1. Gene-educational attainment interactions in a multi-population genome-wide meta-analysis identify novel lipid loci.
- Author
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de las Fuentes L, Schwander KL, Brown MR, Bentley AR, Winkler TW, Sung YJ, Munroe PB, Miller CL, Aschard H, Aslibekyan S, Bartz TM, Bielak LF, Chai JF, Cheng CY, Dorajoo R, Feitosa MF, Guo X, Hartwig FP, Horimoto A, Kolčić I, Lim E, Liu Y, Manning AK, Marten J, Musani SK, Noordam R, Padmanabhan S, Rankinen T, Richard MA, Ridker PM, Smith AV, Vojinovic D, Zonderman AB, Alver M, Boissel M, Christensen K, Freedman BI, Gao C, Giulianini F, Harris SE, He M, Hsu FC, Kühnel B, Laguzzi F, Li X, Lyytikäinen LP, Nolte IM, Poveda A, Rauramaa R, Riaz M, Robino A, Sofer T, Takeuchi F, Tayo BO, van der Most PJ, Verweij N, Ware EB, Weiss S, Wen W, Yanek LR, Zhan Y, Amin N, Arking DE, Ballantyne C, Boerwinkle E, Brody JA, Broeckel U, Campbell A, Canouil M, Chai X, Chen YI, Chen X, Chitrala KN, Concas MP, de Faire U, de Mutsert R, de Silva HJ, de Vries PS, Do A, Faul JD, Fisher V, Floyd JS, Forrester T, Friedlander Y, Girotto G, Gu CC, Hallmans G, Heikkinen S, Heng CK, Homuth G, Hunt S, Ikram MA, Jacobs DR Jr, Kavousi M, Khor CC, Kilpeläinen TO, Koh WP, Komulainen P, Langefeld CD, Liang J, Liu K, Liu J, Lohman K, Mägi R, Manichaikul AW, McKenzie CA, Meitinger T, Milaneschi Y, Nauck M, Nelson CP, O'Connell JR, Palmer ND, Pereira AC, Perls T, Peters A, Polašek O, Raitakari OT, Rice K, Rice TK, Rich SS, Sabanayagam C, Schreiner PJ, Shu XO, Sidney S, Sims M, Smith JA, Starr JM, Strauch K, Tai ES, Taylor KD, Tsai MY, Uitterlinden AG, van Heemst D, Waldenberger M, Wang YX, Wei WB, Wilson G, Xuan D, Yao J, Yu C, Yuan JM, Zhao W, Becker DM, Bonnefond A, Bowden DW, Cooper RS, Deary IJ, Divers J, Esko T, Franks PW, Froguel P, Gieger C, Jonas JB, Kato N, Lakka TA, Leander K, Lehtimäki T, Magnusson PKE, North KE, Ntalla I, Penninx B, Samani NJ, Snieder H, Spedicati B, van der Harst P, Völzke H, Wagenknecht LE, Weir DR, Wojczynski MK, Wu T, Zheng W, Zhu X, Bouchard C, Chasman DI, Evans MK, Fox ER, Gudnason V, Hayward C, Horta BL, Kardia SLR, Krieger JE, Mook-Kanamori DO, Peyser PA, Province MM, Psaty BM, Rudan I, Sim X, Smith BH, van Dam RM, van Duijn CM, Wong TY, Arnett DK, Rao DC, Gauderman J, Liu CT, Morrison AC, Rotter JI, and Fornage M
- 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., Competing Interests: IN is now employed by Celgene. BMP serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. SA is employed by and holds equity in 23andMe, Inc. Authors BK, MW, and CGa were employed by Helmholtz Zentrum München. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 de las Fuentes, Schwander, Brown, Bentley, Winkler, Sung, Munroe, Miller, Aschard, Aslibekyan, Bartz, Bielak, Chai, Cheng, Dorajoo, Feitosa, Guo, Hartwig, Horimoto, Kolčić, Lim, Liu, Manning, Marten, Musani, Noordam, Padmanabhan, Rankinen, Richard, Ridker, Smith, Vojinovic, Zonderman, Alver, Boissel, Christensen, Freedman, Gao, Giulianini, Harris, He, Hsu, Kühnel, Laguzzi, Li, Lyytikäinen, Nolte, Poveda, Rauramaa, Riaz, Robino, Sofer, Takeuchi, Tayo, van der Most, Verweij, Ware, Weiss, Wen, Yanek, Zhan, Amin, Arking, Ballantyne, Boerwinkle, Brody, Broeckel, Campbell, Canouil, Chai, Ida Chen, Chen, Chitrala, Concas, de Faire, de Mutsert, de Silva, de Vries, Do, Faul, Fisher, Floyd, Forrester, Friedlander, Girotto, Gu, Hallmans, Heikkinen, Heng, Homuth, Hunt, Ikram, Jacobs, Kavousi, Khor, Kilpeläinen, Koh, Komulainen, Langefeld, Liang, Liu, Liu, Lohman, Mägi, Manichaikul, McKenzie, Meitinger, Milaneschi, Nauck, Nelson, O’Connell, Palmer, Pereira, Perls, Peters, Polašek, Raitakari, Rice, Rice, Rich, Sabanayagam, Schreiner, Shu, Sidney, Sims, Smith, Starr, Strauch, Tai, Taylor, Tsai, Uitterlinden, van Heemst, Waldenberger, Wang, Wei, Wilson, Xuan, Yao, Yu, Yuan, Zhao, Becker, Bonnefond, Bowden, Cooper, Deary, Divers, Esko, Franks, Froguel, Gieger, Jonas, Kato, Lakka, Leander, Lehtimäki, Magnusson, North, Ntalla, Penninx, Samani, Snieder, Spedicati, van der Harst, Völzke, Wagenknecht, Weir, Wojczynski, Wu, Zheng, Zhu, Bouchard, Chasman, Evans, Fox, Gudnason, Hayward, Horta, Kardia, Krieger, Mook-Kanamori, Peyser, Province, Psaty, Rudan, Sim, Smith, van Dam, van Duijn, Wong, Arnett, Rao, Gauderman, Liu, Morrison, Rotter and Fornage.)- Published
- 2023
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