A compendium of human genes regulating feeding behavior and body weight, its functional characterization and identification of GWAS genes involved in brain-specific PPI network

The Author(s) BMC Genetics 2016, 17(Suppl 3):158 DOI 10.1186/s12863-016-0466-2 RESEARCH Open Access A compendium of human genes regulating feeding behavior and body weight, its functional characterization and identification of GWAS genes involved in brain-specific PPI network Elena V. Ignatieva1,2,3*, Dmitry A. Afonnikov1,2,3, Olga V. Saik1, Evgeny I. Rogaev1,5 and Nikolay A. Kolchanov2,4 From The International Conference on Bioinformatics of Genome Regulation and Structure\Systems Biology (BGRS\SB-2016) Novosibirsk, Russia. 29 August-2 September 2016 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). (Continued on next page) * Correspondence: 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 2 Novosibirsk State University, Novosibirsk 630090, Russia Full list of author information is available at the end of the article © The Author(s). 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. The Author(s) BMC Genetics 2016, 17(Suppl 3):158 Page 90 of 191 (Continued from previous page) 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. Keywords: Feeding behavior, Body weight regulation, Brain, Network, PPIs, GWAS meta-analysis, Database, Background The pathogenesis of obesity is apparently complex. It involves multiple interactions among behavioral, environmental, and genetic factors. According to twin studies, 40–70% of inter-individual variability in body mass index (BMI), commonly used to assess obesity, is attributed to genetic factors [1–3]. Monogenic forms of obesity account for approximately 5% of severe obesity cases [4]. For most of the monogenic forms of obesity in murine models, human counterparts have been found. Eleven monogenic obesity genes have been identified to date [5]. Monogenic obesity results from mutations in genes involved in the hypothalamic appetite regulation system. Loss-of-function mutations causing deficiencies of appetite-regulating hormones or their receptors, such as leptin [6], leptin receptor [7], pro-opiomelanocortin (POMC) [8], and melanocortin 4 receptor (MC4R) [9], are examples of such monogenic syndromes. Furthermore, mutations in the proprotein convertase subtilisin/kexin type 1 (PCSK1) gene, a key component in the proteolytic processing of POMC, cause extreme childhood obesity and abnormal glucose homeostasis [10]. In addition, patients with chromosomal aberrations resulting in disruption or deletion of the single-minded homologue 1 gene (SIM1), which is essential for proper development of the paraventricular nucleus of hypothalamus, have early-onset obesity [11, 12]. Monogenic obesity also results from mutations in some other genes involved in eating behavior and energy balance regulation: (1) brain-derived neurotrophic factor (BDNF) [13]; (2) its receptor, tyrosine receptor kinase B (NTRK2) [14]; (3) SH2B adaptor protein 1 (SH2B1), involved in the regulation of leptin signaling [15, 16]; (4) KSR2, which encodes a scaffolding protein kinase suppressor of Ras 2, participating in signaling pathways relevant to glucose homoeostasis and food intake control [17]; (5) TUB, encoding Tubby bipartite transcription factor [18]. Although not formally defined as a syndrome, the clinical features of TUB deficiency in humans may be consistent with a novel ciliopathy [5]. Most monogenic obesity cases were investigated only in individual families; thus, their true contribution to “common” obesity in the general population is poorly known and, probably, underestimated [4]. A number of syndromes have been identified in addition to monogenic f (...truncated)