Role of BMI‐Associated Loci Identified in GWAS Meta‐Analyses in the Context of Common Childhood Obesity in European Americans

Abstract

Obesity is a serious health concern for children and adolescents, particularly in Western societies, where its incidence is now considered to have reached epidemic proportions. A number of genetic determinants of adult BMI have already been established through genome wide association studies (GWAS), most recently from the GIANT meta‐analysis of such datasets combined. In this current study of European Americans, we examined the 32 loci detected in that GIANT study in the context of common childhood obesity within a cohort of 1,097 cases (defined as BMI ≥95th percentile), together with 2,760 lean controls (defined as BMI <50th percentile), aged between 2 and 18 years old. Nine of these single‐nucleotide polymorphims (SNPs) yielded at least nominal evidence for association with common childhood obesity, namely at the FTO, TMEM18, NRXN3, MC4R, SEC16B, GNPDA2, TNNI3K, QPCTL, and BDNF loci. However, overall 28 of the 32 loci showed directionally consistent effects to that of the adult BMI meta‐analysis. We conclude that among the 32 loci that have been reported to associate with adult BMI in the largest meta‐analysis of BMI to date, at least nine also contribute to the determination of common obesity in childhood in European Americans, as demonstrated by their associations in our pediatric cohort.

Genome-wide analysis of BMI in adolescents and young adults reveals additional insight into the effects of genetic loci over the life course

“…(4). Furthermore, all have been identified as being associated with obesity in children (6,15,17). Interestingly, although SNP rs1561288 showed partial dependence on the previously identified index SNP in the region, we found suggestive evidence for a secondary signal in the POMC region from the conditional analyses.…”

“…The lack of association observed in the adolescent/young adult period for SH2B1 is supported by the published literature. Studies in European pediatric populations have also failed to find an association between SH2B1 and BMI or obesity (6,14,15). It is possible that SH2B1, a neuronal gene implicated in glucose homeostasis and leptin signaling (24,25), fails to play a measurable effect on BMI until other endogenous or exogenous factors that only manifest or accumulate later in life occur.…”

“…In the past 5 years, genome-wide association studies (GWASs) have identified over 30 common genetic loci associated with body mass index (BMI, kg/m 2 ) mainly in European adult samples, with an average age often greater than 50 (4 -10). Whereas several loci identified in adults have also been found to be associated with BMI in childhood (6,(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) and two loci were recently identified in childhood obesity (17), little is known about these obesity susceptibility loci across high-risk periods for weight gain, such as adolescence and young adulthood. The influence of these loci in adolescence and young adulthood remains largely speculative from previously established association studies that illustrate the association of these loci on BMI during middle-aged adulthood and/or childhood.…”

Obesity-associated gene TMEM18 has a role in the central control of appetite and body weight regulation

“…For example, the robust correlation between BMI and polymorphisms in the first intron of the human fat mass and obesity-associated (FTO) gene has been followed by loss and gain of function studies in genetically modified mice, supporting the notion that a number of neighboring genes including IRX3 (which is the gene most likely mediating the effect of the human SNP), RPGRIP1L, and FTO itself can all play a role in the control of energy balance and body composition (7)(8)(9)(10)(11)(12)(13). A strong association between increased BMI and a region of human chromosome 2, near to the gene TMEM18, has been repeatedly demonstrated in both adults and children (2,(14)(15)(16)(17)(18). Like the genes in the vicinity of FTO, TMEM18 had not been recognized as having a role in energy homeostasis before its identification by GWAS, and relatively little is known about its function, save that it is expressed in the brain and that it encodes a 140-aa protein reported to contain three transmembrane domain (19) which may act as a DNAbinding protein (20).…”

Effect of six type II diabetes susceptibility loci and an FTO variant on obesity in Pakistani subjects

“…[11][12][13] This discovery laid the ground for the identification of many variants in other noncandidate genes and it is now accepted that common forms of obesity are product of the combined net effect of many risk variants in different genes. 14,15 The association of common FTO variants, especially rs9939609, with obesity has been confirmed in Caucasians; however, the results in Asian populations are conflicting. [16][17][18][19][20][21][22][23][24][25] In Pakistan, there is limited research in the field of obesity genetics.…”