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1. Exome Sequencing Identifies Genes and Gene Sets Contributing to Severe Childhood Obesity, Linking PHIP Variants to Repressed POMC Transcription

Author

Marenne, Gaëlle, Hendricks, Audrey E., Perdikari, Aliki, Bounds, Rebecca, Payne, Felicity, Keogh, Julia M., Lelliott, Christopher J., Henning, Elana, Pathan, Saad, Ashford, Sofie, Bochukova, Elena G., Mistry, Vanisha, Daly, Allan, Hayward, Caroline, Wareham, Nicholas J., O’Rahilly, Stephen, Langenberg, Claudia, Wheeler, Eleanor, Zeggini, Eleftheria, Farooqi, I. Sadaf, and Barroso, Inês

Published
2020
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2. Human Semaphorin 3 Variants Link Melanocortin Circuit Development and Energy Balance

Author

van der Klaauw, Agatha A., Croizier, Sophie, Mendes de Oliveira, Edson, Stadler, Lukas K.J., Park, Soyoung, Kong, Youxin, Banton, Matthew C., Tandon, Panna, Hendricks, Audrey E., Keogh, Julia M., Riley, Susanna E., Papadia, Sofia, Henning, Elana, Bounds, Rebecca, Bochukova, Elena G., Mistry, Vanisha, O’Rahilly, Stephen, Simerly, Richard B., Minchin, James E.N., Barroso, Inês, Jones, E. Yvonne, Bouret, Sebastien G., and Farooqi, I. Sadaf

Published
2019
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4. CNV analysis in Tourette syndrome implicates large genomic rearrangements in COL8A1 and NRXN1.

Author

Nag, Abhishek, Bochukova, Elena G, Kremeyer, Barbara, Campbell, Desmond D, Muller, Heike, Valencia-Duarte, Ana V, Cardona, Julio, Rivas, Isabel C, Mesa, Sandra C, Cuartas, Mauricio, Garcia, Jharley, Bedoya, Gabriel, Cornejo, William, Herrera, Luis D, Romero, Roxana, Fournier, Eduardo, Reus, Victor I, Lowe, Thomas L, Farooqi, I Sadaf, Tourette Syndrome Association International Consortium for Genetics, Mathews, Carol A, McGrath, Lauren M, Yu, Dongmei, Cook, Ed, Wang, Kai, Scharf, Jeremiah M, Pauls, David L, Freimer, Nelson B, Plagnol, Vincent, and Ruiz-Linares, Andrés

Subjects
Tourette Syndrome Association International Consortium for Genetics, Humans, Tourette Syndrome, Genetic Predisposition to Disease, Calcium-Binding Proteins, Cell Adhesion Molecules, Neuronal, Neural Cell Adhesion Molecules, Nerve Tissue Proteins, Collagen Type IX, Genotype, Polymorphism, Single Nucleotide, Adolescent, Child, Female, Male, DNA Copy Number Variations, Neurodegenerative, Mental Health, Human Genome, Genetics, Brain Disorders, Intellectual and Developmental Disabilities (IDD), Schizophrenia, Neurosciences, Aetiology, 2.1 Biological and endogenous factors, Mental health, General Science & Technology
Abstract

Tourette syndrome (TS) is a neuropsychiatric disorder with a strong genetic component. However, the genetic architecture of TS remains uncertain. Copy number variation (CNV) has been shown to contribute to the genetic make-up of several neurodevelopmental conditions, including schizophrenia and autism. Here we describe CNV calls using SNP chip genotype data from an initial sample of 210 TS cases and 285 controls ascertained in two Latin American populations. After extensive quality control, we found that cases (N = 179) have a significant excess (P = 0.006) of large CNV (>500 kb) calls compared to controls (N = 234). Amongst 24 large CNVs seen only in the cases, we observed four duplications of the COL8A1 gene region. We also found two cases with ∼400 kb deletions involving NRXN1, a gene previously implicated in neurodevelopmental disorders, including TS. Follow-up using multiplex ligation-dependent probe amplification (and including 53 more TS cases) validated the CNV calls and identified additional patients with rearrangements in COL8A1 and NRXN1, but none in controls. Examination of available parents indicates that two out of three NRXN1 deletions detected in the TS cases are de-novo mutations. Our results are consistent with the proposal that rare CNVs play a role in TS aetiology and suggest a possible role for rearrangements in the COL8A1 and NRXN1 gene regions.

Published
2013

6. Disruption of the homeodomain transcription factor orthopedia homeobox (Otp) is associated with obesity and anxiety

Author

Moir, Lee, Bochukova, Elena G., Dumbell, Rebecca, Banks, Gareth, Bains, Rasneer S., Nolan, Patrick M., Scudamore, Cheryl, Simon, Michelle, Watson, Kimberly A., Keogh, Julia, Henning, Elana, Hendricks, Audrey, O'Rahilly, Stephen, Barroso, Inês, Sullivan, Adrienne E., Bersten, David C., Whitelaw, Murray L., Kirsch, Susan, Bentley, Elizabeth, Farooqi, I. Sadaf, and Cox, Roger D.

Published
2017
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8. Steroid receptor coactivator-1 modulates the function of Pomc neurons and energy homeostasis

Author

Yang, Yongjie, van der Klaauw, Agatha A., Zhu, Liangru, Cacciottolo, Tessa M., He, Yanlin, Stadler, Lukas K. J., Wang, Chunmei, Xu, Pingwen, Saito, Kenji, Hinton, Jr., Antentor, Yan, Xiaofeng, Keogh, Julia M., Henning, Elana, Banton, Matthew C., Hendricks, Audrey E., Bochukova, Elena G., Mistry, Vanisha, Lawler, Katherine L., Liao, Lan, Xu, Jianming, O’Rahilly, Stephen, Tong, Qingchun, UK10K Consortium, Inês Barroso, O’Malley, Bert W., Farooqi, I. Sadaf, and Xu, Yong

Published
2019
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9. KSR2 Mutations Are Associated with Obesity, Insulin Resistance, and Impaired Cellular Fuel Oxidation

Author

Pearce, Laura R., Atanassova, Neli, Banton, Matthew C., Bottomley, Bill, van der Klaauw, Agatha A., Revelli, Jean-Pierre, Hendricks, Audrey, Keogh, Julia M., Henning, Elana, Doree, Deon, Jeter-Jones, Sabrina, Garg, Sumedha, Bochukova, Elena G., Bounds, Rebecca, Ashford, Sofie, Gayton, Emma, Hindmarsh, Peter C., Shield, Julian P.H., Crowne, Elizabeth, Barford, David, Wareham, Nick J., O’Rahilly, Stephen, Murphy, Michael P., Powell, David R., Barroso, Ines, and Farooqi, I. Sadaf

Published
2013
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10. Rare variants in single-minded 1 (SIM1) are associated with severe obesity

Author

Ramachandrappa, Shwetha, Raimondo, Anne, Cali, Anna M.G., Keogh, Julia M., Henning, Elana, Saeed, Sadia, Thompson, Amanda, Garg, Sumedha, Bochukova, Elena G., Brage, Soren, Trowse, Victoria, Wheeler, Eleanor, Sullivan, Adrienne E., Dattani, Mehul, Clayton, Peter E., Datta, Vippan, Bruning, John B., Wareham, Nick J., O'Rahilly, Stephen, Peet, Daniel J., Barroso, Ines, Whitelaw, Murray L., and Farooqi, I. Sadaf

Subjects
Obesity -- Genetic aspects, Genetic research, Genetic transcription -- Research, Hypothalamus -- Genetic aspects -- Physiological aspects, Health care industry
Abstract

Single-minded 1 (SIM1) is a basic helix-loop-helix transcription factor involved in the development and function of the paraventricular nucleus of the hypothalamus. Obesity has been reported in Sim1 haploinsufficient mice [...]

Published
2013
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12. Human SH2B1 mutations are associated with maladaptive behaviors and obesity

Author

Doche, Michael E., Bochukova, Elena G., Su, Hsiao-Wen, Pearce, Laura R., Keogh, Julia M., Henning, Elana, Cline, Joel M., Dale, Anne, Cheetham, Tim, Barroso, Ines, Argetsinger, Lawrence S., O'Rahilly, Stephen, Rui, Liangyou, Carter-Su, Christin, and Farooqi, I. Sadaf

Subjects
Gene mutations -- Identification and classification, Obesity -- Genetic aspects -- Care and treatment, Leptin -- Health aspects, Insulin -- Dosage and administration, Cellular signal transduction -- Genetic aspects, Health care industry
Abstract

Src homology 2 B adapter protein 1 (SH2B1) modulates signaling by a variety of ligands that bind to receptor tyrosine kinases or JAK-associated cytokine receptors, including leptin, insulin, growth hormone (GH), and nerve growth factor (NGF). Targeted deletion of SH2B1 in mice results in increased food intake, obesity, and insulin resistance, with an intermediate phenotype seen in heterozygous null mice on a high-fat diet. We identified SH2B1 loss-of-function mutations in a large cohort of patients with severe early-onset obesity. Mutation carriers exhibited hyperphagia, childhood-onset obesity, disproportionate insulin resistance, and reduced final height as adults. Unexpectedly, mutation carriers exhibited a spectrum of behavioral abnormalities that were not reported in controls, including social isolation and aggression. We conclude that SH2B1 plays a critical role in the control of human food intake and body weight and is implicated in maladaptive human behavior., Introduction Leptin is a 16-kDa circulating hormone that regulates energy homeostasis via hypothalamic neurons expressing the leptin receptor (LEPR) (1). Congenital deficiency of leptin and its receptor results in severe [...]

Published
2012
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13. Large, rare chromosomal deletions associated with severe early-onset obesity

Author

Bochukova, Elena G., Huang, Ni, Keogh, Julia, Henning, Elana, Purmann, Carolin, Blaszczyk, Kasia, Saeed, Sadia, Hamilton-Shield, Julian, Clayton-Smith, Jill, O'Rahilly, Stephen, Hurles, Matthew E., and Farooqi, I. Sadaf

Subjects
Obesity -- Research -- Genetic aspects, Insulin resistance -- Research -- Genetic aspects, Mental illness -- Research -- Genetic aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Obesity is a highly heritable and genetically heterogeneous disorder (1). Here we investigated the contribution of copy number variation to obesity in 300 Caucasian patients with severe early-onset obesity, 143 of whom also had developmental delay. Large (>500 kilobases), rare (, Although the rise in obesity prevalence is driven by environmental factors, there is considerable evidence that weight is highly heritable (1,7). Genome-wide association studies (GWAS) have identified common single nucleotide [...]

Published
2010

15. Mutations of ephrin-B1 (EFNB1), a marker of tissue boundary formation, cause craniofrontonasal syndrome

Author

Twigg, Stephen R.F., Kan, Rui, Babbs, Christian, Bochukova, Elena G., Robertson, Stephen P., Wall, Stephen A., Morris-Kay, Gillian M., and Wilkie, Andrew O.M.

Subjects
Membrane proteins -- Research, Science and technology, National Academy of Sciences -- Research
Abstract

Craniofrontonasal syndrome (CFNS) is an X-linked developmental disorder that shows paradoxically greater severity in heterozygous females than in hemizygous males. Females have frontonasal dysplasia and coronal craniosynostosis (fusion of the coronal sutures); in males, hypertelorism is the only typical manifestation. Here, we show that the classical female CFNS phenotype is caused by heterozygous loss-of-function mutations in EFNB1, which encodes a member of the ephrin family of transmembrane ligands for Eph receptor tyrosine kinases. In mice, the orthologous Efnb1 gene is expressed in the frontonasal neural crest and demarcates the position of the future coronal suture. Although EFNB1 is X-inactivated, we did not observe markedly skewed X-inactivation in either blood or cranial periosteum from females with CFNS, indicating that lack of ephrin-B1 does not compromise cell viability in these tissues. We propose that in heterozygous females, patchwork loss of ephrin-B1 disturbs tissue boundary formation at the developing coronal suture, whereas in males deficient in ephrin-B1, an alternative mechanism maintains the normal boundary. This is the only known mutation in the ephrin/Eph receptor signaling system in humans and provides clues to the biogenesis of craniosynostosis.

Published
2004

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

Author

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 Ma, Van Der Schouw, Yvonne, Weiderpass, Elisabete, Quiros, J. Ramon, Sánchez, María José, Navarro, Carmen, Moreno-Iribas, Conchi, Arriola, Larraitz, Melander, Olle, Wennberg, Patrik, Key, Timothy J., Riboli, Elio, Al-Turki, Saeed, 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 G, Dominiczak, Anna, Down, Thomas, Du, Yuanping, Dunham, Ian, Durbin, Richard, Edkins, Sarah, Ekong, Rosemary, Ellis, Peter, Evansa, David M., FitzPatrick, David R., Flicek, Paul, Floyd, James S., Foley, A. Reghan, Franklin, Christopher S., Futema, Marta, Gallagher, Louise, Gaunt, Tom R., Geihs, Matthias, Geschwind, Daniel H., Greenwood, Celia M.T., Griffin, Heather, Grozeva, Detelina, Guo, Xiaosen, Guo, Xueqin, Gurling, Hugh, Hart, Deborah J., 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 D., 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, Nai-Yu, Ward, Kirsten, Whyte, Tamieka, Williams, Hywel J., Williamson, Kathleen A., Wilson, Crispian, Wilson, Scott G., Wong, Kim, Xu, Changjiang, Yang, Jian, Zhang, Feng, Zhang, Pingbo, Zheng, Hou Feng, Hendricks, Audrey E., Bochukova, Elena G., Marenne, Gaã«lle, Keogh, Julia M., Atanassova, Neli, Bounds, Rebecca, Wheeler, Eleanor, Mistry, Vanisha, Henning, Elana, Kã¶rner, Antje, Muddyman, Dawn, Mccarthy, Shane, Hinney, Anke, Hebebrand, Johanne, Scott, Robert A., Langenberg, Claudia, Wareham, Nick J., Surendran, Praveen, Howson, Joanna M., Butterworth, Adam S., Danesh, John, Nordestgaard, Bã¸rge 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, Inãª, Farooqi, I. Sadaf, Benzeval, Michaela, Burton, Jonathan, Buck, Nichola, Jã¤ckle, Annette, Kumari, Meena, Laurie, Heather, Lynn, Peter, Pudney, Stephen, Rabe, Birgitta, Wolke, Dieter, Overvad, Kim, Tjã¸nneland, 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, Weiderpass, Elisabete, Quiros, J. Ramon, Sã¡nchez, Marã­a josã©, 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, Marã­a, Ayub, Muhammad, Bala, Senduran, Barrett, Jeffrey C., Beales, Phil, Bentham, Jamie, Bhattacharyaa, Shoumo, Birney, Ewan, Blackwooda, Dougla, Bobrow, Martin, Bolton, Patrick F., Boustred, Chri, 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, Down, Thoma, Du, Yuanping, Dunham, Ian, Durbin, Richard, Edkins, Sarah, Ekong, Rosemary, Ellis, Peter, Evansa, David M., Fitzpatrick, David R., Flicek, Paul, Floyd, Jame, Foley, A. Reghan, Franklin, Christopher S., Futema, Marta, Gallagher, Louise, Gaunt, Tom R., Geihs, Matthia, Geschwind, Daniel, Greenwood, Celia M. T., Griffin, Heather, Grozeva, Detelina, Guo, Xiaosen, Guo, Xueqin, Gurling, Hugh, Hart, Deborah, Holmans, Peter, Howie, Bryan, Huang, Jie, Huang, Liren, Hubbard, Tim, Humphries, Steve E., Hurles, Matthew E., Hysi, Pirro, Iotchkova, Valentina, Jackson, David K., Jamshidi, Yalda, Joyce, Chri, Karczewski, Konrad J., Kaye, Jane, Keane, Thoma, 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, Lã¶nnqvist, 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, Morris, Jame, Muntoni, Francesco, Northstone, Kate, O'Donovan, Michael C., Onoufriadis, Alexandro, 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, Rehnstrã¶m, Karola, Richards, J. Brent, Ridout, Cheryl K., Ring, Susan, 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, Suvisaari, Jaana, Syrris, Petro, 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, Feng, Zhang, Pingbo, and Zheng, Hou feng

Subjects
Multidisciplinary, Journal Article, General
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 describedw 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.

Published
2017

24. Exome Sequencing Identifies Multiple Genes and Gene-Sets Contributing to Severe Childhood Obesity

Author

Marenne, Gaëlle, primary, Hendricks, Audrey, additional, Perdikari, Aliki, additional, Bounds, Rebecca, additional, Payne, Felicity, additional, Keogh, Julia M., additional, Lelliott, Christopher J., additional, Henning, Elana, additional, Pathan, Saad, additional, Ashford, Sofie, additional, Bochukova, Elena G., additional, Mistry, Vanisha, additional, Daly, Allan, additional, Hayward, Caroline, additional, Wareham, Nicholas J., additional, O'Rahilly, Stephen, additional, Langenberg, Claudia, additional, Wheeler, Eleanor, additional, Zeggini, Eleftheria, additional, Farooqi, I.Sadaf, additional, and Barroso, Ines, additional

Published
2019
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25. Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity

Author

UMC Utrecht, Cardiovasculaire Epidemiologie, Circulatory Health, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, 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 Ma, Van Der Schouw, Yvonne, Weiderpass, Elisabete, Quiros, J. Ramon, Sánchez, María José, Navarro, Carmen, Moreno-Iribas, Conchi, Arriola, Larraitz, Melander, Olle, Wennberg, Patrik, Key, Timothy J., Riboli, Elio, Al-Turki, Saeed, 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 G, Dominiczak, Anna, Down, Thomas, Du, Yuanping, Dunham, Ian, Durbin, Richard, Edkins, Sarah, Ekong, Rosemary, Ellis, Peter, Evansa, David M., FitzPatrick, David R., Flicek, Paul, Floyd, James S., Foley, A. Reghan, Franklin, Christopher S., Futema, Marta, Gallagher, Louise, Gaunt, Tom R., Geihs, Matthias, Geschwind, Daniel H., Greenwood, Celia M.T., Griffin, Heather, Grozeva, Detelina, Guo, Xiaosen, Guo, Xueqin, Gurling, Hugh, Hart, Deborah J., 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 D., 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, Nai-Yu, Ward, Kirsten, Whyte, Tamieka, Williams, Hywel J., Williamson, Kathleen A., Wilson, Crispian, Wilson, Scott G., Wong, Kim, Xu, Changjiang, Yang, Jian, Zhang, Feng, Zhang, Pingbo, Zheng, Hou Feng, UMC Utrecht, Cardiovasculaire Epidemiologie, Circulatory Health, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, 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 Ma, Van Der Schouw, Yvonne, Weiderpass, Elisabete, Quiros, J. Ramon, Sánchez, María José, Navarro, Carmen, Moreno-Iribas, Conchi, Arriola, Larraitz, Melander, Olle, Wennberg, Patrik, Key, Timothy J., Riboli, Elio, Al-Turki, Saeed, 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 G, Dominiczak, Anna, Down, Thomas, Du, Yuanping, Dunham, Ian, Durbin, Richard, Edkins, Sarah, Ekong, Rosemary, Ellis, Peter, Evansa, David M., FitzPatrick, David R., Flicek, Paul, Floyd, James S., Foley, A. Reghan, Franklin, Christopher S., Futema, Marta, Gallagher, Louise, Gaunt, Tom R., Geihs, Matthias, Geschwind, Daniel H., Greenwood, Celia M.T., Griffin, Heather, Grozeva, Detelina, Guo, Xiaosen, Guo, Xueqin, Gurling, Hugh, Hart, Deborah J., 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 D., 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, Nai-Yu, Ward, Kirsten, Whyte, Tamieka, Williams, Hywel J., Williamson, Kathleen A., Wilson, Crispian, Wilson, Scott G., Wong, Kim, Xu, Changjiang, Yang, Jian, Zhang, Feng, Zhang, Pingbo, and Zheng, Hou Feng

Published
2017

26. Functional characterization of obesity-associated variants involving the α and β isoforms of human SH2B1

Author

Pearce, Laura R, Joe, Ray, Doche, Michael E, Su, Hsiao-Wen, Keogh, Julia M, Henning, Elana, Argetsinger, Lawrence S, Bochukova, Elena G, Cline, Joel M, Garg, Sumedha, Saeed, Sadia, Shoelson, Steven, O'Rahilly, Stephen, Barroso, Inês, Rui, Liangyou, Farooqi, I Sadaf, Carter-Su, Christin, Keogh, Julia [0000-0002-0399-4114], Henning, Elana [0000-0002-0399-4114], O'Rahilly, Stephen [0000-0003-2199-4449], Barroso, Ines [0000-0001-5800-4520], Farooqi, Ismaa [0000-0001-7609-3504], and Apollo - University of Cambridge Repository

Subjects
Adult, Leptin, Male, Adolescent, Mutation, Missense, Alternative Splicing, Young Adult, Humans, Insulin, Protein Isoforms, Female, Obesity, Child, Adaptor Proteins, Signal Transducing, Signal Transduction
Abstract

We have previously reported rare variants in sarcoma (Src) homology 2 (SH2) B adaptor protein 1 (SH2B1) in individuals with obesity, insulin resistance, and maladaptive behavior. Here, we identify 4 additional SH2B1 variants by sequencing 500 individuals with severe early-onset obesity. SH2B1 has 4 alternatively spliced isoforms. One variant (T546A) lies within the N-terminal region common to all isoforms. As shown for past variants in this region, T546A impairs SH2B1β enhancement of nerve growth factor-induced neurite outgrowth, and the individual with the T546A variant exhibits mild developmental delay. The other 3 variants (A663V, V695M, and A723V) lie in the C-terminal tail of SH2B1α. SH2B1α variant carriers were hyperinsulinemic but did not exhibit the behavioral phenotype observed in individuals with SH2B1 variants that disrupt all isoforms. In in vitro assays, SH2B1α, like SH2B1β, enhances insulin- and leptin-induced insulin receptor substrate 2 (IRS2) phosphorylation and GH-induced cell motility. None of the variants affect SH2B1α enhancement of insulin- and leptin-induced IRS2 phosphorylation. However, T546A, A663V, and A723V all impair the ability of SH2B1α to enhance GH-induced cell motility. In contrast to SH2B1β, SH2B1α does not enhance nerve growth factor-induced neurite outgrowth. These studies suggest that genetic variants that disrupt isoforms other than SH2B1β may be functionally significant. Further studies are needed to understand the mechanism by which the individual isoforms regulate energy homeostasis and behavior.

Published
2014

27. KSR2 mutations are associated with obesity, insulin resistance, and impaired cellular fuel oxidation

Author

Pearce, Laura R, Atanassova, Neli, Banton, Matthew C, Bottomley, Bill, van der Klaauw, Agatha A, Revelli, Jean-Pierre, Hendricks, Audrey, Keogh, Julia M, Henning, Elana, Doree, Deon, Jeter-Jones, Sabrina, Garg, Sumedha, Bochukova, Elena G, Bounds, Rebecca, Ashford, Sofie, Gayton, Emma, Hindmarsh, Peter C, Shield, Julian PH, Crowne, Elizabeth, Barford, David, Wareham, Nick J, UK10K consortium, O'Rahilly, Stephen, Murphy, Michael P, Powell, David R, Barroso, Ines, Farooqi, I Sadaf, Keogh, Julia [0000-0002-0399-4114], Henning, Elana [0000-0002-0399-4114], Wareham, Nicholas [0000-0003-1422-2993], O'Rahilly, Stephen [0000-0003-2199-4449], Murphy, Mike [0000-0003-1115-9618], Barroso, Ines [0000-0001-5800-4520], Farooqi, Ismaa [0000-0001-7609-3504], and Apollo - University of Cambridge Repository

Subjects
Male, Models, Molecular, Proto-Oncogene Proteins B-raf, MAP Kinase Signaling System, Fatty Acids, Molecular Sequence Data, Age Factors, Hyperphagia, Protein Serine-Threonine Kinases, Protein Structure, Tertiary, Mice, Glucose, Animals, Humans, Female, Amino Acid Sequence, Obesity, Age of Onset, Insulin Resistance, Child, Energy Metabolism, Oxidation-Reduction, Sequence Alignment
Abstract

Kinase suppressor of Ras 2 (KSR2) is an intracellular scaffolding protein involved in multiple signaling pathways. Targeted deletion of Ksr2 leads to obesity in mice, suggesting a role in energy homeostasis. We explored the role of KSR2 in humans by sequencing 2,101 individuals with severe early-onset obesity and 1,536 controls. We identified multiple rare variants in KSR2 that disrupt signaling through the Raf-MEKERK pathway and impair cellular fatty acid oxidation and glucose oxidation in transfected cells; effects that can be ameliorated by the commonly prescribed antidiabetic drug, metformin. Mutation carriers exhibit hyperphagia in childhood, low heart rate, reduced basal metabolic rate and severe insulin resistance. These data establish KSR2 as an important regulator of energy intake, energy expenditure, and substrate utilization in humans. Modulation of KSR2-mediated effects may represent a novel therapeutic strategy for obesity and type 2 diabetes.

Published
2013

28. Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension

Author

Azizan, Elena A B, primary, Poulsen, Hanne, additional, Tuluc, Petronel, additional, Zhou, Junhua, additional, Clausen, Michael V, additional, Lieb, Andreas, additional, Maniero, Carmela, additional, Garg, Sumedha, additional, Bochukova, Elena G, additional, Zhao, Wanfeng, additional, Shaikh, Lalarukh Haris, additional, Brighton, Cheryl A, additional, Teo, Ada E D, additional, Davenport, Anthony P, additional, Dekkers, Tanja, additional, Tops, Bas, additional, Küsters, Benno, additional, Ceral, Jiri, additional, Yeo, Giles S H, additional, Neogi, Sudeshna Guha, additional, McFarlane, Ian, additional, Rosenfeld, Nitzan, additional, Marass, Francesco, additional, Hadfield, James, additional, Margas, Wojciech, additional, Chaggar, Kanchan, additional, Solar, Miroslav, additional, Deinum, Jaap, additional, Dolphin, Annette C, additional, Farooqi, I Sadaf, additional, Striessnig, Joerg, additional, Nissen, Poul, additional, and Brown, Morris J, additional

Published
2013
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29. Genome-wide SNP and CNV analysis identifies common and low-frequency variants associated with severe early-onset obesity

Author

Wheeler, Eleanor, primary, Huang, Ni, additional, Bochukova, Elena G, additional, Keogh, Julia M, additional, Lindsay, Sarah, additional, Garg, Sumedha, additional, Henning, Elana, additional, Blackburn, Hannah, additional, Loos, Ruth J F, additional, Wareham, Nick J, additional, O'Rahilly, Stephen, additional, Hurles, Matthew E, additional, Barroso, Inês, additional, and Farooqi, I Sadaf, additional

Published
2013
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30. Human SH2B1 mutations are associated with maladaptive behaviors and obesity

Author

Doche, Michael E., primary, Bochukova, Elena G., additional, Su, Hsiao-Wen, additional, Pearce, Laura R., additional, Keogh, Julia M., additional, Henning, Elana, additional, Cline, Joel M., additional, Saeed, Sadia, additional, Dale, Anne, additional, Cheetham, Tim, additional, Barroso, Inês, additional, Argetsinger, Lawrence S., additional, O’Rahilly, Stephen, additional, Rui, Liangyou, additional, Carter-Su, Christin, additional, and Farooqi, I. Sadaf, additional

Published
2013
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31. Large, rare chromosomal deletions associated with severe early-onset obesity

Author

Bochukova, Elena G., primary, Huang, Ni, additional, Keogh, Julia, additional, Henning, Elana, additional, Purmann, Carolin, additional, Blaszczyk, Kasia, additional, Saeed, Sadia, additional, Hamilton-Shield, Julian, additional, Clayton-Smith, Jill, additional, O’Rahilly, Stephen, additional, Hurles, Matthew E., additional, and Farooqi, I. Sadaf, additional

Published
2009
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33. CNV Analysis in Tourette Syndrome Implicates Large Genomic Rearrangements in COL8A1 and NRXN1.

Author

Nag, Abhishek, Bochukova, Elena G., Kremeyer, Barbara, Campbell, Desmond D., Muller, Heike, Valencia-Duarte, Ana V., Cardona, Julio, Rivas, Isabel C., Mesa, Sandra C., Cuartas, Mauricio, Garcia, Jharley, Bedoya, Gabriel, Cornejo, William, Herrera, Luis D., Romero, Roxana, Fournier, Eduardo, Reus, Victor I., Lowe, Thomas L., Farooqi, I. Sadaf, and Mathews, Carol A.

Subjects
*TOURETTE syndrome, *NEUROBEHAVIORAL disorders, *GENE rearrangement, *NEURODEVELOPMENTAL treatment, *GENE amplification, *GENETIC mutation, *ETIOLOGY of diseases, *SINGLE nucleotide polymorphisms
Abstract

Tourette syndrome (TS) is a neuropsychiatric disorder with a strong genetic component. However, the genetic architecture of TS remains uncertain. Copy number variation (CNV) has been shown to contribute to the genetic make-up of several neurodevelopmental conditions, including schizophrenia and autism. Here we describe CNV calls using SNP chip genotype data from an initial sample of 210 TS cases and 285 controls ascertained in two Latin American populations. After extensive quality control, we found that cases (N = 179) have a significant excess (P = 0.006) of large CNV (>500 kb) calls compared to controls (N = 234). Amongst 24 large CNVs seen only in the cases, we observed four duplications of the COL8A1 gene region. We also found two cases with ∼400kb deletions involving NRXN1, a gene previously implicated in neurodevelopmental disorders, including TS. Follow-up using multiplex ligation-dependent probe amplification (and including 53 more TS cases) validated the CNV calls and identified additional patients with rearrangements in COL8A1 and NRXN1, but none in controls. Examination of available parents indicates that two out of three NRXN1 deletions detected in the TS cases are de-novo mutations. Our results are consistent with the proposal that rare CNVs play a role in TS aetiology and suggest a possible role for rearrangements in the COL8A1 and NRXN1 gene regions. [ABSTRACT FROM AUTHOR]

Published
2013
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34. CNV Analysis in Tourette Syndrome Implicates Large Genomic Rearrangements in COL8A1 and NRXN1.

Author

Nag, Abhishek, Bochukova, Elena G., Kremeyer, Barbara, Campbell, Desmond D., Muller, Heike, Valencia-Duarte, Ana V., Cardona, Julio, Rivas, Isabel C., Mesa, Sandra C., Cuartas, Mauricio, Garcia, Jharley, Bedoya, Gabriel, Cornejo, William, Herrera, Luis D., Romero, Roxana, Fournier, Eduardo, Reus, Victor I., Lowe, Thomas L., Farooqi, I. Sadaf, and Mathews, Carol A.

Subjects
TOURETTE syndrome, NEUROBEHAVIORAL disorders, GENE rearrangement, NEURODEVELOPMENTAL treatment, GENE amplification, GENETIC mutation, ETIOLOGY of diseases, SINGLE nucleotide polymorphisms
Abstract

Tourette syndrome (TS) is a neuropsychiatric disorder with a strong genetic component. However, the genetic architecture of TS remains uncertain. Copy number variation (CNV) has been shown to contribute to the genetic make-up of several neurodevelopmental conditions, including schizophrenia and autism. Here we describe CNV calls using SNP chip genotype data from an initial sample of 210 TS cases and 285 controls ascertained in two Latin American populations. After extensive quality control, we found that cases (N = 179) have a significant excess (P = 0.006) of large CNV (>500 kb) calls compared to controls (N = 234). Amongst 24 large CNVs seen only in the cases, we observed four duplications of the COL8A1 gene region. We also found two cases with ∼400kb deletions involving NRXN1, a gene previously implicated in neurodevelopmental disorders, including TS. Follow-up using multiplex ligation-dependent probe amplification (and including 53 more TS cases) validated the CNV calls and identified additional patients with rearrangements in COL8A1 and NRXN1, but none in controls. Examination of available parents indicates that two out of three NRXN1 deletions detected in the TS cases are de-novo mutations. Our results are consistent with the proposal that rare CNVs play a role in TS aetiology and suggest a possible role for rearrangements in the COL8A1 and NRXN1 gene regions. [ABSTRACT FROM AUTHOR]

Published
2013
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35. Disruption of the homeodomain transcription factor orthopedia homeobox (Otp) is associated with obesity and anxiety

Author

Moir, Lee, Bochukova, Elena G, Dumbell, Rebecca, Banks, Gareth, Bains, Rasneer S, Nolan, Patrick M, Scudamore, Cheryl, Simon, Michelle, Watson, Kimberly A, Keogh, Julia, Henning, Elana, Hendricks, Audrey, O'Rahilly, Stephen, Barroso, Inês, UK10K Consortium, Sullivan, Adrienne E, Bersten, David C, Whitelaw, Murray L, Kirsch, Susan, Bentley, Elizabeth, Farooqi, I Sadaf, and Cox, Roger D

Subjects
Male, OTP, Hypothalamus, Gene Expression, Nerve Tissue Proteins, Energy balance, Anxiety, Oxytocin, Mouse model, Mice, Databases, Genetic, Animals, Humans, Obesity, Amino Acid Sequence, 2. Zero hunger, Homeodomain Proteins, Base Sequence, Genes, Homeobox, Brain, Chromosome Mapping, Gene Expression Regulation, Developmental, Neurosecretory Systems, Human mutation, Female, Transcriptome, Vasopressin, Transcription Factors
Abstract

OBJECTIVE: Genetic studies in obese rodents and humans can provide novel insights into the mechanisms involved in energy homeostasis. METHODS: In this study, we genetically mapped the chromosomal region underlying the development of severe obesity in a mouse line identified as part of a dominant N-ethyl-N-nitrosourea (ENU) mutagenesis screen. We characterized the metabolic and behavioral phenotype of obese mutant mice and examined changes in hypothalamic gene expression. In humans, we examined genetic data from people with severe early onset obesity. RESULTS: We identified an obese mouse heterozygous for a missense mutation (pR108W) in orthopedia homeobox (Otp), a homeodomain containing transcription factor required for the development of neuroendocrine cell lineages in the hypothalamus, a region of the brain important in the regulation of energy homeostasis. OtpR108W/+ mice exhibit increased food intake, weight gain, and anxiety when in novel environments or singly housed, phenotypes that may be partially explained by reduced hypothalamic expression of oxytocin and arginine vasopressin. R108W affects the highly conserved homeodomain, impairs DNA binding, and alters transcriptional activity in cells. We sequenced OTP in 2548 people with severe early-onset obesity and found a rare heterozygous loss of function variant in the homeodomain (Q153R) in a patient who also had features of attention deficit disorder. CONCLUSIONS: OTP is involved in mammalian energy homeostasis and behavior and appears to be necessary for the development of hypothalamic neural circuits. Further studies will be needed to investigate the contribution of rare variants in OTP to human energy homeostasis.

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

Author

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 JM, 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, and Farooqi IS

Subjects
Animals, Case-Control Studies, Chromogranins chemistry, Chromogranins genetics, Chromogranins metabolism, Female, GTP-Binding Protein alpha Subunits, Gs chemistry, GTP-Binding Protein alpha Subunits, Gs genetics, GTP-Binding Protein alpha Subunits, Gs metabolism, Humans, Male, Mice, Models, Molecular, Mutation, Obesity, Morbid diagnosis, Odds Ratio, Pediatric Obesity diagnosis, Pedigree, Protein Conformation, Rodentia, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Variation, Obesity, Morbid genetics, Pediatric Obesity genetics
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.

Published
2017
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