Leveraging cross-species transcription factor binding site patterns: From diabetes risk loci to disease mechanisms.

Claussnitzer, Melina; Dankel, Simon N.; Klocke, Bernward; Grallert, Harald; Yh, Hsu; Glunk, Viktoria; Berulava, Tea; Sn, Dankel; Lee, Heekyoung K.; Oskolkov, Nikolay; Fadista, Joao; Ehlers, Kerstin; Wahl, Simone; Hoffmann, Christoph; Qian, Kun; Rönn, Tina; Riess, Helene; Müller-Nurasyid, Martina; Bretschneider, Nancy; Schroeder, Timm; Skurk, Thomas; Horsthemke, Bernhard; Spieler, Derek; Klingenspor, Martin; Seifert, Martin; Kern, Michael J.; Mejhert, Niklas; Dahlman, Ingrid; Hansson, Ola; Hauck, Stefanie M.; Blüher, Matthias; Arner, Peter; Groop, Leif; Illig, Thomas; Suhre, Karsten; Hsu, Yi-Hsiang; Mellgren, Gunnar; Hauner, Hans; Laumen, Helmut; Voight, Benjamin F.; Scott, Laura J.; Steinthorsdottir, Valgerdur; Morris, Andrew P.; Dina, Christian; Welch, Ryan P.; Zeggini, Eleftheria; Huth, Cornelia; Aulchenko, Yurii S.; Thorleifsson, Gudmar; McCulloch, Laura J.; Ferreira, Teresa; Amin, Najaf; Wu, Guanming; Willer, Cristen J.; Raychaudhuri, Soumya; McCarroll, Steve A.; Langenberg, Claudia; Hofmann, Oliver M.; Dupuis, Josée; Qi, Lu; Segrè, Ayellet V.; van Hoek, Mandy; Navarro, Pau; Ardlie, Kristin; Balkau, Beverley; Benediktsson, Rafn; Bennett, Amanda J.; Blagieva, Roza; Boerwinkle, Eric; Bonnycastle, Lori L.; Boström, Kristina Bengtsson; Bravenboer, Bert; Bumpstead, Suzannah; Burtt, Noël P.; Charpentier, Guillaume; Chines, Peter S.; Cornelis, Marilyn; Couper, David J.; Crawford, Gabe; Doney, Alex S. F.; Elliott, Katherine S.; Elliott, Amanda L.; Erdos, Michael R.; Fox, Caroline S.; Franklin, Christopher S.; Ganser, Martha; Gieger, Christian; Grarup, Niels; Green, Todd; Griffin, Simon; Groves, Christopher J.; Guiducci, Candace; Hadjadj, Samy; Hassanali, Neelam; Herder, Christian; Isomaa, Bo; Jackson, Anne U.; Johnson, Paul R. V.; Jørgensen, Torben; Kao, Wen H. L.; Klopp, Norman B.; Kong, Augustine; Kraft, Peter; Kuusisto, Johanna; Lauritzen, Torsten; Li, Man; Lieverse, Aloysius; Lindgren, Cecilia M.; Lyssenko, Valeriya; Marre, Michel; DIAGRAM+Consortium,; Meitinger, Thomas; Midthjell, Kristian; Morken, Mario A.; Narisu, Narisu; Nilsson, Peter; Owen, Katharine R.; Payne, Felicity; Perry, John R. B.; Petersen, Ann-Kristin; Platou, Carl; Proença, Christine; Prokopenko, Inga; Rathmann, Wolfgang; Rayner, N. William; Robertson, Neil R.; Rocheleau, Ghislain; Roden, Michael; Sampson, Michael J.; Saxena, Richa; Shields, Beverley M.; Shrader, Peter; Sigurdsson, Gunnar; Sparsø, Thomas; Strassburger, Klaus; Stringham, Heather M.; Sun, Qi; Swift, Amy J.; Thorand, Barbara; Tichet, Jean; Tuomi, Tiinamaija; van Dam, Rob M.; van Haeften, Timon W.; van Herpt, Thijs; van Vliet-Ostaptchouk, Jana V.; Walters, G. Bragi; Mj, Kern; Weedon, Michael N.; Wijmenga, Cisca; Witteman, Jacqueline; Bergman, Richard N.; Cauchi, Stephane; Collins, Francis S.; Gloyn, Anna L.; Gyllensten, Ulf; Hansen, Torben; Hide, Winston A.; Hitman, Graham A.; Hofman, Albert; Hunter, David J.; Hveem, Kristian; Laakso, Markku; Mehjert, N.; Mohlke, Karen L.; Morris, Andrew D.; Palmer, Colin N. A.; Pramstaller, Peter P.; Rudan, Igor; Sijbrands, Eric; Stein, Lincoln D.; Tuomilehto, Jaakko; Uitterlinden, Andre; Walker, Mark; Wareham, Nicholas J.; Watanabe, Richard M.; Abecasis, Goncalo R.; Boehm, Bernhard O.; Campbell, Harry; Daly, Mark J.; Hattersley, Andrew T.; Hu, Frank B.; Meigs, James B.; Pankow, James S.; Pedersen, Oluf; Wichmann, H.-Erich; Barroso, Inês; Florez, Jose C.; Frayling, Timothy M.; Sm, Hauck; Sladek, Rob; Thorsteinsdottir, Unnur; Wilson, James F.; Froguel, Philippe; van Duijn, Cornelia M.; Stefansson, Kari; Altshuler, David; Boehnke, Michael; McCarthy, Mark I.

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Simon N. Dankel
Claussnitzer et al., 2014

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Elsevier, Cell, 1-2(156), p. 343-358, 2014

DOI: 10.1016/j.cell.2013.10.058

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@article{Claussnitzer2014,
  abstract = {Genome-wide association studies have revealed numerous risk loci associated with diverse diseases. However, identification of disease-causing variants within association loci remains a major challenge. Divergence in gene expression due to cis-regulatory variants in noncoding regions is central to disease susceptibility. We show that integrative computational analysis of phylogenetic conservation with a complexity assessment of co-occurring transcription factor binding sites (TFBS) can identify cis-regulatory variants and elucidate their mechanistic role in disease. Analysis of established type 2 diabetes risk loci revealed a striking clustering of distinct homeobox TFBS. We identified the PRRX1 homeobox factor as a repressor of PPARG2 expression in adipose cells and demonstrate its adverse effect on lipid metabolism and systemic insulin sensitivity, dependent on the rs4684847 risk allele that triggers PRRX1 binding. Thus, cross-species conservation analysis at the level of co-occurring TFBS provides a valuable contribution to the translation of genetic association signals to disease-related molecular mechanisms.},
  author = {Claussnitzer, Melina and Dankel, Simon N. and Klocke, Bernward and Grallert, Harald and Yh, Hsu and Glunk, Viktoria and Berulava, Tea and Sn, Dankel and Lee, Heekyoung K. and Oskolkov, Nikolay and Fadista, Joao and Ehlers, Kerstin and Wahl, Simone and Hoffmann, Christoph and Qian, Kun and Rönn, Tina and Riess, Helene and Müller-Nurasyid, Martina and Bretschneider, Nancy and Schroeder, Timm and Skurk, Thomas and Horsthemke, Bernhard and Spieler, Derek and Klingenspor, Martin and Seifert, Martin and Kern, Michael J. and Mejhert, Niklas and Dahlman, Ingrid and Hansson, Ola and Hauck, Stefanie M. and Blüher, Matthias and Arner, Peter and Groop, Leif and Illig, Thomas and Suhre, Karsten and Hsu, Yi-Hsiang and Mellgren, Gunnar and Hauner, Hans and Laumen, Helmut and Voight, Benjamin F. and Scott, Laura J. and Steinthorsdottir, Valgerdur and Morris, Andrew P. and Dina, Christian and Welch, Ryan P. and Zeggini, Eleftheria and Huth, Cornelia and Aulchenko, Yurii S. and Thorleifsson, Gudmar and McCulloch, Laura J. and Ferreira, Teresa and Amin, Najaf and Wu, Guanming and Willer, Cristen J. and Raychaudhuri, Soumya and McCarroll, Steve A. and Langenberg, Claudia and Hofmann, Oliver M. and Dupuis, Josée and Qi, Lu and Segrè, Ayellet V. and van Hoek, Mandy and Navarro, Pau and Ardlie, Kristin and Balkau, Beverley and Benediktsson, Rafn and Bennett, Amanda J. and Blagieva, Roza and Boerwinkle, Eric and Bonnycastle, Lori L. and Boström, Kristina Bengtsson and Bravenboer, Bert and Bumpstead, Suzannah and Burtt, Noël P. and Charpentier, Guillaume and Chines, Peter S. and Cornelis, Marilyn and Couper, David J. and Crawford, Gabe and Doney, Alex S. F. and Elliott, Katherine S. and Elliott, Amanda L. and Erdos, Michael R. and Fox, Caroline S. and Franklin, Christopher S. and Ganser, Martha and Gieger, Christian and Grarup, Niels and Green, Todd and Griffin, Simon and Groves, Christopher J. and Guiducci, Candace and Hadjadj, Samy and Hassanali, Neelam and Herder, Christian and Isomaa, Bo and Jackson, Anne U. and Johnson, Paul R. V. and Jørgensen, Torben and Kao, Wen H. L. and Klopp, Norman B. and Kong, Augustine and Kraft, Peter and Kuusisto, Johanna and Lauritzen, Torsten and Li, Man and Lieverse, Aloysius and Lindgren, Cecilia M. and Lyssenko, Valeriya and Marre, Michel and DIAGRAM+Consortium,  and Meitinger, Thomas and Midthjell, Kristian and Morken, Mario A. and Narisu, Narisu and Nilsson, Peter and Owen, Katharine R. and Payne, Felicity and Perry, John R. B. and Petersen, Ann-Kristin and Platou, Carl and Proença, Christine and Prokopenko, Inga and Rathmann, Wolfgang and Rayner, N. William and Robertson, Neil R. and Rocheleau, Ghislain and Roden, Michael and Sampson, Michael J. and Saxena, Richa and Shields, Beverley M. and Shrader, Peter and Sigurdsson, Gunnar and Sparsø, Thomas and Strassburger, Klaus and Stringham, Heather M. and Sun, Qi and Swift, Amy J. and Thorand, Barbara and Tichet, Jean and Tuomi, Tiinamaija and van Dam, Rob M. and van Haeften, Timon W. and van Herpt, Thijs and van Vliet-Ostaptchouk, Jana V. and Walters, G. Bragi and Mj, Kern and Weedon, Michael N. and Wijmenga, Cisca and Witteman, Jacqueline and Bergman, Richard N. and Cauchi, Stephane and Collins, Francis S. and Gloyn, Anna L. and Gyllensten, Ulf and Hansen, Torben and Hide, Winston A. and Hitman, Graham A. and Hofman, Albert and Hunter, David J. and Hveem, Kristian and Laakso, Markku and Mehjert, N. and Mohlke, Karen L. and Morris, Andrew D. and Palmer, Colin N. A. and Pramstaller, Peter P. and Rudan, Igor and Sijbrands, Eric and Stein, Lincoln D. and Tuomilehto, Jaakko and Uitterlinden, Andre and Walker, Mark and Wareham, Nicholas J. and Watanabe, Richard M. and Abecasis, Goncalo R. and Boehm, Bernhard O. and Campbell, Harry and Daly, Mark J. and Hattersley, Andrew T. and Hu, Frank B. and Meigs, James B. and Pankow, James S. and Pedersen, Oluf and Wichmann, H.-Erich and Barroso, Inês and Florez, Jose C. and Frayling, Timothy M. and Sm, Hauck and Sladek, Rob and Thorsteinsdottir, Unnur and Wilson, James F. and Froguel, Philippe and van Duijn, Cornelia M. and Stefansson, Kari and Altshuler, David and Boehnke, Michael and McCarthy, Mark I.},
  doi = {10.1016/j.cell.2013.10.058},
  journal = {Cell},
  month = {jan},
  pages = {343-358},
  title = {Leveraging cross-species transcription factor binding site patterns: From diabetes risk loci to disease mechanisms.},
  url = {https://www.researchgate.net/profile/Nikolay_Oskolkov/publication/259928914_Leveraging_Cross-Species_Transcription_Factor_Binding_Site_Patterns_From_Diabetes_Risk_Loci_to_Disease_Mechanisms/links/00b7d535bf8315db52000000.pdf},
  volume = {156},
  year = {2014}
}

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Leveraging cross-species transcription factor binding site patterns: From diabetes risk loci to disease mechanisms.

Journal article published in 2014 by Melina Claussnitzer, Simon N. Dankel

, Bernward Klocke, Harald Grallert, Hsu Yh, Viktoria Glunk, Tea Berulava, Dankel Sn, Heekyoung K. Lee, Nikolay Oskolkov, Joao Fadista

, Kerstin Ehlers, Simone Wahl, Christoph Hoffmann, Kun Qian and other authors. Melina Claussnitzer, Simon N. Dankel

, Bernward Klocke, Harald Grallert, Hsu Yh, Viktoria Glunk, Tea Berulava, Dankel Sn, Heekyoung K. Lee, Nikolay Oskolkov, Joao Fadista

, Kerstin Ehlers, Simone Wahl, Christoph Hoffmann, Kun Qian, Tina Rönn, Helene Riess, Martina Müller-Nurasyid, Nancy Bretschneider, Timm Schroeder, Thomas Skurk, Bernhard Horsthemke, Derek Spieler, Martin Klingenspor

, Martin Seifert, Michael J. Kern, Niklas Mejhert, Ingrid Dahlman, Ola Hansson

, Stefanie M. Hauck, Matthias Blüher, Peter Arner, Leif Groop, Thomas Illig, Karsten Suhre

, Yi-Hsiang Hsu, Gunnar Mellgren, Hans Hauner, Helmut Laumen

, Benjamin F. Voight, Laura J. Scott, Valgerdur Steinthorsdottir, Andrew P. Morris, Christian Dina, Ryan P. Welch, Eleftheria Zeggini

, Cornelia Huth, Yurii S. Aulchenko, Gudmar Thorleifsson, Laura J. McCulloch, Teresa Ferreira, Najaf Amin, Guanming Wu, Cristen J. Willer, Soumya Raychaudhuri, Steve A. McCarroll, Claudia Langenberg, Oliver M. Hofmann, Josée Dupuis, Lu Qi, Ayellet V. Segrè, Mandy van Hoek, Pau Navarro, Kristin Ardlie, Beverley Balkau, Rafn Benediktsson, Amanda J. Bennett, Roza Blagieva, Eric Boerwinkle, Lori L. Bonnycastle, Kristina Bengtsson Boström, Bert Bravenboer, Suzannah Bumpstead, Noël P. Burtt, Guillaume Charpentier, Peter S. Chines, Marilyn Cornelis, David J. Couper, Gabe Crawford, Alex S. F. Doney, Katherine S. Elliott, Amanda L. Elliott, Michael R. Erdos, Caroline S. Fox, Christopher S. Franklin, Martha Ganser, Christian Gieger, Niels Grarup, Todd Green, Simon Griffin, Christopher J. Groves, Candace Guiducci, Samy Hadjadj, Neelam Hassanali, Christian Herder, Bo Isomaa, Anne U. Jackson, Paul R. V. Johnson, Torben Jørgensen, Wen H. L. Kao, Norman B. Klopp, Augustine Kong, Peter Kraft, Johanna Kuusisto, Torsten Lauritzen, Man Li, Aloysius Lieverse, Cecilia M. Lindgren, Valeriya Lyssenko, Michel Marre, DIAGRAM+Consortium, Thomas Meitinger, Kristian Midthjell, Mario A. Morken, Narisu Narisu, Peter Nilsson, Katharine R. Owen, Felicity Payne, John R. B. Perry, Ann-Kristin Petersen, Carl Platou, Christine Proença, Inga Prokopenko, Wolfgang Rathmann, N. William Rayner, Neil R. Robertson, Ghislain Rocheleau, Michael Roden, Michael J. Sampson, Richa Saxena, Beverley M. Shields, Peter Shrader, Gunnar Sigurdsson, Thomas Sparsø, Klaus Strassburger, Heather M. Stringham, Qi Sun, Amy J. Swift, Barbara Thorand, Jean Tichet, Tiinamaija Tuomi, Rob M. van Dam, Timon W. van Haeften, Thijs van Herpt, Jana V. van Vliet-Ostaptchouk, G. Bragi Walters, Kern Mj, Michael N. Weedon

, Cisca Wijmenga, Jacqueline Witteman, Richard N. Bergman, Stephane Cauchi, Francis S. Collins, Anna L. Gloyn, Ulf Gyllensten, Torben Hansen, Winston A. Hide

, Graham A. Hitman, Albert Hofman, David J. Hunter, Kristian Hveem, Markku Laakso, N. Mehjert, Karen L. Mohlke, Andrew D. Morris, Colin N. A. Palmer, Peter P. Pramstaller

, Igor Rudan, Eric Sijbrands, Lincoln D. Stein, Jaakko Tuomilehto, Andre Uitterlinden, Mark Walker, Nicholas J. Wareham, Richard M. Watanabe, Goncalo R. Abecasis, Bernhard O. Boehm, Harry Campbell, Mark J. Daly, Andrew T. Hattersley, Frank B. Hu, James B. Meigs, James S. Pankow, Oluf Pedersen, H.-Erich Wichmann, Inês Barroso, Jose C. Florez, Timothy M. Frayling, Hauck Sm, Rob Sladek, Unnur Thorsteinsdottir, James F. Wilson, Philippe Froguel, Cornelia M. van Duijn, Kari Stefansson, David Altshuler, Michael Boehnke, Mark I. McCarthy

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Abstract

Genome-wide association studies have revealed numerous risk loci associated with diverse diseases. However, identification of disease-causing variants within association loci remains a major challenge. Divergence in gene expression due to cis-regulatory variants in noncoding regions is central to disease susceptibility. We show that integrative computational analysis of phylogenetic conservation with a complexity assessment of co-occurring transcription factor binding sites (TFBS) can identify cis-regulatory variants and elucidate their mechanistic role in disease. Analysis of established type 2 diabetes risk loci revealed a striking clustering of distinct homeobox TFBS. We identified the PRRX1 homeobox factor as a repressor of PPARG2 expression in adipose cells and demonstrate its adverse effect on lipid metabolism and systemic insulin sensitivity, dependent on the rs4684847 risk allele that triggers PRRX1 binding. Thus, cross-species conservation analysis at the level of co-occurring TFBS provides a valuable contribution to the translation of genetic association signals to disease-related molecular mechanisms.

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Leveraging cross-species transcription factor binding site patterns: From diabetes risk loci to disease mechanisms.

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