Gene-educational attainment interactions in a multi-population genome-wide meta-analysis identify novel lipid loci
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 David R. , Kavousi Maryam , Khor Chiea Chuen , Kilpeläinen Tuomas O. , Koh Woon-Puay , Komulainen Pirjo , Langefeld Carl D. , Liang Jingjing , Liu Kiang , Liu Jianjun , Lohman Kurt , Mägi Reedik , Manichaikul Ani W. , McKenzie Colin A. , Meitinger Thomas , Milaneschi Yuri , Nauck Matthias , Nelson Christopher P. , O’Connell Jeffrey R. , Palmer Nicholette D. , Pereira Alexandre C. , Perls Thomas , Peters Annette , Polašek Ozren , Raitakari Olli T. , Rice Kenneth , Rice Treva K. , Rich Stephen S. , Sabanayagam Charumathi , Schreiner Pamela J. , Shu Xiao-Ou , Sidney Stephen , Sims Mario , Smith Jennifer A. , Starr John M. , Strauch Konstantin , Tai E. Shyong , Taylor Kent D. , Tsai Michael Y. , Uitterlinden André G. , van Heemst Diana , Waldenberger Melanie , Wang Ya-Xing , Wei Wen-Bin , Wilson Gregory , Xuan Deng , Yao Jie , Yu Caizheng , Yuan Jian-Min , Zhao Wei , Becker Diane M. , Bonnefond Amélie , Bowden Donald W. , Cooper Richard S. , Deary Ian J. , Divers Jasmin , Esko Tõnu , Franks Paul W. , Froguel Philippe , Gieger Christian , Jonas Jost B. , Kato Norihiro , Lakka Timo A. , Leander Karin , Lehtimäki Terho , Magnusson Patrik K. E. , North Kari E. , Ntalla Ioanna , Penninx Brenda , Samani Nilesh J. , Snieder Harold , Spedicati Beatrice , van der Harst Pim , Völzke Henry , Wagenknecht Lynne E. , Weir David R. , Wojczynski Mary K. , Wu Tangchun , Zheng Wei , Zhu Xiaofeng , Bouchard Claude , Chasman Daniel I. , Evans Michele K. , Fox Ervin R. , Gudnason Vilmundur , Hayward Caroline , Horta Bernardo L. , Kardia Sharon L. R. , Krieger Jose Eduardo , Mook-Kanamori Dennis O. , Peyser Patricia A. , Province Michael M. , Psaty Bruce M. , Rudan Igor , Sim Xueling , Smith Blair H. , van Dam Rob M. , van Duijn Cornelia M. , Wong Tien Yin , Arnett Donna K. , Rao Dabeeru C. , Gauderman James , Liu Ching-Ti , Morrison Alanna C. , Rotter Jerome I. , Fornage Myriam 
Published: November 2023

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 &lt; 5 × 10−8) and suggestive (p &lt; 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.