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 并在全球范围内达到流行病的程度。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之间的不平衡，导致脂肪组织过多。 遗传力估计范围为40-85%，表明遗传成分很强。目前的行为和 药物治疗效果有限，凸显了研究遗传学的重要性 为儿童肥胖症的病因学研究制定新的治疗策略。许多顶级信号来自 肥胖的全基因组关联研究（GWAS）位于已经建立的基因附近，例如 MC 4 R和BDNF。通过我的实验室在儿童肥胖全球WAS的国际领导地位， 很明显，儿童肥胖的基因特征与成人非常相似，尽管有显著的差异， 例外. FAIM 2基因座在儿科环境中更为明显，因此在很大程度上被认为是一种免疫调节剂。 被忽视的日期。我们在FAIM 2基因座的精细定位工作已经确定rs7132908是可能的致病基因。 在这个基因组区域的非编码变体。rs7132908位于FAIM 2的3'非翻译区，并位于FAIM 2的3'非翻译区。 注释为候选顺式调节元件的区域。使用人类干细胞衍生的下丘脑神经元 模型，我们观察到rs7132908区域和FAIM 2启动子之间的物理接触， 高分辨率全基因组启动子聚焦Capture-C，确实暗示FAIM 2作为效应基因， 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相关性 通过组织富集分析、基因集富集分析和 啮齿动物研究。FAIM 2编码跨膜蛋白“Fas凋亡抑制分子2”， 表达主要限于中枢神经系统的神经元。转录组范围内的关联 一项研究发现，FAIM 2在脑组织中的表达与儿童体重之间存在显著关联 指数. FAIM 2基因在弓状核中的表达对营养状况有反应，在限制后增加 食物摄取或食物剥夺。这表明FAIM 2可能在代谢激素的下游发挥作用。 我的项目的目标是表征rs7132908的顺式调节活性和FAIM 2在细胞内的功能。 下丘脑弓状核神经元，因为它们与肥胖症的发病机制有关。我假设FAIM 2 表达受rs7132908调节，FAIM 2在神经元对代谢的反应中起作用。 荷尔蒙在我的第一个目标中，我将描述rs7132908风险等位基因在体外对FAIM 2表达的影响。 和体内。在我的第二个目标中，我将研究FAIM 2在弓状核中失调的后果， 神经元对代谢激素的反应。总之，这些发现将提供第一步， 了解FAIM 2基因座如何影响儿童肥胖易感性， 药理学目标，以满足更强大的儿童肥胖治疗的需求。

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.