Gene-educational attainment interactions in a multi-population genome-wide meta-analysis identify novel lipid loci

• Published in: Frontiers in genetics Vol. 14; p. 1235337
• Main Authors: de Las Fuentes, Lisa, Schwander, Karen L, Brown, Michael R, Bentley, Amy R, Winkler, Thomas W, Sung, Yun Ju, Munroe, Patricia B, Miller, Clint L, Aschard, Hugo, Aslibekyan, Stella, Bartz, Traci M, Bielak, Lawrence F, Chai, Jin Fang, Cheng, Ching-Yu, Dorajoo, Rajkumar, Feitosa, Mary F, Guo, Xiuqing, Hartwig, Fernando P, Horimoto, Andrea, Kolčić, Ivana, Lim, Elise, Liu, Yongmei, Manning, Alisa K, Marten, Jonathan, Musani, Solomon K, Noordam, Raymond, Padmanabhan, Sandosh, Rankinen, Tuomo, Richard, Melissa A, Ridker, Paul M, Smith, Albert V, Vojinovic, Dina, Zonderman, Alan B, Alver, Maris, Boissel, Mathilde, Christensen, Kaare, Freedman, Barry I, Gao, Chuan, Giulianini, Franco, Harris, Sarah E, He, Meian, Hsu, Fang-Chi, Kühnel, Brigitte, Laguzzi, Federica, Li, Xiaoyin, Lyytikäinen, Leo-Pekka, Nolte, Ilja M, Poveda, Alaitz, Rauramaa, Rainer, Riaz, Muhammad, Robino, Antonietta, Sofer, Tamar, Takeuchi, Fumihiko, Tayo, Bamidele O, van der Most, Peter J, Verweij, Niek, Ware, Erin B, Weiss, Stefan, Wen, Wanqing, Yanek, Lisa R, Zhan, Yiqiang, Amin, Najaf, Arking, Dan E, Ballantyne, Christie, Boerwinkle, Eric, Brody, Jennifer A, Broeckel, Ulrich, Campbell, Archie, Canouil, Mickaël, Chai, Xiaoran, Chen, Yii-Der Ida, Chen, Xu, Chitrala, Kumaraswamy Naidu, Concas, Maria Pina, de Faire, Ulf, de Mutsert, Renée, de Silva, H Janaka, de Vries, Paul S, Do, Ahn, Faul, Jessica D, Fisher, Virginia, Floyd, James S, Forrester, Terrence, Friedlander, Yechiel, Girotto, Giorgia, Gu, C Charles, Hallmans, Göran, Heikkinen, Sami, Heng, Chew-Kiat, Homuth, Georg, Hunt, Steven, Ikram, M Arfan, Jacobs, Jr, David R, Kavousi, Maryam, Khor, Chiea Chuen, Kilpeläinen, Tuomas O, Koh, Woon-Puay, Komulainen, Pirjo, Langefeld, Carl D, Liang, Jingjing
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media 2023; Frontiers Media S.A
• Subjects: adolescent; adult; aged; Basic Medicine; brain tissue; BRI3 gene; cholesterol; drug repositioning; educational attainment; electrodermal response; female; FILIP1 gene; FOXP1 gene; gene frequency; gene linkage disequilibrium; genetic analysis; genetic association; genome-wide association study; genotyping; glucose; glutathione; haplotype; high density lipoprotein cholesterol; human; interleukin 18; ionotropic receptor; Life Sciences; LINC00290 gene; lipid metabolism; lipids; LMTK2 gene; low density lipoprotein cholesterol; major clinical study; male; MBOAT4 gene; Medical and Health Sciences; Medical Genetics; Medicin och hälsovetenskap; Medicinsk genetik; Medicinska och farmaceutiska grundvetenskaper; meta-analysis; MYO6 gene; olfactory receptor; protein interaction; proton nuclear magnetic resonance; quality control; ribonucleotide reductase; SENP6 gene; single nucleotide polymorphism; SKP2 gene; social status; SRGAP3 gene; STIM1 gene; STX4 gene; TMEM167A gene; TMEM30A gene; triacylglycerol; triglycerides; meta-analysis; cholesterol; lipids; triglycerides; educational attainment; genome-wide association study
• ISSN: 1664-8021; 1664-8021
• DOI: 10.3389/fgene.2023.1235337

Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes. 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 ( < 5 × 10 ) and suggestive ( < 1 × 10 ) 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). 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 ( ), brain ( ), and liver ( ) 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. Genome-wide interaction analysis of educational attainment identified novel lipid loci not previously detected by analyses limited to main genetic effects.