Complete re-sequencing of a 2Mb topological domain encompassing the FTO/IRXB genes identifies a novel obesity-associated region upstream of IRX5

Abstract

BackgroundAssociation studies have identified a number of loci that contribute to an increased body mass index (BMI), the strongest of which is in the first intron of the FTO gene on human chromosome 16q12.2. However, this region is both non-coding and under strong linkage disequilibrium, making it recalcitrant to functional interpretation. Furthermore, the FTO gene is located within a complex cis-regulatory landscape defined by a topologically associated domain that includes the IRXB gene cluster, a trio of developmental regulators. Consequently, at least three genes in this interval have been implicated in the aetiology of obesity.MethodsHere, we sequence a 2 Mb region encompassing the FTO, RPGRIP1L and IRXB cluster genes in 284 individuals from a well-characterised study group of Danish men containing extremely overweight young adults and controls. We further replicate our findings both in an expanded male cohort and an independent female study group. Finally, we compare our variant data with a previous study describing IRX3 and FTO interactions in this region.ResultsWe obtain deep coverage across the entire region, allowing accurate and unequivocal determination of almost every single nucleotide polymorphism and short insertion/deletion. As well as confirming previous findings across the interval, we identify a further novel age-dependent association upstream of IRX5 that imposes a similar burden on BMI to the FTO locus.ConclusionsOur findings are consistent with the hypothesis that chromatin architectures play a role in regulating gene expression levels across topological domains while our targeted sequence approach represents a widely applicable methodology for high-resolution analysis of regional variation across candidate genomic loci.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-015-0250-3) contains supplementary material, which is available to authorized users.

Mapping novel genetic loci associated with female liver weight variations using Collaborative Cross mice

“…The presence of the Irx B cluster induces the complexity of the LWL 1 region due to their multiple regulatory roles in early development. Adjacent to the Irx B cluster, within the significant LWL 1 QTL, we located the fat mass and obesity‐associated ( FTO ) gene and Retinitis pigmentosa GTPase regulator interacting protein 1‐like ( Rpgrip 1l) gene, together identified as a topologically associated domain (TAD) structure in which any transcriptional perturbation during development may potentially affect bodyweight index . The Rpgrip 1l gene (MGI: 1920563) is highly involved in growth/early development and suggested to be a tumor suppressor of hepatocellular carcinoma …”

Genetic association of FTO/IRX region with obesity and overweight in the Polish population

“…This region was selected according to the Hunt et al [38] to encompass a TAD defined in embryonic stem cells [39]. We found 353 SNPs in the tested area.…”

Genetic architecture of early childhood growth phenotypes gives insights into their link with later obesity

“…Therefore, the gene nearest to the lead signals may not necessarily be the gene influenced by the underlying causal variant/s. For example, at the FTO locus more than one gene, which includes the FTO 31,32 , RPGRIP1L 33 and IRX3/IRX5 in the IRXB gene cluster 34,35 have been implicated as the candidates for mediating the observed associations with adult adiposity. Given our index SNP at FTO associated with Age at AR is highly correlated with the BMI associated SNPs at the same locus, it is plausible that the same genes play a role in the regulation of Age at AR and adult adiposity.…”