Variant-to-function analysis of the childhood obesity chr12q13 locus implicates rs7132908 as a causal variant within the 3' UTR of FAIM2.

IF 11.1 Q1 CELL BIOLOGY Cell genomics Pub Date : 2024-05-08 Epub Date: 2024-05-01 DOI:10.1016/j.xgen.2024.100556
Sheridan H Littleton, Khanh B Trang, Christina M Volpe, Kieona Cook, Nicole DeBruyne, Jean Ann Maguire, Mary Ann Weidekamp, Kenyaita M Hodge, Keith Boehm, Sumei Lu, Alessandra Chesi, Jonathan P Bradfield, James A Pippin, Stewart A Anderson, Andrew D Wells, Matthew C Pahl, Struan F A Grant
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Abstract

The ch12q13 locus is among the most significant childhood obesity loci identified in genome-wide association studies. This locus resides in a non-coding region within FAIM2; thus, the underlying causal variant(s) presumably influence disease susceptibility via cis-regulation. We implicated rs7132908 as a putative causal variant by leveraging our in-house 3D genomic data and public domain datasets. Using a luciferase reporter assay, we observed allele-specific cis-regulatory activity of the immediate region harboring rs7132908. We generated isogenic human embryonic stem cell lines homozygous for either rs7132908 allele to assess changes in gene expression and chromatin accessibility throughout a differentiation to hypothalamic neurons, a key cell type known to regulate feeding behavior. The rs7132908 obesity risk allele influenced expression of FAIM2 and other genes and decreased the proportion of neurons produced by differentiation. We have functionally validated rs7132908 as a causal obesity variant that temporally regulates nearby effector genes and influences neurodevelopment and survival.

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儿童肥胖症 chr12q13 位点的变异到功能分析显示,rs7132908 是 FAIM2 3' UTR 中的一个因果变异。
ch12q13位点是全基因组关联研究中发现的最重要的儿童肥胖位点之一。该位点位于 FAIM2 中的非编码区;因此,潜在的因果变异可能通过顺式调控影响疾病易感性。我们利用内部三维基因组数据和公共领域数据集,将 rs7132908 推测为一个因果变异体。通过荧光素酶报告实验,我们观察到了携带 rs7132908 的直接区域的等位基因特异性顺式调节活性。我们生成了rs7132908等位基因同源的人类胚胎干细胞系,以评估在向下丘脑神经元分化的整个过程中基因表达和染色质可及性的变化,下丘脑神经元是已知调节进食行为的关键细胞类型。rs7132908肥胖风险等位基因影响了FAIM2和其他基因的表达,并降低了分化产生的神经元比例。我们从功能上验证了 rs7132908 是肥胖症的因果变异基因,它能在时间上调节附近的效应基因,影响神经发育和存活。
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