Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity

Audrey E. Hendricks, Elena G. Bochukova, Gaëlle Marenne, Julia M. Keogh, Neli Atanassova, Rebecca Bounds, Eleanor Wheeler, Vanisha Mistry, Elana Henning, Antje Körner, Dawn Muddyman, Shane McCarthy, Anke Hinney, Johannes Hebebrand, Robert A. Scott, Claudia Langenberg, Nick J Wareham, Praveen Surendran, Joanna M M Howson, Adam S. Butterworth & 250 others John Danesh, Børge G. Nordestgaard, Sune F. Nielsen, Shoaib Afzal, Sofia Papadia, Sofie Ashford, Sumedha Garg, Glenn L. Millhauser, Rafael I. Palomino, Alexandra Kwasniewska, Ioanna Tachmazidou, Stephen O'Rahilly, Eleftheria Zeggini, Inês Barroso, I. Sadaf Farooqi, Michaela Benzeval, Jonathan Burton, Nicholas Buck, Annette Jäckle, Meena Kumari, Heather Laurie, Peter Lynn, Stephen Pudney, Birgitta Rabe, Dieter Wolke, Kim Overvad, Anne Tjønneland, Francoise Clavel-Chapelon, Rudolf Kaaks, Heiner Boeing, Antonia Trichopoulou, Pietro Ferrari, Domenico Palli, Vittorio Krogha, Salvatore Panico, Rosario Tuminoa, Giuseppe Matullo, Jolanda Boer, Yvonne T. Van Der Schouw, Elisabete Weiderpass, J. Ramon Quiros, María José Sánchez, Carmen Navarro, Conchi Moreno-Iribas, Larraitz Arriola, Olle Melander, Patrik Wennberg, Timothy J. Key, Elio Riboli, Saeed Al Turki, Carl A. Anderson, Richard Anney, Dinu Antony, María Soler Artigas, Muhammad Ayub, Senduran Bala, Jeffrey C. Barrett, Phil Beales, Jamie Bentham, Shoumo Bhattacharyaa, Ewan Birney, Douglas Blackwooda, Martin Bobrow, Patrick F. Bolton, Chris Boustred, Gerome Breen, Mattia Calissanoa, Keren Carss, Ruth Charlton, Krishna Chatterjee, Lu Chen, Antonio Ciampia, Sebahattin Cirak, Peter Clapham, Gail Clement, Guy Coates, Massimiliano Coccaa, David A. Collier, Catherine Cosgrove, Tony Coxa, Nick Craddock, Lucy Crooks, Sarah Curran, David Curtis, Allan Daly, Petr Danecek, Ian N.M. Day, Aaron Day-Williams, Anna F. Dominiczak, Thomas Down, Yuanping Du, Ian Dunham, Richard Durbin, Sarah Edkins, Rosemary Ekong, Peter Ellis, David M. Evansa, David R. Fitzpatrick, Paul Flicek, James Floyd, A. Reghan Foley, Christopher S. Franklin, Marta Futema, Louise Gallagher, Tom R. Gaunt, Matthias Geihs, Daniel Geschwind, Celia M T Greenwood, Heather Griffin, Detelina Grozeva, Xiaosen Guo, Xueqin Guo, Hugh Gurling, Deborah Hart, Peter A. Holmans, Bryan Howie, Jie Huang, Liren Huang, Tim Hubbard, Steve E. Humphries, Matthew E. Hurles, Pirro G. Hysi, Valentina Iotchkova, David K. Jackson, Yalda Jamshidi, Chris Joyce, Konrad J. Karczewski, Jane Kaye, Thomas Keane, John P. Kemp, Karen Kennedy, Alastair Kent, Farrah Khawaja, Margriet Van Kogelenberg, Anja Kolb-Kokocinski, Genevieve Lachance, Cordelia Langford, Daniel Lawson, Irene Lee, Monkol Lek, Rui Li, Yingrui Li, Jieqin Liang, Hong Lin, Ryan Liu, Jouko Lönnqvist, Luis R. Lopes, Margarida Lopes, Daniel G. MacArthur, Massimo Mangino, Jonathan Marchini, John Maslen, Iain Mathieson, Peter McGuffin, Andrew M. McIntosh, Andrew G. McKechanie, Andrew McQuillin, Yasin Memari, Sarah Metrustry, Nicola Migone, Josine L. Min, Hannah M. Mitchison, Alireza Moayyeri, Andrew P. Morris, James Morris, Francesco Muntoni, Kate Northstone, Michael C. O'Donovan, Alexandros Onoufriadis, Karim Oualkacha, Michael J. Owen, Aarno Palotie, Kalliope Panoutsopoulou, Victoria Parker, Jeremy R. Parr, Lavinia Paternoster, Tiina Paunio, Felicity Payne, Stewart J. Payne, John R B Perry, Olli Pietilainen, Vincent Plagnol, Rebecca C. Pollitt, David J. Porteous, Sue Povey, Michael A. Quail, Lydia Quaye, F. Lucy Raymond, Karola Rehnström, J. Brent Richards, Cheryl K. Ridout, Susan M. Ring, Graham R.S. Ritchie, Nicola Roberts, Rachel L. Robinson, David B. Savage, Peter Scambler, Stephan Schiffels, Miriam Schmidts, Nadia Schoenmakers, Richard H. Scott, Robert K. Semple, Eva Serra, Sally I. Sharp, Adam Shaw, Hashem A. Shihab, So Youn Shin, David Skuse, Kerrin S. Small, Carol Smee, Blair H. Smith, George Davey Smith, Nicole Soranzo, Lorraine Southam, Olivera Spasic-Boskovic, Timothy D. Spector, David St Clair, Beate St Pourcain, Jim Stalker, Elizabeth Stevens, Jianping Sun, Gabriela L. Surdulescu, Jaana Suvisaari, Petros Syrris, Rohan Taylor, Jing Tian, Nicholas J. Timpson, Martin D. Tobin, Ana M. Valdes, Anthony M. Vandersteen, Parthiban Vijayarangakannan, Peter M. Visscher, Louise V. Wain, Klaudia Walter, James T R Walters, Guangbiao Wang, Jun Wang, Yu Wang, Kirsten Ward, Tamieka Whyte, Hywel J. Williams, Kathleen A. Williamson, Crispian Wilson, Scott G. Wilson, Kim Wong, Changjiang Xu, Jian Yang, Hai Feng Zhang, Pingbo Zhang, Hou-Feng Zheng

Research output: Contribution to journalArticle

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Abstract

Obesity is a genetically heterogeneous disorder. Using targeted and whole-exome sequencing, we studied 32 human and 87 rodent obesity genes in 2,548 severely obese children and 1,117 controls. We identified 52 variants contributing to obesity in 2% of cases including multiple novel variants in GNAS, which were sometimes found with accelerated growth rather than short stature as described previously. Nominally significant associations were found for rare functional variants in BBS1, BBS9, GNAS, MKKS, CLOCK and ANGPTL6. The p.S284X variant in ANGPTL6 drives the association signal (rs201622589, MAF∼0.1%, odds ratio = 10.13, p-value = 0.042) and results in complete loss of secretion in cells. Further analysis including additional case-control studies and population controls (N = 260,642) did not support association of this variant with obesity (odds ratio = 2.34, p-value = 2.59 × 10-3), highlighting the challenges of testing rare variant associations and the need for very large sample sizes. Further validation in cohorts with severe obesity and engineering the variants in model organisms will be needed to explore whether human variants in ANGPTL6 and other genes that lead to obesity when deleted in mice, do contribute to obesity. Such studies may yield druggable targets for weight loss therapies.

Original languageEnglish
Article number4394
JournalScientific Reports
Volume7
Issue number1
DOIs
Publication statusPublished - 1 Dec 2017

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Morbid Obesity
Pediatric Obesity
Rodentia
Obesity
Genes
Odds Ratio
Exome
Population Control
Sample Size
Case-Control Studies
Weight Loss
Growth

Cite this

Hendricks, A. E., Bochukova, E. G., Marenne, G., Keogh, J. M., Atanassova, N., Bounds, R., ... Zheng, H-F. (2017). Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity. Scientific Reports, 7(1), [4394]. https://doi.org/10.1038/s41598-017-03054-8
Hendricks, Audrey E. ; Bochukova, Elena G. ; Marenne, Gaëlle ; Keogh, Julia M. ; Atanassova, Neli ; Bounds, Rebecca ; Wheeler, Eleanor ; Mistry, Vanisha ; Henning, Elana ; Körner, Antje ; Muddyman, Dawn ; McCarthy, Shane ; Hinney, Anke ; Hebebrand, Johannes ; Scott, Robert A. ; Langenberg, Claudia ; Wareham, Nick J ; Surendran, Praveen ; Howson, Joanna M M ; Butterworth, Adam S. ; Danesh, John ; Nordestgaard, Børge G. ; Nielsen, Sune F. ; Afzal, Shoaib ; Papadia, Sofia ; Ashford, Sofie ; Garg, Sumedha ; Millhauser, Glenn L. ; Palomino, Rafael I. ; Kwasniewska, Alexandra ; Tachmazidou, Ioanna ; O'Rahilly, Stephen ; Zeggini, Eleftheria ; Barroso, Inês ; Farooqi, I. Sadaf ; Benzeval, Michaela ; Burton, Jonathan ; Buck, Nicholas ; Jäckle, Annette ; Kumari, Meena ; Laurie, Heather ; Lynn, Peter ; Pudney, Stephen ; Rabe, Birgitta ; Wolke, Dieter ; Overvad, Kim ; Tjønneland, Anne ; Clavel-Chapelon, Francoise ; Kaaks, Rudolf ; Boeing, Heiner ; Trichopoulou, Antonia ; Ferrari, Pietro ; Palli, Domenico ; Krogha, Vittorio ; Panico, Salvatore ; Tuminoa, Rosario ; Matullo, Giuseppe ; Boer, Jolanda ; Van Der Schouw, Yvonne T. ; Weiderpass, Elisabete ; Quiros, J. Ramon ; Sánchez, María José ; Navarro, Carmen ; Moreno-Iribas, Conchi ; Arriola, Larraitz ; Melander, Olle ; Wennberg, Patrik ; Key, Timothy J. ; Riboli, Elio ; Turki, Saeed Al ; Anderson, Carl A. ; Anney, Richard ; Antony, Dinu ; Soler Artigas, María ; Ayub, Muhammad ; Bala, Senduran ; Barrett, Jeffrey C. ; Beales, Phil ; Bentham, Jamie ; Bhattacharyaa, Shoumo ; Birney, Ewan ; Blackwooda, Douglas ; Bobrow, Martin ; Bolton, Patrick F. ; Boustred, Chris ; Breen, Gerome ; Calissanoa, Mattia ; Carss, Keren ; Charlton, Ruth ; Chatterjee, Krishna ; Chen, Lu ; Ciampia, Antonio ; Cirak, Sebahattin ; Clapham, Peter ; Clement, Gail ; Coates, Guy ; Coccaa, Massimiliano ; Collier, David A. ; Cosgrove, Catherine ; Coxa, Tony ; Craddock, Nick ; Crooks, Lucy ; Curran, Sarah ; Curtis, David ; Daly, Allan ; Danecek, Petr ; Day, Ian N.M. ; Day-Williams, Aaron ; Dominiczak, Anna F. ; Down, Thomas ; Du, Yuanping ; Dunham, Ian ; Durbin, Richard ; Edkins, Sarah ; Ekong, Rosemary ; Ellis, Peter ; Evansa, David M. ; Fitzpatrick, David R. ; Flicek, Paul ; Floyd, James ; Foley, A. Reghan ; Franklin, Christopher S. ; Futema, Marta ; Gallagher, Louise ; Gaunt, Tom R. ; Geihs, Matthias ; Geschwind, Daniel ; Greenwood, Celia M T ; Griffin, Heather ; Grozeva, Detelina ; Guo, Xiaosen ; Guo, Xueqin ; Gurling, Hugh ; Hart, Deborah ; Holmans, Peter A. ; Howie, Bryan ; Huang, Jie ; Huang, Liren ; Hubbard, Tim ; Humphries, Steve E. ; Hurles, Matthew E. ; Hysi, Pirro G. ; Iotchkova, Valentina ; Jackson, David K. ; Jamshidi, Yalda ; Joyce, Chris ; Karczewski, Konrad J. ; Kaye, Jane ; Keane, Thomas ; Kemp, John P. ; Kennedy, Karen ; Kent, Alastair ; Khawaja, Farrah ; Van Kogelenberg, Margriet ; Kolb-Kokocinski, Anja ; Lachance, Genevieve ; Langford, Cordelia ; Lawson, Daniel ; Lee, Irene ; Lek, Monkol ; Li, Rui ; Li, Yingrui ; Liang, Jieqin ; Lin, Hong ; Liu, Ryan ; Lönnqvist, Jouko ; Lopes, Luis R. ; Lopes, Margarida ; MacArthur, Daniel G. ; Mangino, Massimo ; Marchini, Jonathan ; Maslen, John ; Mathieson, Iain ; McGuffin, Peter ; McIntosh, Andrew M. ; McKechanie, Andrew G. ; McQuillin, Andrew ; Memari, Yasin ; Metrustry, Sarah ; Migone, Nicola ; Min, Josine L. ; Mitchison, Hannah M. ; Moayyeri, Alireza ; Morris, Andrew P. ; Morris, James ; Muntoni, Francesco ; Northstone, Kate ; O'Donovan, Michael C. ; Onoufriadis, Alexandros ; Oualkacha, Karim ; Owen, Michael J. ; Palotie, Aarno ; Panoutsopoulou, Kalliope ; Parker, Victoria ; Parr, Jeremy R. ; Paternoster, Lavinia ; Paunio, Tiina ; Payne, Felicity ; Payne, Stewart J. ; Perry, John R B ; Pietilainen, Olli ; Plagnol, Vincent ; Pollitt, Rebecca C. ; Porteous, David J. ; Povey, Sue ; Quail, Michael A. ; Quaye, Lydia ; Raymond, F. Lucy ; Rehnström, Karola ; Richards, J. Brent ; Ridout, Cheryl K. ; Ring, Susan M. ; Ritchie, Graham R.S. ; Roberts, Nicola ; Robinson, Rachel L. ; Savage, David B. ; Scambler, Peter ; Schiffels, Stephan ; Schmidts, Miriam ; Schoenmakers, Nadia ; Scott, Richard H. ; Semple, Robert K. ; Serra, Eva ; Sharp, Sally I. ; Shaw, Adam ; Shihab, Hashem A. ; Shin, So Youn ; Skuse, David ; Small, Kerrin S. ; Smee, Carol ; Smith, Blair H. ; Davey Smith, George ; Soranzo, Nicole ; Southam, Lorraine ; Spasic-Boskovic, Olivera ; Spector, Timothy D. ; St Clair, David ; St Pourcain, Beate ; Stalker, Jim ; Stevens, Elizabeth ; Sun, Jianping ; Surdulescu, Gabriela L. ; Suvisaari, Jaana ; Syrris, Petros ; Taylor, Rohan ; Tian, Jing ; Timpson, Nicholas J. ; Tobin, Martin D. ; Valdes, Ana M. ; Vandersteen, Anthony M. ; Vijayarangakannan, Parthiban ; Visscher, Peter M. ; Wain, Louise V. ; Walter, Klaudia ; Walters, James T R ; Wang, Guangbiao ; Wang, Jun ; Wang, Yu ; Ward, Kirsten ; Whyte, Tamieka ; Williams, Hywel J. ; Williamson, Kathleen A. ; Wilson, Crispian ; Wilson, Scott G. ; Wong, Kim ; Xu, Changjiang ; Yang, Jian ; Zhang, Hai Feng ; Zhang, Pingbo ; Zheng, Hou-Feng. / Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity. In: Scientific Reports. 2017 ; Vol. 7, No. 1.
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title = "Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity",
abstract = "Obesity is a genetically heterogeneous disorder. Using targeted and whole-exome sequencing, we studied 32 human and 87 rodent obesity genes in 2,548 severely obese children and 1,117 controls. We identified 52 variants contributing to obesity in 2{\%} of cases including multiple novel variants in GNAS, which were sometimes found with accelerated growth rather than short stature as described previously. Nominally significant associations were found for rare functional variants in BBS1, BBS9, GNAS, MKKS, CLOCK and ANGPTL6. The p.S284X variant in ANGPTL6 drives the association signal (rs201622589, MAF∼0.1{\%}, odds ratio = 10.13, p-value = 0.042) and results in complete loss of secretion in cells. Further analysis including additional case-control studies and population controls (N = 260,642) did not support association of this variant with obesity (odds ratio = 2.34, p-value = 2.59 × 10-3), highlighting the challenges of testing rare variant associations and the need for very large sample sizes. Further validation in cohorts with severe obesity and engineering the variants in model organisms will be needed to explore whether human variants in ANGPTL6 and other genes that lead to obesity when deleted in mice, do contribute to obesity. Such studies may yield druggable targets for weight loss therapies.",
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Ramon} and S{\'a}nchez, {Mar{\'i}a Jos{\'e}} and Carmen Navarro and Conchi Moreno-Iribas and Larraitz Arriola and Olle Melander and Patrik Wennberg and Key, {Timothy J.} and Elio Riboli and Turki, {Saeed Al} and Anderson, {Carl A.} and Richard Anney and Dinu Antony and {Soler Artigas}, Mar{\'i}a and Muhammad Ayub and Senduran Bala and Barrett, {Jeffrey C.} and Phil Beales and Jamie Bentham and Shoumo Bhattacharyaa and Ewan Birney and Douglas Blackwooda and Martin Bobrow and Bolton, {Patrick F.} and Chris Boustred and Gerome Breen and Mattia Calissanoa and Keren Carss and Ruth Charlton and Krishna Chatterjee and Lu Chen and Antonio Ciampia and Sebahattin Cirak and Peter Clapham and Gail Clement and Guy Coates and Massimiliano Coccaa and Collier, {David A.} and Catherine Cosgrove and Tony Coxa and Nick Craddock and Lucy Crooks and Sarah Curran and David Curtis and Allan Daly and Petr Danecek and Day, {Ian N.M.} and Aaron Day-Williams and Dominiczak, {Anna F.} and Thomas Down and Yuanping Du and Ian Dunham and Richard Durbin and Sarah Edkins and Rosemary Ekong and Peter Ellis and Evansa, {David M.} and Fitzpatrick, {David R.} and Paul Flicek and James Floyd and Foley, {A. Reghan} and Franklin, {Christopher S.} and Marta Futema and Louise Gallagher and Gaunt, {Tom R.} and Matthias Geihs and Daniel Geschwind and Greenwood, {Celia M T} and Heather Griffin and Detelina Grozeva and Xiaosen Guo and Xueqin Guo and Hugh Gurling and Deborah Hart and Holmans, {Peter A.} and Bryan Howie and Jie Huang and Liren Huang and Tim Hubbard and Humphries, {Steve E.} and Hurles, {Matthew E.} and Hysi, {Pirro G.} and Valentina Iotchkova and Jackson, {David K.} and Yalda Jamshidi and Chris Joyce and Karczewski, {Konrad J.} and Jane Kaye and Thomas Keane and Kemp, {John P.} and Karen Kennedy and Alastair Kent and Farrah Khawaja and {Van Kogelenberg}, Margriet and Anja Kolb-Kokocinski and Genevieve Lachance and Cordelia Langford and Daniel Lawson and Irene Lee and Monkol Lek and Rui Li and Yingrui Li and Jieqin Liang and Hong Lin and Ryan Liu and Jouko L{\"o}nnqvist and Lopes, {Luis R.} and Margarida Lopes and MacArthur, {Daniel G.} and Massimo Mangino and Jonathan Marchini and John Maslen and Iain Mathieson and Peter McGuffin and McIntosh, {Andrew M.} and McKechanie, {Andrew G.} and Andrew McQuillin and Yasin Memari and Sarah Metrustry and Nicola Migone and Min, {Josine L.} and Mitchison, {Hannah M.} and Alireza Moayyeri and Morris, {Andrew P.} and James Morris and Francesco Muntoni and Kate Northstone and O'Donovan, {Michael C.} and Alexandros Onoufriadis and Karim Oualkacha and Owen, {Michael J.} and Aarno Palotie and Kalliope Panoutsopoulou and Victoria Parker and Parr, {Jeremy R.} and Lavinia Paternoster and Tiina Paunio and Felicity Payne and Payne, {Stewart J.} and Perry, {John R B} and Olli Pietilainen and Vincent Plagnol and Pollitt, {Rebecca C.} and Porteous, {David J.} and Sue Povey and Quail, {Michael A.} and Lydia Quaye and Raymond, {F. Lucy} and Karola Rehnstr{\"o}m and Richards, {J. Brent} and Ridout, {Cheryl K.} and Ring, {Susan M.} and Ritchie, {Graham R.S.} and Nicola Roberts and Robinson, {Rachel L.} and Savage, {David B.} and Peter Scambler and Stephan Schiffels and Miriam Schmidts and Nadia Schoenmakers and Scott, {Richard H.} and Semple, {Robert K.} and Eva Serra and Sharp, {Sally I.} and Adam Shaw and Shihab, {Hashem A.} and Shin, {So Youn} and David Skuse and Small, {Kerrin S.} and Carol Smee and Smith, {Blair H.} and {Davey Smith}, George and Nicole Soranzo and Lorraine Southam and Olivera Spasic-Boskovic and Spector, {Timothy D.} and {St Clair}, David and {St Pourcain}, Beate and Jim Stalker and Elizabeth Stevens and Jianping Sun and Surdulescu, {Gabriela L.} and Jaana Suvisaari and Petros Syrris and Rohan Taylor and Jing Tian and Timpson, {Nicholas J.} and Tobin, {Martin D.} and Valdes, {Ana M.} and Vandersteen, {Anthony M.} and Parthiban Vijayarangakannan and Visscher, {Peter M.} and Wain, {Louise V.} and Klaudia Walter and Walters, {James T R} and Guangbiao Wang and Jun Wang and Yu Wang and Kirsten Ward and Tamieka Whyte and Williams, {Hywel J.} and Williamson, {Kathleen A.} and Crispian Wilson and Wilson, {Scott G.} and Kim Wong and Changjiang Xu and Jian Yang and Zhang, {Hai Feng} and Pingbo Zhang and Hou-Feng Zheng",
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doi = "10.1038/s41598-017-03054-8",
language = "English",
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journal = "Scientific Reports",
issn = "2045-2322",
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}

Hendricks, AE, Bochukova, EG, Marenne, G, Keogh, JM, Atanassova, N, Bounds, R, Wheeler, E, Mistry, V, Henning, E, Körner, A, Muddyman, D, McCarthy, S, Hinney, A, Hebebrand, J, Scott, RA, Langenberg, C, Wareham, NJ, Surendran, P, Howson, JMM, Butterworth, AS, Danesh, J, Nordestgaard, BG, Nielsen, SF, Afzal, S, Papadia, S, Ashford, S, Garg, S, Millhauser, GL, Palomino, RI, Kwasniewska, A, Tachmazidou, I, O'Rahilly, S, Zeggini, E, Barroso, I, Farooqi, IS, Benzeval, M, Burton, J, Buck, N, Jäckle, A, Kumari, M, Laurie, H, Lynn, P, Pudney, S, Rabe, B, Wolke, D, Overvad, K, Tjønneland, A, Clavel-Chapelon, F, Kaaks, R, Boeing, H, Trichopoulou, A, Ferrari, P, Palli, D, Krogha, V, Panico, S, Tuminoa, R, Matullo, G, Boer, J, Van Der Schouw, YT, Weiderpass, E, Quiros, JR, Sánchez, MJ, Navarro, C, Moreno-Iribas, C, Arriola, L, Melander, O, Wennberg, P, Key, TJ, Riboli, E, Turki, SA, Anderson, CA, Anney, R, Antony, D, Soler Artigas, M, Ayub, M, Bala, S, Barrett, JC, Beales, P, Bentham, J, Bhattacharyaa, S, Birney, E, Blackwooda, D, Bobrow, M, Bolton, PF, Boustred, C, Breen, G, Calissanoa, M, Carss, K, Charlton, R, Chatterjee, K, Chen, L, Ciampia, A, Cirak, S, Clapham, P, Clement, G, Coates, G, Coccaa, M, Collier, DA, Cosgrove, C, Coxa, T, Craddock, N, Crooks, L, Curran, S, Curtis, D, Daly, A, Danecek, P, Day, INM, Day-Williams, A, Dominiczak, AF, Down, T, Du, Y, Dunham, I, Durbin, R, Edkins, S, Ekong, R, Ellis, P, Evansa, DM, Fitzpatrick, DR, Flicek, P, Floyd, J, Foley, AR, Franklin, CS, Futema, M, Gallagher, L, Gaunt, TR, Geihs, M, Geschwind, D, Greenwood, CMT, Griffin, H, Grozeva, D, Guo, X, Guo, X, Gurling, H, Hart, D, Holmans, PA, Howie, B, Huang, J, Huang, L, Hubbard, T, Humphries, SE, Hurles, ME, Hysi, PG, Iotchkova, V, Jackson, DK, Jamshidi, Y, Joyce, C, Karczewski, KJ, Kaye, J, Keane, T, Kemp, JP, Kennedy, K, Kent, A, Khawaja, F, Van Kogelenberg, M, Kolb-Kokocinski, A, Lachance, G, Langford, C, Lawson, D, Lee, I, Lek, M, Li, R, Li, Y, Liang, J, Lin, H, Liu, R, Lönnqvist, J, Lopes, LR, Lopes, M, MacArthur, DG, Mangino, M, Marchini, J, Maslen, J, Mathieson, I, McGuffin, P, McIntosh, AM, McKechanie, AG, McQuillin, A, Memari, Y, Metrustry, S, Migone, N, Min, JL, Mitchison, HM, Moayyeri, A, Morris, AP, Morris, J, Muntoni, F, Northstone, K, O'Donovan, MC, Onoufriadis, A, Oualkacha, K, Owen, MJ, Palotie, A, Panoutsopoulou, K, Parker, V, Parr, JR, Paternoster, L, Paunio, T, Payne, F, Payne, SJ, Perry, JRB, Pietilainen, O, Plagnol, V, Pollitt, RC, Porteous, DJ, Povey, S, Quail, MA, Quaye, L, Raymond, FL, Rehnström, K, Richards, JB, Ridout, CK, Ring, SM, Ritchie, GRS, Roberts, N, Robinson, RL, Savage, DB, Scambler, P, Schiffels, S, Schmidts, M, Schoenmakers, N, Scott, RH, Semple, RK, Serra, E, Sharp, SI, Shaw, A, Shihab, HA, Shin, SY, Skuse, D, Small, KS, Smee, C, Smith, BH, Davey Smith, G, Soranzo, N, Southam, L, Spasic-Boskovic, O, Spector, TD, St Clair, D, St Pourcain, B, Stalker, J, Stevens, E, Sun, J, Surdulescu, GL, Suvisaari, J, Syrris, P, Taylor, R, Tian, J, Timpson, NJ, Tobin, MD, Valdes, AM, Vandersteen, AM, Vijayarangakannan, P, Visscher, PM, Wain, LV, Walter, K, Walters, JTR, Wang, G, Wang, J, Wang, Y, Ward, K, Whyte, T, Williams, HJ, Williamson, KA, Wilson, C, Wilson, SG, Wong, K, Xu, C, Yang, J, Zhang, HF, Zhang, P & Zheng, H-F 2017, 'Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity' Scientific Reports, vol. 7, no. 1, 4394. https://doi.org/10.1038/s41598-017-03054-8

Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity. / Hendricks, Audrey E.; Bochukova, Elena G.; Marenne, Gaëlle; Keogh, Julia M.; Atanassova, Neli; Bounds, Rebecca; Wheeler, Eleanor; Mistry, Vanisha; Henning, Elana; Körner, Antje; Muddyman, Dawn; McCarthy, Shane; Hinney, Anke; Hebebrand, Johannes; Scott, Robert A.; Langenberg, Claudia; Wareham, Nick J; Surendran, Praveen; Howson, Joanna M M; Butterworth, Adam S.; Danesh, John; Nordestgaard, Børge G.; Nielsen, Sune F.; Afzal, Shoaib; Papadia, Sofia; Ashford, Sofie; Garg, Sumedha; Millhauser, Glenn L.; Palomino, Rafael I.; Kwasniewska, Alexandra; Tachmazidou, Ioanna; O'Rahilly, Stephen; Zeggini, Eleftheria; Barroso, Inês; Farooqi, I. Sadaf; Benzeval, Michaela; Burton, Jonathan; Buck, Nicholas; Jäckle, Annette; Kumari, Meena; Laurie, Heather; Lynn, Peter; Pudney, Stephen; Rabe, Birgitta; Wolke, Dieter; Overvad, Kim; Tjønneland, Anne; Clavel-Chapelon, Francoise; Kaaks, Rudolf; Boeing, Heiner; Trichopoulou, Antonia; Ferrari, Pietro; Palli, Domenico; Krogha, Vittorio; Panico, Salvatore; Tuminoa, Rosario; Matullo, Giuseppe; Boer, Jolanda; Van Der Schouw, Yvonne T.; Weiderpass, Elisabete; Quiros, J. Ramon; Sánchez, María José; Navarro, Carmen; Moreno-Iribas, Conchi; Arriola, Larraitz; Melander, Olle; Wennberg, Patrik; Key, Timothy J.; Riboli, Elio; Turki, Saeed Al; Anderson, Carl A.; Anney, Richard; Antony, Dinu; Soler Artigas, María; Ayub, Muhammad; Bala, Senduran; Barrett, Jeffrey C.; Beales, Phil; Bentham, Jamie; Bhattacharyaa, Shoumo; Birney, Ewan; Blackwooda, Douglas; Bobrow, Martin; Bolton, Patrick F.; Boustred, Chris; Breen, Gerome; Calissanoa, Mattia; Carss, Keren; Charlton, Ruth; Chatterjee, Krishna; Chen, Lu; Ciampia, Antonio; Cirak, Sebahattin; Clapham, Peter; Clement, Gail; Coates, Guy; Coccaa, Massimiliano; Collier, David A.; Cosgrove, Catherine; Coxa, Tony; Craddock, Nick; Crooks, Lucy; Curran, Sarah; Curtis, David; Daly, Allan; Danecek, Petr; Day, Ian N.M.; Day-Williams, Aaron; Dominiczak, Anna F.; Down, Thomas; Du, Yuanping; Dunham, Ian; Durbin, Richard; Edkins, Sarah; Ekong, Rosemary; Ellis, Peter; Evansa, David M.; Fitzpatrick, David R.; Flicek, Paul; Floyd, James; Foley, A. Reghan; Franklin, Christopher S.; Futema, Marta; Gallagher, Louise; Gaunt, Tom R.; Geihs, Matthias; Geschwind, Daniel; Greenwood, Celia M T; Griffin, Heather; Grozeva, Detelina; Guo, Xiaosen; Guo, Xueqin; Gurling, Hugh; Hart, Deborah; Holmans, Peter A.; Howie, Bryan; Huang, Jie; Huang, Liren; Hubbard, Tim; Humphries, Steve E.; Hurles, Matthew E.; Hysi, Pirro G.; Iotchkova, Valentina; Jackson, David K.; Jamshidi, Yalda; Joyce, Chris; Karczewski, Konrad J.; Kaye, Jane; Keane, Thomas; Kemp, John P.; Kennedy, Karen; Kent, Alastair; Khawaja, Farrah; Van Kogelenberg, Margriet; Kolb-Kokocinski, Anja; Lachance, Genevieve; Langford, Cordelia; Lawson, Daniel; Lee, Irene; Lek, Monkol; Li, Rui; Li, Yingrui; Liang, Jieqin; Lin, Hong; Liu, Ryan; Lönnqvist, Jouko; Lopes, Luis R.; Lopes, Margarida; MacArthur, Daniel G.; Mangino, Massimo; Marchini, Jonathan; Maslen, John; Mathieson, Iain; McGuffin, Peter; McIntosh, Andrew M.; McKechanie, Andrew G.; McQuillin, Andrew; Memari, Yasin; Metrustry, Sarah; Migone, Nicola; Min, Josine L.; Mitchison, Hannah M.; Moayyeri, Alireza; Morris, Andrew P.; Morris, James; Muntoni, Francesco; Northstone, Kate; O'Donovan, Michael C.; Onoufriadis, Alexandros; Oualkacha, Karim; Owen, Michael J.; Palotie, Aarno; Panoutsopoulou, Kalliope; Parker, Victoria; Parr, Jeremy R.; Paternoster, Lavinia; Paunio, Tiina; Payne, Felicity; Payne, Stewart J.; Perry, John R B; Pietilainen, Olli; Plagnol, Vincent; Pollitt, Rebecca C.; Porteous, David J.; Povey, Sue; Quail, Michael A.; Quaye, Lydia; Raymond, F. Lucy; Rehnström, Karola; Richards, J. Brent; Ridout, Cheryl K.; Ring, Susan M.; Ritchie, Graham R.S.; Roberts, Nicola; Robinson, Rachel L.; Savage, David B.; Scambler, Peter; Schiffels, Stephan; Schmidts, Miriam; Schoenmakers, Nadia; Scott, Richard H.; Semple, Robert K.; Serra, Eva; Sharp, Sally I.; Shaw, Adam; Shihab, Hashem A.; Shin, So Youn; Skuse, David; Small, Kerrin S.; Smee, Carol; Smith, Blair H.; Davey Smith, George; Soranzo, Nicole; Southam, Lorraine; Spasic-Boskovic, Olivera; Spector, Timothy D.; St Clair, David; St Pourcain, Beate; Stalker, Jim; Stevens, Elizabeth; Sun, Jianping; Surdulescu, Gabriela L.; Suvisaari, Jaana; Syrris, Petros; Taylor, Rohan; Tian, Jing; Timpson, Nicholas J.; Tobin, Martin D.; Valdes, Ana M.; Vandersteen, Anthony M.; Vijayarangakannan, Parthiban; Visscher, Peter M.; Wain, Louise V.; Walter, Klaudia; Walters, James T R; Wang, Guangbiao; Wang, Jun; Wang, Yu; Ward, Kirsten; Whyte, Tamieka; Williams, Hywel J.; Williamson, Kathleen A.; Wilson, Crispian; Wilson, Scott G.; Wong, Kim; Xu, Changjiang; Yang, Jian; Zhang, Hai Feng; Zhang, Pingbo; Zheng, Hou-Feng.

In: Scientific Reports, Vol. 7, No. 1, 4394, 01.12.2017.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity

AU - Hendricks, Audrey E.

AU - Bochukova, Elena G.

AU - Marenne, Gaëlle

AU - Keogh, Julia M.

AU - Atanassova, Neli

AU - Bounds, Rebecca

AU - Wheeler, Eleanor

AU - Mistry, Vanisha

AU - Henning, Elana

AU - Körner, Antje

AU - Muddyman, Dawn

AU - McCarthy, Shane

AU - Hinney, Anke

AU - Hebebrand, Johannes

AU - Scott, Robert A.

AU - Langenberg, Claudia

AU - Wareham, Nick J

AU - Surendran, Praveen

AU - Howson, Joanna M M

AU - Butterworth, Adam S.

AU - Danesh, John

AU - Nordestgaard, Børge G.

AU - Nielsen, Sune F.

AU - Afzal, Shoaib

AU - Papadia, Sofia

AU - Ashford, Sofie

AU - Garg, Sumedha

AU - Millhauser, Glenn L.

AU - Palomino, Rafael I.

AU - Kwasniewska, Alexandra

AU - Tachmazidou, Ioanna

AU - O'Rahilly, Stephen

AU - Zeggini, Eleftheria

AU - Barroso, Inês

AU - Farooqi, I. Sadaf

AU - Benzeval, Michaela

AU - Burton, Jonathan

AU - Buck, Nicholas

AU - Jäckle, Annette

AU - Kumari, Meena

AU - Laurie, Heather

AU - Lynn, Peter

AU - Pudney, Stephen

AU - Rabe, Birgitta

AU - Wolke, Dieter

AU - Overvad, Kim

AU - Tjønneland, Anne

AU - Clavel-Chapelon, Francoise

AU - Kaaks, Rudolf

AU - Boeing, Heiner

AU - Trichopoulou, Antonia

AU - Ferrari, Pietro

AU - Palli, Domenico

AU - Krogha, Vittorio

AU - Panico, Salvatore

AU - Tuminoa, Rosario

AU - Matullo, Giuseppe

AU - Boer, Jolanda

AU - Van Der Schouw, Yvonne T.

AU - Weiderpass, Elisabete

AU - Quiros, J. Ramon

AU - Sánchez, María José

AU - Navarro, Carmen

AU - Moreno-Iribas, Conchi

AU - Arriola, Larraitz

AU - Melander, Olle

AU - Wennberg, Patrik

AU - Key, Timothy J.

AU - Riboli, Elio

AU - Turki, Saeed Al

AU - Anderson, Carl A.

AU - Anney, Richard

AU - Antony, Dinu

AU - Soler Artigas, María

AU - Ayub, Muhammad

AU - Bala, Senduran

AU - Barrett, Jeffrey C.

AU - Beales, Phil

AU - Bentham, Jamie

AU - Bhattacharyaa, Shoumo

AU - Birney, Ewan

AU - Blackwooda, Douglas

AU - Bobrow, Martin

AU - Bolton, Patrick F.

AU - Boustred, Chris

AU - Breen, Gerome

AU - Calissanoa, Mattia

AU - Carss, Keren

AU - Charlton, Ruth

AU - Chatterjee, Krishna

AU - Chen, Lu

AU - Ciampia, Antonio

AU - Cirak, Sebahattin

AU - Clapham, Peter

AU - Clement, Gail

AU - Coates, Guy

AU - Coccaa, Massimiliano

AU - Collier, David A.

AU - Cosgrove, Catherine

AU - Coxa, Tony

AU - Craddock, Nick

AU - Crooks, Lucy

AU - Curran, Sarah

AU - Curtis, David

AU - Daly, Allan

AU - Danecek, Petr

AU - Day, Ian N.M.

AU - Day-Williams, Aaron

AU - Dominiczak, Anna F.

AU - Down, Thomas

AU - Du, Yuanping

AU - Dunham, Ian

AU - Durbin, Richard

AU - Edkins, Sarah

AU - Ekong, Rosemary

AU - Ellis, Peter

AU - Evansa, David M.

AU - Fitzpatrick, David R.

AU - Flicek, Paul

AU - Floyd, James

AU - Foley, A. Reghan

AU - Franklin, Christopher S.

AU - Futema, Marta

AU - Gallagher, Louise

AU - Gaunt, Tom R.

AU - Geihs, Matthias

AU - Geschwind, Daniel

AU - Greenwood, Celia M T

AU - Griffin, Heather

AU - Grozeva, Detelina

AU - Guo, Xiaosen

AU - Guo, Xueqin

AU - Gurling, Hugh

AU - Hart, Deborah

AU - Holmans, Peter A.

AU - Howie, Bryan

AU - Huang, Jie

AU - Huang, Liren

AU - Hubbard, Tim

AU - Humphries, Steve E.

AU - Hurles, Matthew E.

AU - Hysi, Pirro G.

AU - Iotchkova, Valentina

AU - Jackson, David K.

AU - Jamshidi, Yalda

AU - Joyce, Chris

AU - Karczewski, Konrad J.

AU - Kaye, Jane

AU - Keane, Thomas

AU - Kemp, John P.

AU - Kennedy, Karen

AU - Kent, Alastair

AU - Khawaja, Farrah

AU - Van Kogelenberg, Margriet

AU - Kolb-Kokocinski, Anja

AU - Lachance, Genevieve

AU - Langford, Cordelia

AU - Lawson, Daniel

AU - Lee, Irene

AU - Lek, Monkol

AU - Li, Rui

AU - Li, Yingrui

AU - Liang, Jieqin

AU - Lin, Hong

AU - Liu, Ryan

AU - Lönnqvist, Jouko

AU - Lopes, Luis R.

AU - Lopes, Margarida

AU - MacArthur, Daniel G.

AU - Mangino, Massimo

AU - Marchini, Jonathan

AU - Maslen, John

AU - Mathieson, Iain

AU - McGuffin, Peter

AU - McIntosh, Andrew M.

AU - McKechanie, Andrew G.

AU - McQuillin, Andrew

AU - Memari, Yasin

AU - Metrustry, Sarah

AU - Migone, Nicola

AU - Min, Josine L.

AU - Mitchison, Hannah M.

AU - Moayyeri, Alireza

AU - Morris, Andrew P.

AU - Morris, James

AU - Muntoni, Francesco

AU - Northstone, Kate

AU - O'Donovan, Michael C.

AU - Onoufriadis, Alexandros

AU - Oualkacha, Karim

AU - Owen, Michael J.

AU - Palotie, Aarno

AU - Panoutsopoulou, Kalliope

AU - Parker, Victoria

AU - Parr, Jeremy R.

AU - Paternoster, Lavinia

AU - Paunio, Tiina

AU - Payne, Felicity

AU - Payne, Stewart J.

AU - Perry, John R B

AU - Pietilainen, Olli

AU - Plagnol, Vincent

AU - Pollitt, Rebecca C.

AU - Porteous, David J.

AU - Povey, Sue

AU - Quail, Michael A.

AU - Quaye, Lydia

AU - Raymond, F. Lucy

AU - Rehnström, Karola

AU - Richards, J. Brent

AU - Ridout, Cheryl K.

AU - Ring, Susan M.

AU - Ritchie, Graham R.S.

AU - Roberts, Nicola

AU - Robinson, Rachel L.

AU - Savage, David B.

AU - Scambler, Peter

AU - Schiffels, Stephan

AU - Schmidts, Miriam

AU - Schoenmakers, Nadia

AU - Scott, Richard H.

AU - Semple, Robert K.

AU - Serra, Eva

AU - Sharp, Sally I.

AU - Shaw, Adam

AU - Shihab, Hashem A.

AU - Shin, So Youn

AU - Skuse, David

AU - Small, Kerrin S.

AU - Smee, Carol

AU - Smith, Blair H.

AU - Davey Smith, George

AU - Soranzo, Nicole

AU - Southam, Lorraine

AU - Spasic-Boskovic, Olivera

AU - Spector, Timothy D.

AU - St Clair, David

AU - St Pourcain, Beate

AU - Stalker, Jim

AU - Stevens, Elizabeth

AU - Sun, Jianping

AU - Surdulescu, Gabriela L.

AU - Suvisaari, Jaana

AU - Syrris, Petros

AU - Taylor, Rohan

AU - Tian, Jing

AU - Timpson, Nicholas J.

AU - Tobin, Martin D.

AU - Valdes, Ana M.

AU - Vandersteen, Anthony M.

AU - Vijayarangakannan, Parthiban

AU - Visscher, Peter M.

AU - Wain, Louise V.

AU - Walter, Klaudia

AU - Walters, James T R

AU - Wang, Guangbiao

AU - Wang, Jun

AU - Wang, Yu

AU - Ward, Kirsten

AU - Whyte, Tamieka

AU - Williams, Hywel J.

AU - Williamson, Kathleen A.

AU - Wilson, Crispian

AU - Wilson, Scott G.

AU - Wong, Kim

AU - Xu, Changjiang

AU - Yang, Jian

AU - Zhang, Hai Feng

AU - Zhang, Pingbo

AU - Zheng, Hou-Feng

PY - 2017/12/1

Y1 - 2017/12/1

N2 - Obesity is a genetically heterogeneous disorder. Using targeted and whole-exome sequencing, we studied 32 human and 87 rodent obesity genes in 2,548 severely obese children and 1,117 controls. We identified 52 variants contributing to obesity in 2% of cases including multiple novel variants in GNAS, which were sometimes found with accelerated growth rather than short stature as described previously. Nominally significant associations were found for rare functional variants in BBS1, BBS9, GNAS, MKKS, CLOCK and ANGPTL6. The p.S284X variant in ANGPTL6 drives the association signal (rs201622589, MAF∼0.1%, odds ratio = 10.13, p-value = 0.042) and results in complete loss of secretion in cells. Further analysis including additional case-control studies and population controls (N = 260,642) did not support association of this variant with obesity (odds ratio = 2.34, p-value = 2.59 × 10-3), highlighting the challenges of testing rare variant associations and the need for very large sample sizes. Further validation in cohorts with severe obesity and engineering the variants in model organisms will be needed to explore whether human variants in ANGPTL6 and other genes that lead to obesity when deleted in mice, do contribute to obesity. Such studies may yield druggable targets for weight loss therapies.

AB - Obesity is a genetically heterogeneous disorder. Using targeted and whole-exome sequencing, we studied 32 human and 87 rodent obesity genes in 2,548 severely obese children and 1,117 controls. We identified 52 variants contributing to obesity in 2% of cases including multiple novel variants in GNAS, which were sometimes found with accelerated growth rather than short stature as described previously. Nominally significant associations were found for rare functional variants in BBS1, BBS9, GNAS, MKKS, CLOCK and ANGPTL6. The p.S284X variant in ANGPTL6 drives the association signal (rs201622589, MAF∼0.1%, odds ratio = 10.13, p-value = 0.042) and results in complete loss of secretion in cells. Further analysis including additional case-control studies and population controls (N = 260,642) did not support association of this variant with obesity (odds ratio = 2.34, p-value = 2.59 × 10-3), highlighting the challenges of testing rare variant associations and the need for very large sample sizes. Further validation in cohorts with severe obesity and engineering the variants in model organisms will be needed to explore whether human variants in ANGPTL6 and other genes that lead to obesity when deleted in mice, do contribute to obesity. Such studies may yield druggable targets for weight loss therapies.

UR - http://www.scopus.com/inward/record.url?scp=85021671193&partnerID=8YFLogxK

U2 - 10.1038/s41598-017-03054-8

DO - 10.1038/s41598-017-03054-8

M3 - Article

VL - 7

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

IS - 1

M1 - 4394

ER -