Débora R. Sobreira, Amelia C. Joslin, Qi Zhang, Iain Williamson, Grace T. Hansen et al.
Whereas coding variants often have pleiotropic effects across multiple tissues, noncoding variants are thought to mediate their phenotypic effects by specific tissue and temporal regulation of gene expression. Here, we investigated the genetic and functional architecture of a genomic region within the FTO gene that is strongly associated with obesity risk. We show that multiple variants on a common haplotype modify the regulatory properties of several enhancers targeting IRX3 and IRX5 from megabase distances. We demonstrate that these enhancers affect gene expression in multiple tissues, including adipose and brain, and impart regulatory effects during a restricted temporal window. Our data indicate that the genetic architecture of disease-associated loci may involve extensive pleiotropy, allelic heterogeneity, shared allelic effects across tissues, and temporally restricted effects.
Débora R. Sobreira, Amelia C. Joslin, Qi Zhang, Iain Williamson, Grace T. Hansen, Kathryn M. Farris, Noboru J. Sakabe, Nasa Sinnott-Armstrong, Grazyna Bozek, Sharon O. Jensen-Cody, Kyle H. Flippo, Carole Ober, Wendy A. Bickmore, Matthew Potthoff, Mengjie Chen, Melina Claussnitzer, Ivy Aneas, Marcelo A. Nóbrega. Extensive pleiotropism and allelic heterogeneity mediate metabolic effects of IRX3 and IRX5. 2021-06-04. https://doi.org/10.1126/science.abf1008
A biallelic library of 87 common FTO-locus variants in high LD with rs1558902 was tested in mouse HT22 hippocampal neuronal cells using an episomal plasmid MPRA. This processed table retains the 18 variants that the authors reported as enhancer-active in at least three assay replicates and flags the three reported allele-specific enhancer effects.
A biallelic library of 87 common FTO-locus variants in high LD with rs1558902 was tested in mouse 3T3-L1 preadipocytes using an episomal plasmid MPRA. This processed table retains the 21 variants that the authors reported as enhancer-active in at least three assay replicates and flags the five reported allele-specific enhancer effects.
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