Authors

Lisa de las Fuentes, Washington University School of Medicine in St. Louis
Karen L. Schwander, Washington University School of Medicine in St. Louis
Michael R. Brown, University of Texas School of Public Health
Amy R. Bentley, National Human Genome Research Institute (NHGRI)
Thomas W. Winkler, Universität Regensburg
Yun Ju Sung, Washington University School of Medicine in St. Louis
Patricia B. Munroe, Queen Mary University of London
Clint L. Miller, University of Virginia School of Medicine
Hugo Aschard, Harvard T.H. Chan School of Public Health
Stella Aslibekyan, Department of Epidemiology
Traci M. Bartz, University of Washington School of Medicine
Lawrence F. Bielak, University of Michigan School of Public Health
Jin Fang Chai, National University of Singapore
Ching Yu Cheng, Singapore Eye Research Institute
Rajkumar Dorajoo, A-Star, Genome Institute of Singapore
Mary F. Feitosa, Washington University School of Medicine in St. Louis
Xiuqing Guo, Harbor-UCLA Medical Center
Fernando P. Hartwig, Universidade Federal de Pelotas, Faculdade de Medicina
Andrea Horimoto, Universidade de São Paulo
Ivana Kolčić, School of Medicine, University of Split
Elise Lim, School of Public Health
Yongmei Liu, Duke University School of Medicine
Alisa K. Manning, Massachusetts General Hospital
Jonathan Marten, MRC Human Genetics Unit
Solomon K. Musani, University of Mississippi School of Medicine
Raymond Noordam, Leids Universitair Medisch Centrum
Sandosh Padmanabhan, College of Medical, Veterinary & Life Sciences
Tuomo Rankinen, Pennington Biomedical Research Center
Melissa A. Richard, McGovern Medical School
Paul M. Ridker, Brigham and Women's Hospital
Albert V. Smith, University of Michigan School of Public Health
Dina Vojinovic, Erasmus MC
Alan B. Zonderman, National Institute on Aging (NIA)

Document Type

Article

Publication Date

1-1-2023

Abstract

Introduction: Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes. Methods: A two-stage genome-wide meta-analysis of low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG) levels was performed while accounting for gene-educational attainment interactions in up to 226,315 individuals from five population groups. We considered two educational attainment variables: “Some College” (yes/no, for any education beyond high school) and “Graduated College” (yes/no, for completing a 4-year college degree). Genome-wide significant (p < 5 × 10−8) and suggestive (p < 1 × 10−6) variants were identified in Stage 1 (in up to 108,784 individuals) through genome-wide analysis, and those variants were followed up in Stage 2 studies (in up to 117,531 individuals). Results: In combined analysis of Stages 1 and 2, we identified 18 novel lipid loci (nine for LDL, seven for HDL, and two for TG) by two degree-of-freedom (2 DF) joint tests of main and interaction effects. Four loci showed significant interaction with educational attainment. Two loci were significant only in cross-population analyses. Several loci include genes with known or suggested roles in adipose (FOXP1, MBOAT4, SKP2, STIM1, STX4), brain (BRI3, FILIP1, FOXP1, LINC00290, LMTK2, MBOAT4, MYO6, SENP6, SRGAP3, STIM1, TMEM167A, TMEM30A), and liver (BRI3, FOXP1) biology, highlighting the potential importance of brain-adipose-liver communication in the regulation of lipid metabolism. An investigation of the potential druggability of genes in identified loci resulted in five gene targets shown to interact with drugs approved by the Food and Drug Administration, including genes with roles in adipose and brain tissue. Discussion: Genome-wide interaction analysis of educational attainment identified novel lipid loci not previously detected by analyses limited to main genetic effects.

Publication Source (Journal or Book title)

Frontiers in Genetics

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