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

    13 Citations (Scopus)

    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.",
    author = "Hendricks, {Audrey E.} and Bochukova, {Elena G.} and Ga{\"e}lle Marenne and Keogh, {Julia M.} and Neli Atanassova and Rebecca Bounds and Eleanor Wheeler and Vanisha Mistry and Elana Henning and Antje K{\"o}rner and Dawn Muddyman and Shane McCarthy and Anke Hinney and Johannes Hebebrand and Scott, {Robert A.} and Claudia Langenberg and Wareham, {Nick J} and Praveen Surendran and Howson, {Joanna M M} and Butterworth, {Adam S.} and John Danesh and Nordestgaard, {B{\o}rge G.} and Nielsen, {Sune F.} and Shoaib Afzal and Sofia Papadia and Sofie Ashford and Sumedha Garg and Millhauser, {Glenn L.} and Palomino, {Rafael I.} and Alexandra Kwasniewska and Ioanna Tachmazidou and Stephen O'Rahilly and Eleftheria Zeggini and In{\^e}s Barroso and Farooqi, {I. 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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",
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    journal = "Scientific Reports",
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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 -