Functional Analysis of Seven Genes Linked to Body Mass Index and Adiposity by Genome-Wide Association Studies: A Review

Abstract

Genome-wide association studies (GWAS) have identified a total of about 40 single nucleotide polymorphisms (SNPs) that show significant linkage to body mass index, a widely utilised surrogate measure of adiposity. However, only 8 of these associations have been confirmed by follow-up GWAS using more sophisticated measures of adiposity (computed tomography). Among these 8, there is a SNP close to the gene FTO which has been the subject of considerable work to diagnose its function. The remaining 7 SNPs are adjacent to, or within, the genes NEGR1, TMEM18, ETV5, FLJ35779, LINGO2, SH2B1 and GIPR, most of which are less well studied than FTO, particularly in the context of obesity. This article reviews the available data on the functions of these genes, including information gleaned from studies in humans and animal models. At present, we have virtually no information on the putative mechanism associating the genes FLJ35779 and LINGO2 to obesity. All of these genes are expressed in the brain, and for 2 of them (SH2B1 and GIPR), a direct link to the appetite regulation system is known. SH2B1 is an enhancer of intracellular signalling in the JAK-STAT pathway, and GIPR is the receptor for an appetite-linked hormone (GIP) produced by the alimentary tract. NEGR1, ETV5 and SH2B1 all have suggested roles in neurite outgrowth, and hence SNPs adjacent to these genes may affect development of the energy balance circuitry. Although the genes have central patterns of gene expression, implying a central neuronal connection to energy balance, for at least 4 of them (NEGR1, TMEM18, SH2B1 and GIPR), there are also significant peripheral functions related to adipose tissue biology. These functions may contribute to their effects on the obese phenotype.

Structural variants caused byAluinsertions are associated with risks for many human diseases

“…37). Although the effect has been attributed to the transmembrane protein 18 (TMEM18), a transcriptional repressor that sequesters sequences at the membrane, there is debate concerning whether TMEM18 is involved in obesity regulation through expression in adipose tissue or the central nervous system (38). The causative variant(s) remain unclear even after targeted resequencing efforts that focused mainly on the TMEM18 coding sequence (39)(40)(41); it is presumed that the risk haplotype contains a noncoding regulatory variant.…”

Genome-Wide Association Study Identification of Novel Loci Associated with Airway Responsiveness in Chronic Obstructive Pulmonary Disease

“…In addition, using the RegulomeDB website, rs10813121 in chromosome 9 was found to bind to seven proteins, among them STAT3 and Nrf-2, a key transcription factor that regulates antioxidant defense in macrophages and epithelial cells (35). The leucine-rich repeat and Ig domaincontaining 2 gene (LINGO2) is expressed in neuronal tissue, and variants have been associated with essential tremor and Parkinson's disease as well as obesity (36)(37)(38). The function of LINGO2 is currently unclear, and further investigation is needed to understand its potential role in the pathogenesis of airway responsiveness.…”

Discussing the Putative Role of Obesity-Associated Genes in the Etiopathogenesis of Eating Disorders

“…Rs7498665 in SH2B1 is one of the SNPs initially identified in GWAS with significant linkage to BMI whose association has been confirmed by follow-up studies using computed tomography as a measure of adiposity [161]. With regard to its involvement in ED, and as in the case of the other BMI-related polymorphisms, Brandys et al could not find an association of rs7498665 with AN risk [127].…”

“…In addition, the nutritional state has been shown in animal models to affect the expression of Etv5 in important areas for feeding behavior [180], although this overexpression did not translate into significant changes of eating habits [181]. In any case, it has been suggested that, being a transcription factor, the possibility that ETV5 influences energy balance by transcriptional regulation of key genes linked to food intake in the hypothalamus seems highly likely [161]. Interestingly, BDNF has been shown to have a principal role orchestrating ETV5-mediated cellular migration [182].…”