Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity

Tuomas O. Kilpeläinen; Amy R. Bentley; Raymond Noordam; Yun Ju Sung; Karen Schwander; Thomas W. Winkler; Hermina Jakupović; Daniel I. Chasman; Alisa Manning; Ioanna Ntalla; Hugues Aschard; Michael R. Brown; Lisa de las Fuentes; Nora Franceschini; Xiuqing Guo; Dina Vojinovic; Stella Aslibekyan; Mary F. Feitosa; Minjung Kho; Solomon K. Musani; Melissa Richard; Heming Wang; Zhe Wang; Traci M. Bartz; Lawrence F. Bielak; Archie Campbell; Rajkumar Dorajoo; Virginia Fisher; Fernando P. Hartwig; Andrea R. V. R. Horimoto; Changwei Li; Kurt K. Lohman; Jonathan Marten; Xueling Sim; Albert V. Smith; Salman M. Tajuddin; Maris Alver; Marzyeh Amini; Mathilde Boissel; Jin Fang Chai; Xu Chen; Jasmin Divers; Evangelos Evangelou; Chuan Gao; Mariaelisa Graff; Sarah E. Harris; Meian He; Fang-Chi Hsu; Anne U. Jackson; Jing Hua Zhao; Aldi T. Kraja; Brigitte Kühnel; Federica Laguzzi; Leo-Pekka Lyytikäinen; Ilja M. Nolte; Rainer Rauramaa; Muhammad Riaz; Antonietta Robino; Rico Rueedi; Heather M. Stringham; Fumihiko Takeuchi; Peter J. van der Most; Tibor V. Varga; Niek Verweij; Erin B. Ware; Wanqing Wen; Xiaoyin Li; Lisa R. Yanek; Najaf Amin; Donna K. Arnett; Eric Boerwinkle; Marco Brumat; Brian Cade; Mickaël Canouil; Yii-Der Ida Chen; Maria Pina Concas; John Connell; Renée de Mutsert; H. Janaka de Silva; Paul S. de Vries; Ayşe Demirkan; Jingzhong Ding; Charles B. Eaton; Jessica D. Faul; Yechiel Friedlander; Kelley P. Gabriel; Mohsen Ghanbari; Franco Giulianini; Chi Charles Gu; Dongfeng Gu; Tamara B. Harris; Jiang He; Sami Heikkinen; Chew-Kiat Heng; Steven C. Hunt; M. Arfan Ikram; Jost B. Jonas; Woon-Puay Koh; Pirjo Komulainen; Jose E. Krieger; Stephen B. Kritchevsky; Zoltán Kutalik; Johanna Kuusisto; Carl D. Langefeld; Claudia Langenberg; Lenore J. Launer; Karin Leander; Rozenn N. Lemaitre; Cora E. Lewis; Jingjing Liang; Behrooz Z. Alizadeh; H. Marike Boezen; Lude Franke; Gerjan Navis; Marianne Rots; Morris Swertz; Bruce H. R. Wolffenbuttel; Cisca Wijmenga; Jianjun Liu; Reedik Mägi; Ani Manichaikul; Thomas Meitinger; Andres Metspalu; Yuri Milaneschi; Karen L. Mohlke; Thomas H. Mosley; Alison D. Murray; Mike A. Nalls; Ei-Ei Khaing Nang; Christopher P. Nelson; Sotoodehnia Nona; Jill M. Norris; Chiamaka Vivian Nwuba; Jeff O’Connell; Nicholette D. Palmer; George J. Papanicolau; Raha Pazoki; Nancy L. Pedersen; Annette Peters; Patricia A. Peyser; Ozren Polasek; David J. Porteous; Alaitz Poveda; Olli T. Raitakari; Stephen S. Rich; Neil Risch; Jennifer G. Robinson; Lynda M. Rose; Igor Rudan; Pamela J. Schreiner; Robert A. Scott; Stephen S. Sidney; Mario Sims; Jennifer A. Smith; Harold Snieder; Tamar Sofer; John M. Starr; Barbara Sternfeld; Konstantin Strauch; Hua Tang; Kent D. Taylor; Michael Y. Tsai; Jaakko Tuomilehto; André G. Uitterlinden; M. Yldau van der Ende; Diana van Heemst; Trudy Voortman; Melanie Waldenberger; Patrik Wennberg; Gregory Wilson; Yong-Bing Xiang; Jie Yao; Caizheng Yu; Jian-Min Yuan; Wei Zhao; Alan B. Zonderman; Diane M. Becker; Michael Boehnke; Donald W. Bowden; Ulf de Faire; Ian J. Deary; Paul Elliott; Tõnu Esko; Barry I. Freedman; Philippe Froguel; Paolo Gasparini; Christian Gieger; Norihiro Kato; Markku Laakso; Timo A. Lakka; Terho Lehtimäki; Patrik K. E. Magnusson; Albertine J. Oldehinkel; Brenda W. J. H. Penninx; Nilesh J. Samani; Xiao-Ou Shu; Pim van der Harst; Jana V. Van Vliet-Ostaptchouk; Peter Vollenweider; Lynne E. Wagenknecht; Ya X. Wang; Nicholas J. Wareham; David R. Weir; Tangchun Wu; Wei Zheng; Xiaofeng Zhu; Michele K. Evans; Paul W. Franks; Vilmundur Gudnason; Caroline Hayward; Bernardo L. Horta; Tanika N. Kelly; Yongmei Liu; Kari E. North; Alexandre C. Pereira; Paul M. Ridker; E. Shyong Tai; Rob M. van Dam; Ervin R. Fox; Sharon L. R. Kardia; Ching-Ti Liu; Dennis O. Mook-Kanamori; Michael A. Province; Susan Redline; Cornelia M. van Duijn; Jerome I. Rotter; Charles B. Kooperberg; W. James Gauderman; Bruce M. Psaty; Kenneth Rice; Patricia B. Munroe; Myriam Fornage; L. Adrienne Cupples; Charles N. Rotimi; Alanna C. Morrison; Dabeeru C. Rao; Ruth J. F. Loos; Lifelines Cohort Study

doi:10.1038/s41467-018-08008-w

Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity

Tuomas O. Kilpeläinen (Corresponding Author), Amy R. Bentley, Raymond Noordam, Yun Ju Sung, Karen Schwander, Thomas W. Winkler, Hermina Jakupović, Daniel I. Chasman, Alisa Manning, Ioanna Ntalla, Hugues Aschard, Michael R. Brown, Lisa de las Fuentes, Nora Franceschini, Xiuqing Guo, Dina Vojinovic, Stella Aslibekyan, Mary F. Feitosa, Minjung Kho, Solomon K. MusaniMelissa Richard, Heming Wang, Zhe Wang, Traci M. Bartz, Lawrence F. Bielak, Archie Campbell, Rajkumar Dorajoo, Virginia Fisher, Fernando P. Hartwig, Andrea R. V. R. Horimoto, Changwei Li, Kurt K. Lohman, Jonathan Marten, Xueling Sim, Albert V. Smith, Salman M. Tajuddin, Maris Alver, Marzyeh Amini, Mathilde Boissel, Jin Fang Chai, Xu Chen, Jasmin Divers, Evangelos Evangelou, Chuan Gao, Mariaelisa Graff, Sarah E. Harris, Meian He, Fang-Chi Hsu, Anne U. Jackson, Jing Hua Zhao, Aldi T. Kraja, Brigitte Kühnel, Federica Laguzzi, Leo-Pekka Lyytikäinen, Ilja M. Nolte, Rainer Rauramaa, Muhammad Riaz, Antonietta Robino, Rico Rueedi, Heather M. Stringham, Fumihiko Takeuchi, Peter J. van der Most, Tibor V. Varga, Niek Verweij, Erin B. Ware, Wanqing Wen, Xiaoyin Li, Lisa R. Yanek, Najaf Amin, Donna K. Arnett, Eric Boerwinkle, Marco Brumat, Brian Cade, Mickaël Canouil, Yii-Der Ida Chen, Maria Pina Concas, John Connell, Renée de Mutsert, H. Janaka de Silva, Paul S. de Vries, Ayşe Demirkan, Jingzhong Ding, Charles B. Eaton, Jessica D. Faul, Yechiel Friedlander, Kelley P. Gabriel, Mohsen Ghanbari, Franco Giulianini, Chi Charles Gu, Dongfeng Gu, Tamara B. Harris, Jiang He, Sami Heikkinen, Chew-Kiat Heng, Steven C. Hunt, M. Arfan Ikram, Jost B. Jonas, Woon-Puay Koh, Pirjo Komulainen, Jose E. Krieger, Stephen B. Kritchevsky, Zoltán Kutalik, Johanna Kuusisto, Carl D. Langefeld, Claudia Langenberg, Lenore J. Launer, Karin Leander, Rozenn N. Lemaitre, Cora E. Lewis, Jingjing Liang, Behrooz Z. Alizadeh, H. Marike Boezen, Lude Franke, Gerjan Navis, Marianne Rots, Morris Swertz, Bruce H. R. Wolffenbuttel, Cisca Wijmenga, Jianjun Liu, Reedik Mägi, Ani Manichaikul, Thomas Meitinger, Andres Metspalu, Yuri Milaneschi, Karen L. Mohlke, Thomas H. Mosley, Alison D. Murray, Mike A. Nalls, Ei-Ei Khaing Nang, Christopher P. Nelson, Sotoodehnia Nona, Jill M. Norris, Chiamaka Vivian Nwuba, Jeff O’Connell, Nicholette D. Palmer, George J. Papanicolau, Raha Pazoki, Nancy L. Pedersen, Annette Peters, Patricia A. Peyser, Ozren Polasek, David J. Porteous, Alaitz Poveda, Olli T. Raitakari, Stephen S. Rich, Neil Risch, Jennifer G. Robinson, Lynda M. Rose, Igor Rudan, Pamela J. Schreiner, Robert A. Scott, Stephen S. Sidney, Mario Sims, Jennifer A. Smith, Harold Snieder, Tamar Sofer, John M. Starr, Barbara Sternfeld, Konstantin Strauch, Hua Tang, Kent D. Taylor, Michael Y. Tsai, Jaakko Tuomilehto, André G. Uitterlinden, M. Yldau van der Ende, Diana van Heemst, Trudy Voortman, Melanie Waldenberger, Patrik Wennberg, Gregory Wilson, Yong-Bing Xiang, Jie Yao, Caizheng Yu, Jian-Min Yuan, Wei Zhao, Alan B. Zonderman, Diane M. Becker, Michael Boehnke, Donald W. Bowden, Ulf de Faire, Ian J. Deary, Paul Elliott, Tõnu Esko, Barry I. Freedman, Philippe Froguel, Paolo Gasparini, Christian Gieger, Norihiro Kato, Markku Laakso, Timo A. Lakka, Terho Lehtimäki, Patrik K. E. Magnusson, Albertine J. Oldehinkel, Brenda W. J. H. Penninx, Nilesh J. Samani, Xiao-Ou Shu, Pim van der Harst, Jana V. Van Vliet-Ostaptchouk, Peter Vollenweider, Lynne E. Wagenknecht, Ya X. Wang, Nicholas J. Wareham, David R. Weir, Tangchun Wu, Wei Zheng, Xiaofeng Zhu, Michele K. Evans, Paul W. Franks, Vilmundur Gudnason, Caroline Hayward, Bernardo L. Horta, Tanika N. Kelly, Yongmei Liu, Kari E. North, Alexandre C. Pereira, Paul M. Ridker, E. Shyong Tai, Rob M. van Dam, Ervin R. Fox, Sharon L. R. Kardia, Ching-Ti Liu, Dennis O. Mook-Kanamori, Michael A. Province, Susan Redline, Cornelia M. van Duijn, Jerome I. Rotter, Charles B. Kooperberg, W. James Gauderman, Bruce M. Psaty, Kenneth Rice, Patricia B. Munroe, Myriam Fornage, L. Adrienne Cupples, Charles N. Rotimi, Alanna C. Morrison, Dabeeru C. Rao (Corresponding Author), Ruth J. F. Loos (Corresponding Author), Lifelines Cohort Study

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Abstract

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.

Original language	English
Article number	376
Number of pages	11
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-08008-w
Publication status	Published - 22 Jan 2019

Bibliographical note

The present work was largely supported by a grant from the US National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (R01HL118305). The full list of acknowledgments appears in the Supplementary Notes 3 and 4.

Keywords

Adolescent
Adult
African Continental Ancestry Group/genetics
Aged
Aged, 80 and over
Asian Continental Ancestry Group/genetics
Brazil
Calcium-Binding Proteins/genetics
Cholesterol, HDL/blood
Cholesterol, LDL/blood
Cholesterol/blood
European Continental Ancestry Group/genetics
Exercise
Female
Genetic Loci/genetics
Genome-Wide Association Study
Genotype
Hispanic Americans/genetics
Humans
LIM-Homeodomain Proteins/genetics
Lipid Metabolism/genetics
Lipids/blood
Male
Membrane Proteins/genetics
Microtubule-Associated Proteins/genetics
Middle Aged
Muscle Proteins/genetics
Nerve Tissue Proteins/genetics
Transcription Factors/genetics
Triglycerides/blood
Young Adult

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Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity
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Cite this

Kilpeläinen, T. O., Bentley, A. R., Noordam, R., Sung, Y. J., Schwander, K., Winkler, T. W., Jakupović, H., Chasman, D. I., Manning, A., Ntalla, I., Aschard, H., Brown, M. R., de las Fuentes, L., Franceschini, N., Guo, X., Vojinovic, D., Aslibekyan, S., Feitosa, M. F., Kho, M., ... Study, L. C. (2019). Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity. Nature Communications, 10(1), Article 376. https://doi.org/10.1038/s41467-018-08008-w

Kilpeläinen, TO, Bentley, AR, Noordam, R, Sung, YJ, Schwander, K, Winkler, TW, Jakupović, H, Chasman, DI, Manning, A, Ntalla, I, Aschard, H, Brown, MR, de las Fuentes, L, Franceschini, N, Guo, X, Vojinovic, D, Aslibekyan, S, Feitosa, MF, Kho, M, Musani, SK, Richard, M, Wang, H, Wang, Z, Bartz, TM, Bielak, LF, Campbell, A, Dorajoo, R, Fisher, V, Hartwig, FP, Horimoto, ARVR, Li, C, Lohman, KK, Marten, J, Sim, X, Smith, AV, Tajuddin, SM, Alver, M, Amini, M, Boissel, M, Chai, JF, Chen, X, Divers, J, Evangelou, E, Gao, C, Graff, M, Harris, SE, He, M, Hsu, F-C, Jackson, AU, Zhao, JH, Kraja, AT, Kühnel, B, Laguzzi, F, Lyytikäinen, L-P, Nolte, IM, Rauramaa, R, Riaz, M, Robino, A, Rueedi, R, Stringham, HM, Takeuchi, F, van der Most, PJ, Varga, TV, Verweij, N, Ware, EB, Wen, W, Li, X, Yanek, LR, Amin, N, Arnett, DK, Boerwinkle, E, Brumat, M, Cade, B, Canouil, M, Chen, Y-DI, Concas, MP, Connell, J, de Mutsert, R, de Silva, HJ, de Vries, PS, Demirkan, A, Ding, J, Eaton, CB, Faul, JD, Friedlander, Y, Gabriel, KP, Ghanbari, M, Giulianini, F, Gu, CC, Gu, D, Harris, TB, He, J, Heikkinen, S, Heng, C-K, Hunt, SC, Ikram, MA, Jonas, JB, Koh, W-P, Komulainen, P, Krieger, JE, Kritchevsky, SB, Kutalik, Z, Kuusisto, J, Langefeld, CD, Langenberg, C, Launer, LJ, Leander, K, Lemaitre, RN, Lewis, CE, Liang, J, Alizadeh, BZ, Boezen, HM, Franke, L, Navis, G, Rots, M, Swertz, M, Wolffenbuttel, BHR, Wijmenga, C, Liu, J, Mägi, R, Manichaikul, A, Meitinger, T, Metspalu, A, Milaneschi, Y, Mohlke, KL, Mosley, TH, Murray, AD, Nalls, MA, Nang, E-EK, Nelson, CP, Nona, S, Norris, JM, Nwuba, CV, O’Connell, J, Palmer, ND, Papanicolau, GJ, Pazoki, R, Pedersen, NL, Peters, A, Peyser, PA, Polasek, O, Porteous, DJ, Poveda, A, Raitakari, OT, Rich, SS, Risch, N, Robinson, JG, Rose, LM, Rudan, I, Schreiner, PJ, Scott, RA, Sidney, SS, Sims, M, Smith, JA, Snieder, H, Sofer, T, Starr, JM, Sternfeld, B, Strauch, K, Tang, H, Taylor, KD, Tsai, MY, Tuomilehto, J, Uitterlinden, AG, van der Ende, MY, van Heemst, D, Voortman, T, Waldenberger, M, Wennberg, P, Wilson, G, Xiang, Y-B, Yao, J, Yu, C, Yuan, J-M, Zhao, W, Zonderman, AB, Becker, DM, Boehnke, M, Bowden, DW, de Faire, U, Deary, IJ, Elliott, P, Esko, T, Freedman, BI, Froguel, P, Gasparini, P, Gieger, C, Kato, N, Laakso, M, Lakka, TA, Lehtimäki, T, Magnusson, PKE, Oldehinkel, AJ, Penninx, BWJH, Samani, NJ, Shu, X-O, van der Harst, P, Van Vliet-Ostaptchouk, JV, Vollenweider, P, Wagenknecht, LE, Wang, YX, Wareham, NJ, Weir, DR, Wu, T, Zheng, W, Zhu, X, Evans, MK, Franks, PW, Gudnason, V, Hayward, C, Horta, BL, Kelly, TN, Liu, Y, North, KE, Pereira, AC, Ridker, PM, Tai, ES, van Dam, RM, Fox, ER, Kardia, SLR, Liu, C-T, Mook-Kanamori, DO, Province, MA, Redline, S, van Duijn, CM, Rotter, JI, Kooperberg, CB, Gauderman, WJ, Psaty, BM, Rice, K, Munroe, PB, Fornage, M, Cupples, LA, Rotimi, CN, Morrison, AC, Rao, DC, Loos, RJF & Study, LC 2019, 'Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity', Nature Communications, vol. 10, no. 1, 376. https://doi.org/10.1038/s41467-018-08008-w

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title = "Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity",

abstract = "Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.",

keywords = "Adolescent, Adult, African Continental Ancestry Group/genetics, Aged, Aged, 80 and over, Asian Continental Ancestry Group/genetics, Brazil, Calcium-Binding Proteins/genetics, Cholesterol, HDL/blood, Cholesterol, LDL/blood, Cholesterol/blood, European Continental Ancestry Group/genetics, Exercise, Female, Genetic Loci/genetics, Genome-Wide Association Study, Genotype, Hispanic Americans/genetics, Humans, LIM-Homeodomain Proteins/genetics, Lipid Metabolism/genetics, Lipids/blood, Male, Membrane Proteins/genetics, Microtubule-Associated Proteins/genetics, Middle Aged, Muscle Proteins/genetics, Nerve Tissue Proteins/genetics, Transcription Factors/genetics, Triglycerides/blood, Young Adult",

author = "Kilpel{\"a}inen, {Tuomas O.} and Bentley, {Amy R.} and Raymond Noordam and Sung, {Yun Ju} and Karen Schwander and Winkler, {Thomas W.} and Hermina Jakupovi{\'c} and Chasman, {Daniel I.} and Alisa Manning and Ioanna Ntalla and Hugues Aschard and Brown, {Michael R.} and {de las Fuentes}, Lisa and Nora Franceschini and Xiuqing Guo and Dina Vojinovic and Stella Aslibekyan and Feitosa, {Mary F.} and Minjung Kho and Musani, {Solomon K.} and Melissa Richard and Heming Wang and Zhe Wang and Bartz, {Traci M.} and Bielak, {Lawrence F.} and Archie Campbell and Rajkumar Dorajoo and Virginia Fisher and Hartwig, {Fernando P.} and Horimoto, {Andrea R. V. R.} and Changwei Li and Lohman, {Kurt K.} and Jonathan Marten and Xueling Sim and Smith, {Albert V.} and Tajuddin, {Salman M.} and Maris Alver and Marzyeh Amini and Mathilde Boissel and Chai, {Jin Fang} and Xu Chen and Jasmin Divers and Evangelos Evangelou and Chuan Gao and Mariaelisa Graff and Harris, {Sarah E.} and Meian He and Fang-Chi Hsu and Jackson, {Anne U.} and Zhao, {Jing Hua} and Kraja, {Aldi T.} and Brigitte K{\"u}hnel and Federica Laguzzi and Leo-Pekka Lyytik{\"a}inen and Nolte, {Ilja M.} and Rainer Rauramaa and Muhammad Riaz and Antonietta Robino and Rico Rueedi and Stringham, {Heather M.} and Fumihiko Takeuchi and {van der Most}, {Peter J.} and Varga, {Tibor V.} and Niek Verweij and Ware, {Erin B.} and Wanqing Wen and Xiaoyin Li and Yanek, {Lisa R.} and Najaf Amin and Arnett, {Donna K.} and Eric Boerwinkle and Marco Brumat and Brian Cade and Micka{\"e}l Canouil and Chen, {Yii-Der Ida} and Concas, {Maria Pina} and John Connell and {de Mutsert}, Ren{\'e}e and {de Silva}, {H. Janaka} and {de Vries}, {Paul S.} and Ay{\c s}e Demirkan and Jingzhong Ding and Eaton, {Charles B.} and Faul, {Jessica D.} and Yechiel Friedlander and Gabriel, {Kelley P.} and Mohsen Ghanbari and Franco Giulianini and Gu, {Chi Charles} and Dongfeng Gu and Harris, {Tamara B.} and Jiang He and Sami Heikkinen and Chew-Kiat Heng and Hunt, {Steven C.} and Ikram, {M. Arfan} and Jonas, {Jost B.} and Woon-Puay Koh and Pirjo Komulainen and Krieger, {Jose E.} and Kritchevsky, {Stephen B.} and Zolt{\'a}n Kutalik and Johanna Kuusisto and Langefeld, {Carl D.} and Claudia Langenberg and Launer, {Lenore J.} and Karin Leander and Lemaitre, {Rozenn N.} and Lewis, {Cora E.} and Jingjing Liang and Alizadeh, {Behrooz Z.} and Boezen, {H. Marike} and Lude Franke and Gerjan Navis and Marianne Rots and Morris Swertz and Wolffenbuttel, {Bruce H. R.} and Cisca Wijmenga and Jianjun Liu and Reedik M{\"a}gi and Ani Manichaikul and Thomas Meitinger and Andres Metspalu and Yuri Milaneschi and Mohlke, {Karen L.} and Mosley, {Thomas H.} and Murray, {Alison D.} and Nalls, {Mike A.} and Nang, {Ei-Ei Khaing} and Nelson, {Christopher P.} and Sotoodehnia Nona and Norris, {Jill M.} and Nwuba, {Chiamaka Vivian} and Jeff O{\textquoteright}Connell and Palmer, {Nicholette D.} and Papanicolau, {George J.} and Raha Pazoki and Pedersen, {Nancy L.} and Annette Peters and Peyser, {Patricia A.} and Ozren Polasek and Porteous, {David J.} and Alaitz Poveda and Raitakari, {Olli T.} and Rich, {Stephen S.} and Neil Risch and Robinson, {Jennifer G.} and Rose, {Lynda M.} and Igor Rudan and Schreiner, {Pamela J.} and Scott, {Robert A.} and Sidney, {Stephen S.} and Mario Sims and Smith, {Jennifer A.} and Harold Snieder and Tamar Sofer and Starr, {John M.} and Barbara Sternfeld and Konstantin Strauch and Hua Tang and Taylor, {Kent D.} and Tsai, {Michael Y.} and Jaakko Tuomilehto and Uitterlinden, {Andr{\'e} G.} and {van der Ende}, {M. Yldau} and {van Heemst}, Diana and Trudy Voortman and Melanie Waldenberger and Patrik Wennberg and Gregory Wilson and Yong-Bing Xiang and Jie Yao and Caizheng Yu and Jian-Min Yuan and Wei Zhao and Zonderman, {Alan B.} and Becker, {Diane M.} and Michael Boehnke and Bowden, {Donald W.} and {de Faire}, Ulf and Deary, {Ian J.} and Paul Elliott and T{\~o}nu Esko and Freedman, {Barry I.} and Philippe Froguel and Paolo Gasparini and Christian Gieger and Norihiro Kato and Markku Laakso and Lakka, {Timo A.} and Terho Lehtim{\"a}ki and Magnusson, {Patrik K. E.} and Oldehinkel, {Albertine J.} and Penninx, {Brenda W. J. H.} and Samani, {Nilesh J.} and Xiao-Ou Shu and {van der Harst}, Pim and {Van Vliet-Ostaptchouk}, {Jana V.} and Peter Vollenweider and Wagenknecht, {Lynne E.} and Wang, {Ya X.} and Wareham, {Nicholas J.} and Weir, {David R.} and Tangchun Wu and Wei Zheng and Xiaofeng Zhu and Evans, {Michele K.} and Franks, {Paul W.} and Vilmundur Gudnason and Caroline Hayward and Horta, {Bernardo L.} and Kelly, {Tanika N.} and Yongmei Liu and North, {Kari E.} and Pereira, {Alexandre C.} and Ridker, {Paul M.} and Tai, {E. Shyong} and {van Dam}, {Rob M.} and Fox, {Ervin R.} and Kardia, {Sharon L. R.} and Ching-Ti Liu and Mook-Kanamori, {Dennis O.} and Province, {Michael A.} and Susan Redline and {van Duijn}, {Cornelia M.} and Rotter, {Jerome I.} and Kooperberg, {Charles B.} and Gauderman, {W. James} and Psaty, {Bruce M.} and Kenneth Rice and Munroe, {Patricia B.} and Myriam Fornage and Cupples, {L. Adrienne} and Rotimi, {Charles N.} and Morrison, {Alanna C.} and Rao, {Dabeeru C.} and Loos, {Ruth J. F.} and Study, {Lifelines Cohort}",

note = "The present work was largely supported by a grant from the US National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (R01HL118305). The full list of acknowledgments appears in the Supplementary Notes 3 and 4.",

year = "2019",

month = jan,

day = "22",

doi = "10.1038/s41467-018-08008-w",

language = "English",

volume = "10",

journal = "Nature Communications",

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TY - JOUR

T1 - Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity

AU - Kilpeläinen, Tuomas O.

AU - Bentley, Amy R.

AU - Noordam, Raymond

AU - Sung, Yun Ju

AU - Schwander, Karen

AU - Winkler, Thomas W.

AU - Jakupović, Hermina

AU - Chasman, Daniel I.

AU - Manning, Alisa

AU - Ntalla, Ioanna

AU - Aschard, Hugues

AU - Brown, Michael R.

AU - de las Fuentes, Lisa

AU - Franceschini, Nora

AU - Guo, Xiuqing

AU - Vojinovic, Dina

AU - Aslibekyan, Stella

AU - Feitosa, Mary F.

AU - Kho, Minjung

AU - Musani, Solomon K.

AU - Richard, Melissa

AU - Wang, Heming

AU - Wang, Zhe

AU - Bartz, Traci M.

AU - Bielak, Lawrence F.

AU - Campbell, Archie

AU - Dorajoo, Rajkumar

AU - Fisher, Virginia

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N1 - The present work was largely supported by a grant from the US National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (R01HL118305). The full list of acknowledgments appears in the Supplementary Notes 3 and 4.

PY - 2019/1/22

Y1 - 2019/1/22

N2 - Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.

AB - Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.

KW - Adolescent

KW - Adult

KW - African Continental Ancestry Group/genetics

KW - Aged

KW - Aged, 80 and over

KW - Asian Continental Ancestry Group/genetics

KW - Brazil

KW - Calcium-Binding Proteins/genetics

KW - Cholesterol, HDL/blood

KW - Cholesterol, LDL/blood

KW - Cholesterol/blood

KW - European Continental Ancestry Group/genetics

KW - Exercise

KW - Female

KW - Genetic Loci/genetics

KW - Genome-Wide Association Study

KW - Genotype

KW - Hispanic Americans/genetics

KW - Humans

KW - LIM-Homeodomain Proteins/genetics

KW - Lipid Metabolism/genetics

KW - Lipids/blood

KW - Male

KW - Membrane Proteins/genetics

KW - Microtubule-Associated Proteins/genetics

KW - Middle Aged

KW - Muscle Proteins/genetics

KW - Nerve Tissue Proteins/genetics

KW - Transcription Factors/genetics

KW - Triglycerides/blood

KW - Young Adult

UR - http://www.scopus.com/inward/record.url?scp=85060388984&partnerID=8YFLogxK

UR - http://www.mendeley.com/research/multiancestry-study-blood-lipid-levels-identifies-four-loci-interacting-physical-activity

U2 - 10.1038/s41467-018-08008-w

DO - 10.1038/s41467-018-08008-w

M3 - Article

C2 - 30670697

SN - 2041-1723

VL - 10

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 376

ER -

Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity

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