1. Variant-to-function analysis of the childhood obesity chr12q13 locus implicates rs7132908 as a causal variant within the 3' UTR of FAIM2.
- Author
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Littleton SH, Trang KB, Volpe CM, Cook K, DeBruyne N, Maguire JA, Weidekamp MA, Hodge KM, Boehm K, Lu S, Chesi A, Bradfield JP, Pippin JA, Anderson SA, Wells AD, Pahl MC, and Grant SFA
- Subjects
- Child, Humans, Alleles, Cell Differentiation genetics, Chromosomes, Human, Pair 12 genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Human Embryonic Stem Cells metabolism, Neurons metabolism, Polymorphism, Single Nucleotide genetics, 3' Untranslated Regions genetics, Pediatric Obesity genetics, Membrane Proteins genetics, Apoptosis Regulatory Proteins genetics
- 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., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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