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. Musani & 218 others 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

Research output: Contribution to journal › Article

4 Citations (Scopus)
3 Downloads (Pure)

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 languageEnglish
Article number376
Number of pages11
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - 22 Jan 2019

Fingerprint

loci
blood
cholesterol
lipids
Blood
Exercise
Lipids
hardware description languages
LDL Cholesterol
HDL Cholesterol
Genes
lipid metabolism
Ports and harbors
Genetic Loci
harbors
genome
Muscle
metabolism
muscles
Lipid Metabolism

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

ASJC Scopus subject areas

  • Physics and Astronomy(all)
  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Kilpeläinen, T. O., Bentley, A. R., Noordam, R., Sung, Y. J., Schwander, K., Winkler, T. W., ... Study, L. C. (2019). Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity. Nature Communications, 10(1), [376]. https://doi.org/10.1038/s41467-018-08008-w

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

In: Nature Communications, Vol. 10, No. 1, 376, 22.01.2019.

Research output: Contribution to journal › Article

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
Kilpeläinen TO, Bentley AR, Noordam R, Sung YJ, Schwander K, Winkler TW et al. Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity. Nature Communications. 2019 Jan 22;10(1). 376. https://doi.org/10.1038/s41467-018-08008-w
Kilpeläinen, Tuomas O. ; Bentley, Amy R. ; Noordam, Raymond ; Sung, Yun Ju ; Schwander, Karen ; Winkler, Thomas W. ; Jakupović, Hermina ; Chasman, Daniel I. ; Manning, Alisa ; Ntalla, Ioanna ; Aschard, Hugues ; Brown, Michael R. ; de las Fuentes, Lisa ; Franceschini, Nora ; Guo, Xiuqing ; Vojinovic, Dina ; Aslibekyan, Stella ; Feitosa, Mary F. ; Kho, Minjung ; Musani, Solomon K. ; Richard, Melissa ; Wang, Heming ; Wang, Zhe ; Bartz, Traci M. ; Bielak, Lawrence F. ; Campbell, Archie ; Dorajoo, Rajkumar ; Fisher, Virginia ; Hartwig, Fernando P. ; Horimoto, Andrea R. V. R. ; Li, Changwei ; Lohman, Kurt K. ; Marten, Jonathan ; Sim, Xueling ; Smith, Albert V. ; Tajuddin, Salman M. ; Alver, Maris ; Amini, Marzyeh ; Boissel, Mathilde ; Chai, Jin Fang ; Chen, Xu ; Divers, Jasmin ; Evangelou, Evangelos ; Gao, Chuan ; Graff, Mariaelisa ; Harris, Sarah E. ; He, Meian ; Hsu, Fang-Chi ; Jackson, Anne U. ; Zhao, Jing Hua ; Kraja, Aldi T. ; Kühnel, Brigitte ; Laguzzi, Federica ; Lyytikäinen, Leo-Pekka ; Nolte, Ilja M. ; Rauramaa, Rainer ; Riaz, Muhammad ; Robino, Antonietta ; Rueedi, Rico ; Stringham, Heather M. ; Takeuchi, Fumihiko ; van der Most, Peter J. ; Varga, Tibor V. ; Verweij, Niek ; Ware, Erin B. ; Wen, Wanqing ; Li, Xiaoyin ; Yanek, Lisa R. ; Amin, Najaf ; Arnett, Donna K. ; Boerwinkle, Eric ; Brumat, Marco ; Cade, Brian ; Canouil, Mickaël ; Chen, Yii-Der Ida ; Concas, Maria Pina ; Connell, John ; de Mutsert, Renée ; de Silva, H. Janaka ; de Vries, Paul S. ; Demirkan, Ayşe ; Ding, Jingzhong ; Eaton, Charles B. ; Faul, Jessica D. ; Friedlander, Yechiel ; Gabriel, Kelley P. ; Ghanbari, Mohsen ; Giulianini, Franco ; Gu, Chi Charles ; Gu, Dongfeng ; Harris, Tamara B. ; He, Jiang ; Heikkinen, Sami ; Heng, Chew-Kiat ; Hunt, Steven C. ; Ikram, M. Arfan ; Jonas, Jost B. ; Koh, Woon-Puay ; Komulainen, Pirjo ; Krieger, Jose E. ; Kritchevsky, Stephen B. ; Kutalik, Zoltán ; Kuusisto, Johanna ; Langefeld, Carl D. ; Langenberg, Claudia ; Launer, Lenore J. ; Leander, Karin ; Lemaitre, Rozenn N. ; Lewis, Cora E. ; Liang, Jingjing ; Alizadeh, Behrooz Z. ; Boezen, H. Marike ; Franke, Lude ; Navis, Gerjan ; Rots, Marianne ; Swertz, Morris ; Wolffenbuttel, Bruce H. R. ; Wijmenga, Cisca ; Liu, Jianjun ; Mägi, Reedik ; Manichaikul, Ani ; Meitinger, Thomas ; Metspalu, Andres ; Milaneschi, Yuri ; Mohlke, Karen L. ; Mosley, Thomas H. ; Murray, Alison D. ; Nalls, Mike A. ; Nang, Ei-Ei Khaing ; Nelson, Christopher P. ; Nona, Sotoodehnia ; Norris, Jill M. ; Nwuba, Chiamaka Vivian ; O’Connell, Jeff ; Palmer, Nicholette D. ; Papanicolau, George J. ; Pazoki, Raha ; Pedersen, Nancy L. ; Peters, Annette ; Peyser, Patricia A. ; Polasek, Ozren ; Porteous, David J. ; Poveda, Alaitz ; Raitakari, Olli T. ; Rich, Stephen S. ; Risch, Neil ; Robinson, Jennifer G. ; Rose, Lynda M. ; Rudan, Igor ; Schreiner, Pamela J. ; Scott, Robert A. ; Sidney, Stephen S. ; Sims, Mario ; Smith, Jennifer A. ; Snieder, Harold ; Sofer, Tamar ; Starr, John M. ; Sternfeld, Barbara ; Strauch, Konstantin ; Tang, Hua ; Taylor, Kent D. ; Tsai, Michael Y. ; Tuomilehto, Jaakko ; Uitterlinden, André G. ; van der Ende, M. Yldau ; van Heemst, Diana ; Voortman, Trudy ; Waldenberger, Melanie ; Wennberg, Patrik ; Wilson, Gregory ; Xiang, Yong-Bing ; Yao, Jie ; Yu, Caizheng ; Yuan, Jian-Min ; Zhao, Wei ; Zonderman, Alan B. ; Becker, Diane M. ; Boehnke, Michael ; Bowden, Donald W. ; de Faire, Ulf ; Deary, Ian J. ; Elliott, Paul ; Esko, Tõnu ; Freedman, Barry I. ; Froguel, Philippe ; Gasparini, Paolo ; Gieger, Christian ; Kato, Norihiro ; Laakso, Markku ; Lakka, Timo A. ; Lehtimäki, Terho ; Magnusson, Patrik K. E. ; Oldehinkel, Albertine J. ; Penninx, Brenda W. J. H. ; Samani, Nilesh J. ; Shu, Xiao-Ou ; van der Harst, Pim ; Van Vliet-Ostaptchouk, Jana V. ; Vollenweider, Peter ; Wagenknecht, Lynne E. ; Wang, Ya X. ; Wareham, Nicholas J. ; Weir, David R. ; Wu, Tangchun ; Zheng, Wei ; Zhu, Xiaofeng ; Evans, Michele K. ; Franks, Paul W. ; Gudnason, Vilmundur ; Hayward, Caroline ; Horta, Bernardo L. ; Kelly, Tanika N. ; Liu, Yongmei ; North, Kari E. ; Pereira, Alexandre C. ; Ridker, Paul M. ; Tai, E. Shyong ; van Dam, Rob M. ; Fox, Ervin R. ; Kardia, Sharon L. R. ; Liu, Ching-Ti ; Mook-Kanamori, Dennis O. ; Province, Michael A. ; Redline, Susan ; van Duijn, Cornelia M. ; Rotter, Jerome I. ; Kooperberg, Charles B. ; Gauderman, W. James ; Psaty, Bruce M. ; Rice, Kenneth ; Munroe, Patricia B. ; Fornage, Myriam ; Cupples, L. Adrienne ; Rotimi, Charles N. ; Morrison, Alanna C. ; Rao, Dabeeru C. ; Loos, Ruth J. F. ; Study, Lifelines Cohort. / Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity. In: Nature Communications. 2019 ; Vol. 10, No. 1.
@article{02ff0db8eb894ccb80c62671aea60d70,
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 Jakupović 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 Ayşe 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’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 = "1",
day = "22",
doi = "10.1038/s41467-018-08008-w",
language = "English",
volume = "10",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",

}

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

AU - Hartwig, Fernando P.

AU - Horimoto, Andrea R. V. R.

AU - Li, Changwei

AU - Lohman, Kurt K.

AU - Marten, Jonathan

AU - Sim, Xueling

AU - Smith, Albert V.

AU - Tajuddin, Salman M.

AU - Alver, Maris

AU - Amini, Marzyeh

AU - Boissel, Mathilde

AU - Chai, Jin Fang

AU - Chen, Xu

AU - Divers, Jasmin

AU - Evangelou, Evangelos

AU - Gao, Chuan

AU - Graff, Mariaelisa

AU - Harris, Sarah E.

AU - He, Meian

AU - Hsu, Fang-Chi

AU - Jackson, Anne U.

AU - Zhao, Jing Hua

AU - Kraja, Aldi T.

AU - Kühnel, Brigitte

AU - Laguzzi, Federica

AU - Lyytikäinen, Leo-Pekka

AU - Nolte, Ilja M.

AU - Rauramaa, Rainer

AU - Riaz, Muhammad

AU - Robino, Antonietta

AU - Rueedi, Rico

AU - Stringham, Heather M.

AU - Takeuchi, Fumihiko

AU - van der Most, Peter J.

AU - Varga, Tibor V.

AU - Verweij, Niek

AU - Ware, Erin B.

AU - Wen, Wanqing

AU - Li, Xiaoyin

AU - Yanek, Lisa R.

AU - Amin, Najaf

AU - Arnett, Donna K.

AU - Boerwinkle, Eric

AU - Brumat, Marco

AU - Cade, Brian

AU - Canouil, Mickaël

AU - Chen, Yii-Der Ida

AU - Concas, Maria Pina

AU - Connell, John

AU - de Mutsert, Renée

AU - de Silva, H. Janaka

AU - de Vries, Paul S.

AU - Demirkan, Ayşe

AU - Ding, Jingzhong

AU - Eaton, Charles B.

AU - Faul, Jessica D.

AU - Friedlander, Yechiel

AU - Gabriel, Kelley P.

AU - Ghanbari, Mohsen

AU - Giulianini, Franco

AU - Gu, Chi Charles

AU - Gu, Dongfeng

AU - Harris, Tamara B.

AU - He, Jiang

AU - Heikkinen, Sami

AU - Heng, Chew-Kiat

AU - Hunt, Steven C.

AU - Ikram, M. Arfan

AU - Jonas, Jost B.

AU - Koh, Woon-Puay

AU - Komulainen, Pirjo

AU - Krieger, Jose E.

AU - Kritchevsky, Stephen B.

AU - Kutalik, Zoltán

AU - Kuusisto, Johanna

AU - Langefeld, Carl D.

AU - Langenberg, Claudia

AU - Launer, Lenore J.

AU - Leander, Karin

AU - Lemaitre, Rozenn N.

AU - Lewis, Cora E.

AU - Liang, Jingjing

AU - Alizadeh, Behrooz Z.

AU - Boezen, H. Marike

AU - Franke, Lude

AU - Navis, Gerjan

AU - Rots, Marianne

AU - Swertz, Morris

AU - Wolffenbuttel, Bruce H. R.

AU - Wijmenga, Cisca

AU - Liu, Jianjun

AU - Mägi, Reedik

AU - Manichaikul, Ani

AU - Meitinger, Thomas

AU - Metspalu, Andres

AU - Milaneschi, Yuri

AU - Mohlke, Karen L.

AU - Mosley, Thomas H.

AU - Murray, Alison D.

AU - Nalls, Mike A.

AU - Nang, Ei-Ei Khaing

AU - Nelson, Christopher P.

AU - Nona, Sotoodehnia

AU - Norris, Jill M.

AU - Nwuba, Chiamaka Vivian

AU - O’Connell, Jeff

AU - Palmer, Nicholette D.

AU - Papanicolau, George J.

AU - Pazoki, Raha

AU - Pedersen, Nancy L.

AU - Peters, Annette

AU - Peyser, Patricia A.

AU - Polasek, Ozren

AU - Porteous, David J.

AU - Poveda, Alaitz

AU - Raitakari, Olli T.

AU - Rich, Stephen S.

AU - Risch, Neil

AU - Robinson, Jennifer G.

AU - Rose, Lynda M.

AU - Rudan, Igor

AU - Schreiner, Pamela J.

AU - Scott, Robert A.

AU - Sidney, Stephen S.

AU - Sims, Mario

AU - Smith, Jennifer A.

AU - Snieder, Harold

AU - Sofer, Tamar

AU - Starr, John M.

AU - Sternfeld, Barbara

AU - Strauch, Konstantin

AU - Tang, Hua

AU - Taylor, Kent D.

AU - Tsai, Michael Y.

AU - Tuomilehto, Jaakko

AU - Uitterlinden, André G.

AU - van der Ende, M. Yldau

AU - van Heemst, Diana

AU - Voortman, Trudy

AU - Waldenberger, Melanie

AU - Wennberg, Patrik

AU - Wilson, Gregory

AU - Xiang, Yong-Bing

AU - Yao, Jie

AU - Yu, Caizheng

AU - Yuan, Jian-Min

AU - Zhao, Wei

AU - Zonderman, Alan B.

AU - Becker, Diane M.

AU - Boehnke, Michael

AU - Bowden, Donald W.

AU - de Faire, Ulf

AU - Deary, Ian J.

AU - Elliott, Paul

AU - Esko, Tõnu

AU - Freedman, Barry I.

AU - Froguel, Philippe

AU - Gasparini, Paolo

AU - Gieger, Christian

AU - Kato, Norihiro

AU - Laakso, Markku

AU - Lakka, Timo A.

AU - Lehtimäki, Terho

AU - Magnusson, Patrik K. E.

AU - Oldehinkel, Albertine J.

AU - Penninx, Brenda W. J. H.

AU - Samani, Nilesh J.

AU - Shu, Xiao-Ou

AU - van der Harst, Pim

AU - Van Vliet-Ostaptchouk, Jana V.

AU - Vollenweider, Peter

AU - Wagenknecht, Lynne E.

AU - Wang, Ya X.

AU - Wareham, Nicholas J.

AU - Weir, David R.

AU - Wu, Tangchun

AU - Zheng, Wei

AU - Zhu, Xiaofeng

AU - Evans, Michele K.

AU - Franks, Paul W.

AU - Gudnason, Vilmundur

AU - Hayward, Caroline

AU - Horta, Bernardo L.

AU - Kelly, Tanika N.

AU - Liu, Yongmei

AU - North, Kari E.

AU - Pereira, Alexandre C.

AU - Ridker, Paul M.

AU - Tai, E. Shyong

AU - van Dam, Rob M.

AU - Fox, Ervin R.

AU - Kardia, Sharon L. R.

AU - Liu, Ching-Ti

AU - Mook-Kanamori, Dennis O.

AU - Province, Michael A.

AU - Redline, Susan

AU - van Duijn, Cornelia M.

AU - Rotter, Jerome I.

AU - Kooperberg, Charles B.

AU - Gauderman, W. James

AU - Psaty, Bruce M.

AU - Rice, Kenneth

AU - Munroe, Patricia B.

AU - Fornage, Myriam

AU - Cupples, L. Adrienne

AU - Rotimi, Charles N.

AU - Morrison, Alanna C.

AU - Rao, Dabeeru C.

AU - Loos, Ruth J. F.

AU - Study, Lifelines Cohort

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

VL - 10

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 376

ER -

Access to Document

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

    © The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

    Final published version, 1 MBLicence: CC BY