Investigating the role of the FAIM2 locus in predisposition to childhood obesity

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ABSTRACT Childhood obesity is a complex, polygenic disease affecting over 13 million children in the United States and reaching epidemic proportions around the world. An individual’s lifestyle and genetic predisposition may cause an imbalance between food intake and energy expenditure, resulting in excess adipose tissue. Heritability estimates that range from 40-85% indicate a strong genetic component. Current behavioral and pharmacological treatments have only modest results, highlighting the importance of investigating the genetic etiology of childhood obesity for the development of new treatment strategies. Many of the top signals from genome-wide association studies (GWAS) of obesity reside near already well-established genes, such as MC4R and BDNF. Through my lab’s international leadership of GWAS of childhood obesity, it has become clear that the genetic signature of obesity in children is very similar to adults, although there is a significant exception. The FAIM2 locus is much more pronounced in the pediatric setting and thus has been largely overlooked to date. Our fine-mapping efforts at the FAIM2 locus have identified rs7132908 as the likely causal non-coding variant in this genomic region. rs7132908 resides in the 3’ untranslated region of FAIM2 and is in a region annotated as a candidate cis-regulatory element. Using a human stem cell-derived hypothalamic neuron model, we have observed a physical contact between the rs7132908 region and the FAIM2 promoter utilizing high-resolution genome-wide promoter-focused Capture-C, indeed implicating FAIM2 as the effector gene at this locus. This cell model is biologically relevant as neural populations of the hypothalamic arcuate nucleus have been implicated in childhood obesity by tissue enrichment analysis, gene set enrichment analysis and rodent studies. FAIM2 encodes the transmembrane protein ‘Fas apoptotic inhibitory molecule 2’ and its expression is largely restricted to neurons of the central nervous system. A transcriptome-wide association study identified a significant association between FAIM2 expression in brain tissue and childhood body mass index. Faim2 gene expression in the arcuate nucleus responds to nutritional status, increasing after restricted food intake or food deprivation. This suggests that FAIM2 may function downstream of metabolic hormones. The goal of my project is to characterize the cis-regulatory activity of rs7132908 and the function of FAIM2 in hypothalamic arcuate nucleus neurons as they relate to the pathogenesis of obesity. I hypothesize that FAIM2 expression is regulated by rs7132908 and that FAIM2 functions in the neuronal response to metabolic hormones. In my first aim, I will characterize the effect of the rs7132908 risk allele on FAIM2 expression in vitro and in vivo. In my second aim, I will investigate the consequences of FAIM2 dysregulation in arcuate nucleus neurons responding to metabolic hormones. Taken together, these findings will provide a first step toward understanding how the FAIM2 locus contributes to childhood obesity predisposition and may identify novel pharmacological targets to answer the demands for more robust childhood obesity treatment.