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

摘要 儿童肥胖症是一种复杂的多基因疾病，影响着美国1300多万儿童 并在世界范围内达到流行的比例。一个人的生活方式和遗传倾向可能 导致食物摄入和能量消耗不平衡，导致脂肪组织过剩。 遗传力估计在40%-85%之间，表明有很强的遗传成分。当前行为和 药物治疗只有不大的效果，凸显了研究遗传疾病的重要性。 为儿童肥胖症的病因学制定新的治疗策略。许多最重要的信号来自 肥胖症的全基因组关联研究(GWAS)位于已经确定的基因附近，例如 MC4R和BDNF。通过我的实验室对儿童肥胖症的全球领先地位，它已经成为 显然，儿童肥胖的遗传特征与成人非常相似，尽管有显著的 例外情况。FAIM2基因座在儿科环境中更为明显，因此在很大程度上 到目前为止被忽视了。我们对FAIM2基因座的精细定位工作已经确定rs7132908是可能的原因 这一基因组区域的非编码变体。Rs7132908位于FAIM2的3‘非翻译区，位于 标记为候选顺式调控元件的区域。使用人类干细胞来源的下丘脑神经元 模型中，我们观察到rs7132908区域与FAIM2启动子之间的物理接触 高分辨率全基因组启动子聚焦的捕获-C，实际上暗示FAIM2作为效应基因在 这个轨迹。该细胞模型与下丘脑弓状核的神经细胞群具有生物学意义。 通过组织浓缩分析、基因集浓缩分析和 啮齿动物研究。FAIM2编码跨膜蛋白Fas凋亡抑制分子2及其 表达在很大程度上局限于中枢神经系统的神经元。全转录组的关联 研究发现，FAIM2在脑组织中的表达与儿童期体重显著相关 指数。Faim2基因在弓状核中的表达对营养状态做出反应，限制后表达增加 食物摄入或食物匮乏。这表明FAIM2可能在代谢激素下游发挥作用。 我的项目的目标是表征rs7132908的顺式调节活性和FAIM2在 下丘脑弓状核神经元与肥胖发病机制的关系。我假设FAIM2 表达受rs7132908调节，FAIM2在神经元对代谢的反应中发挥作用 荷尔蒙。在我的第一个目标中，我将在体外表征rs7132908风险等位基因对FAIM2表达的影响 在活体内。在我的第二个目标中，我将研究FAIM2在弓状核中失调的后果 神经元对代谢荷尔蒙做出反应。综上所述，这些发现将为 了解FAIM2基因座如何与儿童肥胖易感性有关，并可能识别新的 药理学目标，以满足更有力的儿童肥胖症治疗的需求。

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.