. Whitsel, Jessica I. Lundin, Alison E. Fohner, Megan T. Lynch, James S. Pankow, Braxton D. Mitchell, Yao Hu, Gina M. Peloso, Laura M. Raffield, Huichun Xu, Megan L. Grove, Mariaelisa Graff, Scott M. Ratliff, Yuxuan Wang, Jennifer A. Smith, Joshua C. Bis, Burcu F. Darst, Jennifer A. Brody, Stephen S. Rich, Michael Y. Tsai, S Lani Park, Alex P. Reiner, Mindy D Szeto, Annette Peters, Rui Xia, Myriam Fornage, Jerome I. Rotter, Weihua Guan, Nona Sotoodehnia, Bruce M. Psaty, K.E. North, Jeff Haessler, Sharon L. R. Kardia, Leslie A. Lange
article en
1 citations

Abstract

Circulating lipid concentrations are clinically associated with cardiometabolic diseases. The phenotypic variance explained by identified genetic variants remains limited, highlighting the importance of searching for additional factors beyond genetic sequence variants. DNA methylation has been linked to lipid concentrations in previous studies, although most of the studies harbored moderate sample sizes and exhibited underrepresentation of non-European ancestry populations. In addition, knowledge of nongenetic factors on lipid profiles is extremely limited. In the Population Architecture Using Genomics and Epidemiology (PAGE) Study, we performed methylome-wide association analysis on 9,561 participants from diverse race and ethnicity backgrounds for HDL-c, LDL-c, TC, and TG levels, and also tested interactions between smoking or alcohol intake and methylation in their association with lipid levels. We identified novel CpG sites at 16 loci (P < 1.18E-7) with successful replication on 3,215 participants. One additional novel locus was identified in the self-reported White participants (P = 4.66E-8). Although no additional CpG sites were identified in the genome-wide interaction analysis, 13 reported CpG sites showed significant heterogeneous association across smoking or alcohol intake strata. By mapping novel and reported CpG sites to genes, we identified enriched pathways directly linked to lipid metabolism as well as ones spanning various biological functions. These findings provide new insights into the regulation of lipid concentrations.

Clinical EpigeneticsVol. 17(1)
Boston University (US), University of North Carolina at Chapel Hill (US), University of Southern California (US), University of Hawaiʻi at Mānoa (US), University of Maryland, Baltimore (US), National Institutes of Health (US), University of Minnesota (US), University of Hawaii System (US), Colorado School of Public Health (US), Baylor College of Medicine (US), University of Washington (US), University of Michigan (US), UCLA Medical Center (US), Fred Hutch Cancer Center (US), Brown Foundation (US), National Cancer Institute (US), Center for Cancer Research (US), Harbor–UCLA Medical Center (US), University of Hawaii Cancer Center, University of Virginia (US), The University of Texas Health Science Center at Houston (US)
U.S. Department of Health and Human Services, National Institutes of Health, National Institute on Aging, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Cancer Institute, National Center for Advancing Translational Sciences, National Institute on Minority Health and Health Disparities
Good health and well-being
Openalex Percentile: Top 17%
Genetic Associations and Epidemiology
1.82
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.