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

Lisa de las Fuentes; Karen L. Schwander; Michael R. Brown; Amy R. Bentley; Thomas W. Winkler; Yun Ju Sung; Patricia B. Munroe; Clint L. Miller; Hugo Aschard; Stella Aslibekyan; Traci M. Bartz; Lawrence F. Bielak; Jin Fang Chai; Ching-Yu Cheng; Rajkumar Dorajoo; Mary F. Feitosa; Xiuqing Guo; Fernando P. Hartwig; Andrea Horimoto; Ivana Kolčić; Elise Lim; Yongmei Liu; Alisa K. Manning; Jonathan Marten; Solomon K. Musani; Raymond Noordam; Sandosh Padmanabhan; Tuomo Rankinen; Melissa A. Richard; Paul M. Ridker; Albert V. Smith; Dina Vojinovic; Alan B. Zonderman; Maris Alver; Mathilde Boissel; Kaare Christensen; Barry I. Freedman; Chuan Gao; Franco Giulianini; Sarah E. Harris; Meian He; Fang-Chi Hsu; Brigitte Kühnel; Federica Laguzzi; Xiaoyin Li; Leo-Pekka Lyytikäinen; Ilja M. Nolte; Alaitz Poveda; Rainer Rauramaa; Muhammad Riaz; Antonietta Robino; Tamar Sofer; Fumihiko Takeuchi; Bamidele O. Tayo; Peter J. van der Most; Niek Verweij; Erin B. Ware; Stefan Weiss; Wanqing Wen; Lisa R. Yanek; Yiqiang Zhan; Najaf Amin; Dan E. Arking; Christie Ballantyne; Eric Boerwinkle; Jennifer A. Brody; Ulrich Broeckel; Archie Campbell; Mickaël Canouil; Xiaoran Chai; Yii-Der Ida Chen; Xu Chen; Kumaraswamy Naidu Chitrala; Maria Pina Concas; Ulf de Faire; Renée de Mutsert; H. Janaka de Silva; Paul S. de Vries; Ahn Do; Jessica D. Faul; Virginia Fisher; James S. Floyd; Terrence Forrester; Yechiel Friedlander; Giorgia Girotto; C. Charles Gu; G. ran Hallmans; Sami Heikkinen; Chew-Kiat Heng; Georg Homuth; Steven Hunt; M. Arfan Ikram; David R. Jacobs; Maryam Kavousi; Chiea Chuen Khor; Tuomas O. Kilpeläinen; Woon-Puay Koh; Pirjo Komulainen; Carl D. Langefeld; Jingjing Liang; Kiang Liu; Jianjun Liu; Kurt Lohman; Reedik Mägi; Ani W. Manichaikul; Colin A. McKenzie; Thomas Meitinger; Yuri Milaneschi; Matthias Nauck; Christopher P. Nelson; Jeffrey R. O’Connell; Nicholette D. Palmer; Alexandre C. Pereira; Thomas Perls; Annette Peters; Ozren Polašek; Olli T. Raitakari; Kenneth Rice; Treva K. Rice; Stephen S. Rich; Charumathi Sabanayagam; Pamela J. Schreiner; Xiao-Ou Shu; Stephen Sidney; Mario Sims; Jennifer A. Smith; John M. Starr; Konstantin Strauch; E. Shyong Tai; Kent D. Taylor; Michael Y. Tsai; André G. Uitterlinden; Diana van Heemst; Melanie Waldenberger; Ya-Xing Wang; Wen-Bin Wei; Gregory Wilson; Deng Xuan; Jie Yao; Caizheng Yu; Jian-Min Yuan; Wei Zhao; Diane M. Becker; Amélie Bonnefond; Donald W. Bowden; Richard S. Cooper; Ian J. Deary; Jasmin Divers; T. nu Esko; Paul W. Franks; Philippe Froguel; Christian Gieger; Jost B. Jonas; Norihiro Kato; Timo A. Lakka; Karin Leander; Terho Lehtimäki; Patrik K. E. Magnusson; Kari E. North; Ioanna Ntalla; Brenda Penninx; Nilesh J. Samani; Harold Snieder; Beatrice Spedicati; Pim van der Harst; Henry Völzke; Lynne E. Wagenknecht; David R. Weir; Mary K. Wojczynski; Tangchun Wu; Wei Zheng; Xiaofeng Zhu; Claude Bouchard; Daniel I. Chasman; Michele K. Evans; Ervin R. Fox; Vilmundur Gudnason; Caroline Hayward; Bernardo L. Horta; Sharon L. R. Kardia; Jose Eduardo Krieger; Dennis O. Mook-Kanamori; Patricia A. Peyser; Michael M. Province; Bruce M. Psaty; Igor Rudan; Xueling Sim; Blair H. Smith; Rob M. van Dam; Cornelia M. van Duijn; Tien Yin Wong; Donna K. Arnett; Dabeeru C. Rao; James Gauderman; Ching-Ti Liu; Alanna C. Morrison; Jerome I. Rotter; Myriam Fornage

doi:https://doi.org/10.3389/fgene.2023.1235337

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

Lisa de las Fuentes, Karen L. Schwander, Michael R. Brown, Amy R. Bentley, Thomas W. Winkler, Yun Ju Sung, Patricia B. Munroe, Clint L. Miller, Hugo Aschard, Stella Aslibekyan, Traci M. Bartz, Lawrence F. Bielak, Jin Fang Chai, Ching-Yu Cheng, Rajkumar Dorajoo, Mary F. Feitosa, Xiuqing Guo, Fernando P. Hartwig, Andrea Horimoto, Ivana KolčićElise Lim, Yongmei Liu, Alisa K. Manning, Jonathan Marten, Solomon K. Musani, Raymond Noordam, Sandosh Padmanabhan, Tuomo Rankinen, Melissa A. Richard, Paul M. Ridker, Albert V. Smith, Dina Vojinovic, Alan B. Zonderman, Maris Alver, Mathilde Boissel, Kaare Christensen, Barry I. Freedman, Chuan Gao, Franco Giulianini, Sarah E. Harris, Meian He, Fang-Chi Hsu, Brigitte Kühnel, Federica Laguzzi, Xiaoyin Li, Leo-Pekka Lyytikäinen, Ilja M. Nolte, Alaitz Poveda, Rainer Rauramaa, Muhammad Riaz, Antonietta Robino, Tamar Sofer, Fumihiko Takeuchi, Bamidele O. Tayo, Peter J. van der Most, Niek Verweij, Erin B. Ware, Stefan Weiss, Wanqing Wen, Lisa R. Yanek, Yiqiang Zhan, Najaf Amin, Dan E. Arking, Christie Ballantyne, Eric Boerwinkle, Jennifer A. Brody, Ulrich Broeckel, Archie Campbell, Mickaël Canouil, Xiaoran Chai, Yii-Der Ida Chen, Xu Chen, Kumaraswamy Naidu Chitrala, Maria Pina Concas, Ulf de Faire, Renée de Mutsert, H. Janaka de Silva, Paul S. de Vries, Ahn Do, Jessica D. Faul, Virginia Fisher, James S. Floyd, Terrence Forrester, Yechiel Friedlander, Giorgia Girotto, C. Charles Gu, G. ran Hallmans, Sami Heikkinen, Chew-Kiat Heng, Georg Homuth, Steven Hunt, M. Arfan Ikram, David R. Jacobs, Maryam Kavousi, Chiea Chuen Khor, Tuomas O. Kilpeläinen, Woon-Puay Koh, Pirjo Komulainen, Carl D. Langefeld, Jingjing Liang, Kiang Liu, Jianjun Liu, Kurt Lohman, Reedik Mägi, Ani W. Manichaikul, Colin A. McKenzie, Thomas Meitinger, Yuri Milaneschi, Matthias Nauck, Christopher P. Nelson, Jeffrey R. O’Connell, Nicholette D. Palmer, Alexandre C. Pereira, Thomas Perls, Annette Peters, Ozren Polašek, Olli T. Raitakari, Kenneth Rice, Treva K. Rice, Stephen S. Rich, Charumathi Sabanayagam, Pamela J. Schreiner, Xiao-Ou Shu, Stephen Sidney, Mario Sims, Jennifer A. Smith, John M. Starr, Konstantin Strauch, E. Shyong Tai, Kent D. Taylor, Michael Y. Tsai, André G. Uitterlinden, Diana van Heemst, Melanie Waldenberger, Ya-Xing Wang, Wen-Bin Wei, Gregory Wilson, Deng Xuan, Jie Yao, Caizheng Yu, Jian-Min Yuan, Wei Zhao, Diane M. Becker, Amélie Bonnefond, Donald W. Bowden, Richard S. Cooper, Ian J. Deary, Jasmin Divers, T. nu Esko, Paul W. Franks, Philippe Froguel, Christian Gieger, Jost B. Jonas, Norihiro Kato, Timo A. Lakka, Karin Leander, Terho Lehtimäki, Patrik K. E. Magnusson, Kari E. North, Ioanna Ntalla, Brenda Penninx, Nilesh J. Samani, Harold Snieder, Beatrice Spedicati, Pim van der Harst, Henry Völzke, Lynne E. Wagenknecht, David R. Weir, Mary K. Wojczynski, Tangchun Wu, Wei Zheng, Xiaofeng Zhu, Claude Bouchard, Daniel I. Chasman, Michele K. Evans, Ervin R. Fox, Vilmundur Gudnason, Caroline Hayward, Bernardo L. Horta, Sharon L. R. Kardia, Jose Eduardo Krieger, Dennis O. Mook-Kanamori, Patricia A. Peyser, Michael M. Province, Bruce M. Psaty, Igor Rudan, Xueling Sim, Blair H. Smith, Rob M. van Dam, Cornelia M. van Duijn, Tien Yin Wong, Donna K. Arnett, Dabeeru C. Rao, James Gauderman, Ching-Ti Liu, Alanna C. Morrison, Jerome I. Rotter, Myriam Fornage

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Article number	1235337
Journal	Frontiers in genetics
Volume	14
DOIs	https://doi.org/10.3389/fgene.2023.1235337
Publication status	Published - 2023

Keywords

cholesterol
educational attainment
genome-wide association study
lipids
meta-analysis
triglycerides

Access to Document

https://doi.org/10.3389/fgene.2023.1235337

Cite this

de las Fuentes, L., Schwander, K. L., Brown, M. R., Bentley, A. R., Winkler, T. W., Sung, Y. J., Munroe, P. B., Miller, C. L., Aschard, H., Aslibekyan, S., Bartz, T. M., Bielak, L. F., Chai, J. F., Cheng, C.-Y., Dorajoo, R., Feitosa, M. F., Guo, X., Hartwig, F. P., Horimoto, A., ... Fornage, M. (2023). Gene-educational attainment interactions in a multi-population genome-wide meta-analysis identify novel lipid loci. Frontiers in genetics, 14, Article 1235337. https://doi.org/10.3389/fgene.2023.1235337

@article{33521ec3a9004913a367e9a15944d061,

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

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.",

keywords = "cholesterol, educational attainment, genome-wide association study, lipids, meta-analysis, triglycerides",

author = "{de las Fuentes}, Lisa and Schwander, {Karen L.} and Brown, {Michael R.} and Bentley, {Amy R.} and Winkler, {Thomas W.} and Sung, {Yun Ju} and Munroe, {Patricia B.} and Miller, {Clint L.} and Hugo Aschard and Stella Aslibekyan and Bartz, {Traci M.} and Bielak, {Lawrence F.} and Chai, {Jin Fang} and Ching-Yu Cheng and Rajkumar Dorajoo and Feitosa, {Mary F.} and Xiuqing Guo and Hartwig, {Fernando P.} and Andrea Horimoto and Ivana Kol{\v c}i{\'c} and Elise Lim and Yongmei Liu and Manning, {Alisa K.} and Jonathan Marten and Musani, {Solomon K.} and Raymond Noordam and Sandosh Padmanabhan and Tuomo Rankinen and Richard, {Melissa A.} and Ridker, {Paul M.} and Smith, {Albert V.} and Dina Vojinovic and Zonderman, {Alan B.} and Maris Alver and Mathilde Boissel and Kaare Christensen and Freedman, {Barry I.} and Chuan Gao and Franco Giulianini and Harris, {Sarah E.} and Meian He and Fang-Chi Hsu and Brigitte K{\"u}hnel and Federica Laguzzi and Xiaoyin Li and Leo-Pekka Lyytik{\"a}inen and Nolte, {Ilja M.} and Alaitz Poveda and Rainer Rauramaa and Muhammad Riaz and Antonietta Robino and Tamar Sofer and Fumihiko Takeuchi and Tayo, {Bamidele O.} and {van der Most}, {Peter J.} and Niek Verweij and Ware, {Erin B.} and Stefan Weiss and Wanqing Wen and Yanek, {Lisa R.} and Yiqiang Zhan and Najaf Amin and Arking, {Dan E.} and Christie Ballantyne and Eric Boerwinkle and Brody, {Jennifer A.} and Ulrich Broeckel and Archie Campbell and Micka{\"e}l Canouil and Xiaoran Chai and Chen, {Yii-Der Ida} and Xu Chen and Chitrala, {Kumaraswamy Naidu} and Concas, {Maria Pina} and {de Faire}, Ulf and {de Mutsert}, Ren{\'e}e and {de Silva}, {H. Janaka} and {de Vries}, {Paul S.} and Ahn Do and Faul, {Jessica D.} and Virginia Fisher and Floyd, {James S.} and Terrence Forrester and Yechiel Friedlander and Giorgia Girotto and Gu, {C. Charles} and Hallmans, {G. ran} and Sami Heikkinen and Chew-Kiat Heng and Georg Homuth and Steven Hunt and Ikram, {M. Arfan} and Jacobs, {David R.} and Maryam Kavousi and Khor, {Chiea Chuen} and Kilpel{\"a}inen, {Tuomas O.} and Woon-Puay Koh and Pirjo Komulainen and Langefeld, {Carl D.} and Jingjing Liang and Kiang Liu and Jianjun Liu and Kurt Lohman and Reedik M{\"a}gi and Manichaikul, {Ani W.} and McKenzie, {Colin A.} and Thomas Meitinger and Yuri Milaneschi and Matthias Nauck and Nelson, {Christopher P.} and O{\textquoteright}Connell, {Jeffrey R.} and Palmer, {Nicholette D.} and Pereira, {Alexandre C.} and Thomas Perls and Annette Peters and Ozren Pola{\v s}ek and Raitakari, {Olli T.} and Kenneth Rice and Rice, {Treva K.} and Rich, {Stephen S.} and Charumathi Sabanayagam and Schreiner, {Pamela J.} and Xiao-Ou Shu and Stephen Sidney and Mario Sims and Smith, {Jennifer A.} and Starr, {John M.} and Konstantin Strauch and Tai, {E. Shyong} and Taylor, {Kent D.} and Tsai, {Michael Y.} and Uitterlinden, {Andr{\'e} G.} and {van Heemst}, Diana and Melanie Waldenberger and Ya-Xing Wang and Wen-Bin Wei and Gregory Wilson and Deng Xuan and Jie Yao and Caizheng Yu and Jian-Min Yuan and Wei Zhao and Becker, {Diane M.} and Am{\'e}lie Bonnefond and Bowden, {Donald W.} and Cooper, {Richard S.} and Deary, {Ian J.} and Jasmin Divers and Esko, {T. nu} and Franks, {Paul W.} and Philippe Froguel and Christian Gieger and Jonas, {Jost B.} and Norihiro Kato and Lakka, {Timo A.} and Karin Leander and Terho Lehtim{\"a}ki and Magnusson, {Patrik K. E.} and North, {Kari E.} and Ioanna Ntalla and Brenda Penninx and Samani, {Nilesh J.} and Harold Snieder and Beatrice Spedicati and {van der Harst}, Pim and Henry V{\"o}lzke and Wagenknecht, {Lynne E.} and Weir, {David R.} and Wojczynski, {Mary K.} and Tangchun Wu and Wei Zheng and Xiaofeng Zhu and Claude Bouchard and Chasman, {Daniel I.} and Evans, {Michele K.} and Fox, {Ervin R.} and Vilmundur Gudnason and Caroline Hayward and Horta, {Bernardo L.} and Kardia, {Sharon L. R.} and Krieger, {Jose Eduardo} and Mook-Kanamori, {Dennis O.} and Peyser, {Patricia A.} and Province, {Michael M.} and Psaty, {Bruce M.} and Igor Rudan and Xueling Sim and Smith, {Blair H.} and {van Dam}, {Rob M.} and {van Duijn}, {Cornelia M.} and Wong, {Tien Yin} and Arnett, {Donna K.} and Rao, {Dabeeru C.} and James Gauderman and Ching-Ti Liu and Morrison, {Alanna C.} and Rotter, {Jerome I.} and Myriam Fornage",

note = "Funding Information: This project was largely supported by two grants from the U.S. National Heart, Lung, and Blood Institute (NHLBI), the National Institutes of Health, R01HL118305 and R01HL156991. This research was supported in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health (AB). An NHLBI career development award (K25HL121091) enabled YS to play an important role on this project. The full set of study-specific funding sources and acknowledgments appear in the . Funding Information: This project was largely supported by two grants from the U.S. National Heart, Lung, and Blood Institute (NHLBI), the National Institutes of Health, R01HL118305 and R01HL156991. This research was supported in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health (AB). An NHLBI career development award (K25HL121091) enabled YS to play an important role on this project. The full set of study-specific funding sources and acknowledgments appear in the Supplementary Material. Publisher Copyright: Copyright {\textcopyright} 2023 de las Fuentes",

year = "2023",

doi = "https://doi.org/10.3389/fgene.2023.1235337",

language = "English",

volume = "14",

journal = "Frontiers in genetics",

issn = "1664-8021",

publisher = "Frontiers Media S.A.",

}

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, C-Y, 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, F-C, Kühnel, B, Laguzzi, F, Li, X, Lyytikäinen, L-P, 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, Y-DI, 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, GR, Heikkinen, S, Heng, C-K, Homuth, G, Hunt, S, Ikram, MA, Jacobs, DR, Kavousi, M, Khor, CC, Kilpeläinen, TO, Koh, W-P, 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, X-O, Sidney, S, Sims, M, Smith, JA, Starr, JM, Strauch, K, Tai, ES, Taylor, KD, Tsai, MY, Uitterlinden, AG, van Heemst, D, Waldenberger, M, Wang, Y-X, Wei, W-B, Wilson, G, Xuan, D, Yao, J, Yu, C, Yuan, J-M, Zhao, W, Becker, DM, Bonnefond, A, Bowden, DW, Cooper, RS, Deary, IJ, Divers, J, Esko, TN, 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, C-T, Morrison, AC, Rotter, JI & Fornage, M 2023, 'Gene-educational attainment interactions in a multi-population genome-wide meta-analysis identify novel lipid loci', Frontiers in genetics, vol. 14, 1235337. https://doi.org/10.3389/fgene.2023.1235337

TY - JOUR

T1 - Gene-educational attainment interactions in a multi-population genome-wide meta-analysis identify novel lipid loci

AU - de las Fuentes, Lisa

AU - Schwander, Karen L.

AU - Brown, Michael R.

AU - Bentley, Amy R.

AU - Winkler, Thomas W.

AU - Sung, Yun Ju

AU - Munroe, Patricia B.

AU - Miller, Clint L.

AU - Aschard, Hugo

AU - Aslibekyan, Stella

AU - Bartz, Traci M.

AU - Bielak, Lawrence F.

AU - Chai, Jin Fang

AU - Cheng, Ching-Yu

AU - Dorajoo, Rajkumar

AU - Feitosa, Mary F.

AU - Guo, Xiuqing

AU - Hartwig, Fernando P.

AU - Horimoto, Andrea

AU - Kolčić, Ivana

AU - Lim, Elise

AU - Liu, Yongmei

AU - Manning, Alisa K.

AU - Marten, Jonathan

AU - Musani, Solomon K.

AU - Noordam, Raymond

AU - Padmanabhan, Sandosh

AU - Rankinen, Tuomo

AU - Richard, Melissa A.

AU - Ridker, Paul M.

AU - Smith, Albert V.

AU - Vojinovic, Dina

AU - Zonderman, Alan B.

AU - Alver, Maris

AU - Boissel, Mathilde

AU - Christensen, Kaare

AU - Freedman, Barry I.

AU - Gao, Chuan

AU - Giulianini, Franco

AU - Harris, Sarah E.

AU - He, Meian

AU - Hsu, Fang-Chi

AU - Kühnel, Brigitte

AU - Laguzzi, Federica

AU - Li, Xiaoyin

AU - Lyytikäinen, Leo-Pekka

AU - Nolte, Ilja M.

AU - Poveda, Alaitz

AU - Rauramaa, Rainer

AU - Riaz, Muhammad

AU - Robino, Antonietta

AU - Sofer, Tamar

AU - Takeuchi, Fumihiko

AU - Tayo, Bamidele O.

AU - van der Most, Peter J.

AU - Verweij, Niek

AU - Ware, Erin B.

AU - Weiss, Stefan

AU - Wen, Wanqing

AU - Yanek, Lisa R.

AU - Zhan, Yiqiang

AU - Amin, Najaf

AU - Arking, Dan E.

AU - Ballantyne, Christie

AU - Boerwinkle, Eric

AU - Brody, Jennifer A.

AU - Broeckel, Ulrich

AU - Campbell, Archie

AU - Canouil, Mickaël

AU - Chai, Xiaoran

AU - Chen, Yii-Der Ida

AU - Chen, Xu

AU - Chitrala, Kumaraswamy Naidu

AU - Concas, Maria Pina

AU - de Faire, Ulf

AU - de Mutsert, Renée

AU - de Silva, H. Janaka

AU - de Vries, Paul S.

AU - Do, Ahn

AU - Faul, Jessica D.

AU - Fisher, Virginia

AU - Floyd, James S.

AU - Forrester, Terrence

AU - Friedlander, Yechiel

AU - Girotto, Giorgia

AU - Gu, C. Charles

AU - Hallmans, G. ran

AU - Heikkinen, Sami

AU - Heng, Chew-Kiat

AU - Homuth, Georg

AU - Hunt, Steven

AU - Ikram, M. Arfan

AU - Jacobs, David R.

AU - Kavousi, Maryam

AU - Khor, Chiea Chuen

AU - Kilpeläinen, Tuomas O.

AU - Koh, Woon-Puay

AU - Komulainen, Pirjo

AU - Langefeld, Carl D.

AU - Liang, Jingjing

AU - Liu, Kiang

AU - Liu, Jianjun

AU - Lohman, Kurt

AU - Mägi, Reedik

AU - Manichaikul, Ani W.

AU - McKenzie, Colin A.

AU - Meitinger, Thomas

AU - Milaneschi, Yuri

AU - Nauck, Matthias

AU - Nelson, Christopher P.

AU - O’Connell, Jeffrey R.

AU - Palmer, Nicholette D.

AU - Pereira, Alexandre C.

AU - Perls, Thomas

AU - Peters, Annette

AU - Polašek, Ozren

AU - Raitakari, Olli T.

AU - Rice, Kenneth

AU - Rice, Treva K.

AU - Rich, Stephen S.

AU - Sabanayagam, Charumathi

AU - Schreiner, Pamela J.

AU - Shu, Xiao-Ou

AU - Sidney, Stephen

AU - Sims, Mario

AU - Smith, Jennifer A.

AU - Starr, John M.

AU - Strauch, Konstantin

AU - Tai, E. Shyong

AU - Taylor, Kent D.

AU - Tsai, Michael Y.

AU - Uitterlinden, André G.

AU - van Heemst, Diana

AU - Waldenberger, Melanie

AU - Wang, Ya-Xing

AU - Wei, Wen-Bin

AU - Wilson, Gregory

AU - Xuan, Deng

AU - Yao, Jie

AU - Yu, Caizheng

AU - Yuan, Jian-Min

AU - Zhao, Wei

AU - Becker, Diane M.

AU - Bonnefond, Amélie

AU - Bowden, Donald W.

AU - Cooper, Richard S.

AU - Deary, Ian J.

AU - Divers, Jasmin

AU - Esko, T. nu

AU - Franks, Paul W.

AU - Froguel, Philippe

AU - Gieger, Christian

AU - Jonas, Jost B.

AU - Kato, Norihiro

AU - Lakka, Timo A.

AU - Leander, Karin

AU - Lehtimäki, Terho

AU - Magnusson, Patrik K. E.

AU - North, Kari E.

AU - Ntalla, Ioanna

AU - Penninx, Brenda

AU - Samani, Nilesh J.

AU - Snieder, Harold

AU - Spedicati, Beatrice

AU - van der Harst, Pim

AU - Völzke, Henry

AU - Wagenknecht, Lynne E.

AU - Weir, David R.

AU - Wojczynski, Mary K.

AU - Wu, Tangchun

AU - Zheng, Wei

AU - Zhu, Xiaofeng

AU - Bouchard, Claude

AU - Chasman, Daniel I.

AU - Evans, Michele K.

AU - Fox, Ervin R.

AU - Gudnason, Vilmundur

AU - Hayward, Caroline

AU - Horta, Bernardo L.

AU - Kardia, Sharon L. R.

AU - Krieger, Jose Eduardo

AU - Mook-Kanamori, Dennis O.

AU - Peyser, Patricia A.

AU - Province, Michael M.

AU - Psaty, Bruce M.

AU - Rudan, Igor

AU - Sim, Xueling

AU - Smith, Blair H.

AU - van Dam, Rob M.

AU - van Duijn, Cornelia M.

AU - Wong, Tien Yin

AU - Arnett, Donna K.

AU - Rao, Dabeeru C.

AU - Gauderman, James

AU - Liu, Ching-Ti

AU - Morrison, Alanna C.

AU - Rotter, Jerome I.

AU - Fornage, Myriam

N1 - Funding Information: This project was largely supported by two grants from the U.S. National Heart, Lung, and Blood Institute (NHLBI), the National Institutes of Health, R01HL118305 and R01HL156991. This research was supported in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health (AB). An NHLBI career development award (K25HL121091) enabled YS to play an important role on this project. The full set of study-specific funding sources and acknowledgments appear in the . Funding Information: This project was largely supported by two grants from the U.S. National Heart, Lung, and Blood Institute (NHLBI), the National Institutes of Health, R01HL118305 and R01HL156991. This research was supported in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health (AB). An NHLBI career development award (K25HL121091) enabled YS to play an important role on this project. The full set of study-specific funding sources and acknowledgments appear in the Supplementary Material. Publisher Copyright: Copyright © 2023 de las Fuentes

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

KW - cholesterol

KW - educational attainment

KW - genome-wide association study

KW - lipids

KW - meta-analysis

KW - triglycerides

UR - http://www.scopus.com/inward/record.url?scp=85177065494&partnerID=8YFLogxK

U2 - https://doi.org/10.3389/fgene.2023.1235337

DO - https://doi.org/10.3389/fgene.2023.1235337

M3 - Article

C2 - 38028628

SN - 1664-8021

VL - 14

JO - Frontiers in genetics

JF - Frontiers in genetics

M1 - 1235337

ER -

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

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