Elena V Ignatieva1,2,3, Dmitry A Afonnikov4,5,6, Olga V Saik4, Evgeny I Rogaev4,7, Nikolay A Kolchanov5,8. 1. Center for Brain Neurobiology and Neurogenetics, The Federal Research Center Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russia. eignat@bionet.nsc.ru. 2. Novosibirsk State University, Novosibirsk, 630090, Russia. eignat@bionet.nsc.ru. 3. Laboratory of Evolutionary Bioinformatics and Theoretical Genetics, The Federal Research Center Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russia. eignat@bionet.nsc.ru. 4. Center for Brain Neurobiology and Neurogenetics, The Federal Research Center Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russia. 5. Novosibirsk State University, Novosibirsk, 630090, Russia. 6. Laboratory of Evolutionary Bioinformatics and Theoretical Genetics, The Federal Research Center Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russia. 7. BNRI, Department of Psychiatry, University of Massachusetts Medical School, Worcester, MA, 15604, USA. 8. Department of Systems Biology, The Federal Research Center Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russia.
Abstract
BACKGROUND: Obesity is heritable. It predisposes to many diseases. The objectives of this study were to create a compendium of genes relevant to feeding behavior (FB) and/or body weight (BW) regulation; to construct and to analyze networks formed by associations between genes/proteins; and to identify the most significant genes, biological processes/pathways, and tissues/organs involved in BW regulation. RESULTS: The compendium of genes controlling FB or BW includes 578 human genes. Candidate genes were identified from various sources, including previously published original research and review articles, GWAS meta-analyses, and OMIM (Online Mendelian Inheritance in Man). All genes were ranked according to knowledge about their biological role in body weight regulation and classified according to expression patterns or functional characteristics. Substantial and overrepresented numbers of genes from the compendium encoded cell surface receptors, signaling molecules (hormones, neuropeptides, cytokines), transcription factors, signal transduction proteins, cilium and BBSome components, and lipid binding proteins or were present in the brain-specific list of tissue-enriched genes identified with TSEA tool. We identified 27 pathways from KEGG, REACTOME and BIOCARTA whose genes were overrepresented in the compendium. Networks formed by physical interactions or homological relationships between proteins or interactions between proteins involved in biochemical/signaling pathways were reconstructed and analyzed. Subnetworks and clusters identified by the MCODE tool included genes/proteins associated with cilium morphogenesis, signal transduction proteins (particularly, G protein-coupled receptors, kinases or proteins involved in response to insulin stimulus) and transcription regulation (particularly nuclear receptors). We ranked GWAS genes according to the number of neighbors in three networks and revealed 22 GWAS genes involved in the brain-specific PPI network. On the base of the most reliable PPIs functioning in the brain tissue, new regulatory schemes interpreting relevance to BW regulation are proposed for three GWAS genes (ETV5, LRP1B, and NDUFS3). CONCLUSIONS: A compendium comprising 578 human genes controlling FB or BW was designed, and the most significant functional groups of genes, biological processes/pathways, and tissues/organs involved in BW regulation were revealed. We ranked genes from the GWAS meta-analysis set according to the number and quality of associations in the networks and then according to their involvement in the brain-specific PPI network and proposed new regulatory schemes involving three GWAS genes (ETV5, LRP1B, and NDUFS3) in BW regulation. The compendium is expected to be useful for pathology risk estimation and for design of new pharmacological approaches in the treatment of human obesity.
BACKGROUND:Obesity is heritable. It predisposes to many diseases. The objectives of this study were to create a compendium of genes relevant to feeding behavior (FB) and/or body weight (BW) regulation; to construct and to analyze networks formed by associations between genes/proteins; and to identify the most significant genes, biological processes/pathways, and tissues/organs involved in BW regulation. RESULTS: The compendium of genes controlling FB or BW includes 578 human genes. Candidate genes were identified from various sources, including previously published original research and review articles, GWAS meta-analyses, and OMIM (Online Mendelian Inheritance in Man). All genes were ranked according to knowledge about their biological role in body weight regulation and classified according to expression patterns or functional characteristics. Substantial and overrepresented numbers of genes from the compendium encoded cell surface receptors, signaling molecules (hormones, neuropeptides, cytokines), transcription factors, signal transduction proteins, cilium and BBSome components, and lipid binding proteins or were present in the brain-specific list of tissue-enriched genes identified with TSEA tool. We identified 27 pathways from KEGG, REACTOME and BIOCARTA whose genes were overrepresented in the compendium. Networks formed by physical interactions or homological relationships between proteins or interactions between proteins involved in biochemical/signaling pathways were reconstructed and analyzed. Subnetworks and clusters identified by the MCODE tool included genes/proteins associated with cilium morphogenesis, signal transduction proteins (particularly, G protein-coupled receptors, kinases or proteins involved in response to insulin stimulus) and transcription regulation (particularly nuclear receptors). We ranked GWAS genes according to the number of neighbors in three networks and revealed 22 GWAS genes involved in the brain-specific PPI network. On the base of the most reliable PPIs functioning in the brain tissue, new regulatory schemes interpreting relevance to BW regulation are proposed for three GWAS genes (ETV5, LRP1B, and NDUFS3). CONCLUSIONS: A compendium comprising 578 human genes controlling FB or BW was designed, and the most significant functional groups of genes, biological processes/pathways, and tissues/organs involved in BW regulation were revealed. We ranked genes from the GWAS meta-analysis set according to the number and quality of associations in the networks and then according to their involvement in the brain-specific PPI network and proposed new regulatory schemes involving three GWAS genes (ETV5, LRP1B, and NDUFS3) in BW regulation. The compendium is expected to be useful for pathology risk estimation and for design of new pharmacological approaches in the treatment of humanobesity.
Authors: Patrick Aloy; Bettina Böttcher; Hugo Ceulemans; Christina Leutwein; Christian Mellwig; Susanne Fischer; Anne-Claude Gavin; Peer Bork; Giulio Superti-Furga; Luis Serrano; Robert B Russell Journal: Science Date: 2004-03-26 Impact factor: 47.728
Authors: Keri L Monda; Gary K Chen; Kira C Taylor; Cameron Palmer; Todd L Edwards; Leslie A Lange; Maggie C Y Ng; Adebowale A Adeyemo; Matthew A Allison; Lawrence F Bielak; Guanjie Chen; Mariaelisa Graff; Marguerite R Irvin; Suhn K Rhie; Guo Li; Yongmei Liu; Youfang Liu; Yingchang Lu; Michael A Nalls; Yan V Sun; Mary K Wojczynski; Lisa R Yanek; Melinda C Aldrich; Adeyinka Ademola; Christopher I Amos; Elisa V Bandera; Cathryn H Bock; Angela Britton; Ulrich Broeckel; Quiyin Cai; Neil E Caporaso; Chris S Carlson; John Carpten; Graham Casey; Wei-Min Chen; Fang Chen; Yii-Der I Chen; Charleston W K Chiang; Gerhard A Coetzee; Ellen Demerath; Sandra L Deming-Halverson; Ryan W Driver; Patricia Dubbert; Mary F Feitosa; Ye Feng; Barry I Freedman; Elizabeth M Gillanders; Omri Gottesman; Xiuqing Guo; Talin Haritunians; Tamara Harris; Curtis C Harris; Anselm J M Hennis; Dena G Hernandez; Lorna H McNeill; Timothy D Howard; Barbara V Howard; Virginia J Howard; Karen C Johnson; Sun J Kang; Brendan J Keating; Suzanne Kolb; Lewis H Kuller; Abdullah Kutlar; Carl D Langefeld; Guillaume Lettre; Kurt Lohman; Vaneet Lotay; Helen Lyon; Joann E Manson; William Maixner; Yan A Meng; Kristine R Monroe; Imran Morhason-Bello; Adam B Murphy; Josyf C Mychaleckyj; Rajiv Nadukuru; Katherine L Nathanson; Uma Nayak; Amidou N'diaye; Barbara Nemesure; Suh-Yuh Wu; M Cristina Leske; Christine Neslund-Dudas; Marian Neuhouser; Sarah Nyante; Heather Ochs-Balcom; Adesola Ogunniyi; Temidayo O Ogundiran; Oladosu Ojengbede; Olufunmilayo I Olopade; Julie R Palmer; Edward A Ruiz-Narvaez; Nicholette D Palmer; Michael F Press; Evandine Rampersaud; Laura J Rasmussen-Torvik; Jorge L Rodriguez-Gil; Babatunde Salako; Eric E Schadt; Ann G Schwartz; Daniel A Shriner; David Siscovick; Shad B Smith; Sylvia Wassertheil-Smoller; Elizabeth K Speliotes; Margaret R Spitz; Lara Sucheston; Herman Taylor; Bamidele O Tayo; Margaret A Tucker; David J Van Den Berg; Digna R Velez Edwards; Zhaoming Wang; John K Wiencke; Thomas W Winkler; John S Witte; Margaret Wrensch; Xifeng Wu; James J Yang; Albert M Levin; Taylor R Young; Neil A Zakai; Mary Cushman; Krista A Zanetti; Jing Hua Zhao; Wei Zhao; Yonglan Zheng; Jie Zhou; Regina G Ziegler; Joseph M Zmuda; Jyotika K Fernandes; Gary S Gilkeson; Diane L Kamen; Kelly J Hunt; Ida J Spruill; Christine B Ambrosone; Stefan Ambs; Donna K Arnett; Larry Atwood; Diane M Becker; Sonja I Berndt; Leslie Bernstein; William J Blot; Ingrid B Borecki; Erwin P Bottinger; Donald W Bowden; Gregory Burke; Stephen J Chanock; Richard S Cooper; Jingzhong Ding; David Duggan; Michele K Evans; Caroline Fox; W Timothy Garvey; Jonathan P Bradfield; Hakon Hakonarson; Struan F A Grant; Ann Hsing; Lisa Chu; Jennifer J Hu; Dezheng Huo; Sue A Ingles; Esther M John; Joanne M Jordan; Edmond K Kabagambe; Sharon L R Kardia; Rick A Kittles; Phyllis J Goodman; Eric A Klein; Laurence N Kolonel; Loic Le Marchand; Simin Liu; Barbara McKnight; Robert C Millikan; Thomas H Mosley; Badri Padhukasahasram; L Keoki Williams; Sanjay R Patel; Ulrike Peters; Curtis A Pettaway; Patricia A Peyser; Bruce M Psaty; Susan Redline; Charles N Rotimi; Benjamin A Rybicki; Michèle M Sale; Pamela J Schreiner; Lisa B Signorello; Andrew B Singleton; Janet L Stanford; Sara S Strom; Michael J Thun; Mara Vitolins; Wei Zheng; Jason H Moore; Scott M Williams; Shamika Ketkar; Xiaofeng Zhu; Alan B Zonderman; Charles Kooperberg; George J Papanicolaou; Brian E Henderson; Alex P Reiner; Joel N Hirschhorn; Ruth J F Loos; Kari E North; Christopher A Haiman Journal: Nat Genet Date: 2013-04-14 Impact factor: 38.330