Human Genetics

, Volume 134, Issue 11–12, pp 1183–1193 | Cite as

Scrutinizing the FTO locus: compelling evidence for a complex, long-range regulatory context

  • Mathias Rask-Andersen
  • Markus Sällman Almén
  • Helgi B. Schiöth
Original Investigation


Single nucleotide polymorphisms (SNPs) within a genetic region including the first two introns of the gene encoding FTO have consistently been shown to be the strongest genetic factors influencing body mass index (BMI). However, this same also contains several regulatory DNA elements that affect the expression of IRX3 and IRX5, which respectively, are located approximately 500 kb and 1.2 Mbp downstream from the BMI-associated FTO locus. Through these affected regulatory elements, genetic variation at the FTO locus influences adipocyte development leading to decreased thermogenesis and increased lipid storage. These findings provide a genomic model for the functional implications of genetic variations at this locus, and also demonstrate the importance of accounting for chromatin–chromatin interactions when constructing hypotheses for the mechanisms of trait and disease-associated common genetic variants. Several consortia have generated genome-wide datasets describing different aspects of chromatin biology which can be utilized to predict functionality and propose biologically relevant descriptions of specific DNA regions. Here, we review some of the publically available data resources on genome function and organization that can be used to gain an overview of genetic regions of interest and to generate testable hypotheses for future studies. We use the BMI- and obesity-associated FTO locus as a subject as it poses an illustrative example on the value of these resources. We find that public databases strongly support long-range interactions between regulatory elements in the FTO locus with the IRXB cluster genes IRX3 and IRX5. Chromatin configuration capture data also support interactions across a large region stretching across from the RPGRIP1L gene, FTO and the IRXB gene cluster.


Chromatin Interaction Promoter Interaction Encode Consortium Fantom Consortium Body Mass Regulation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



MRA was supported by the Swedish Brain Research Foundation, The Lars Hierta Memorial Foundation and the Fredrik O Ingrid Thuring Foundation. Studies were supported by the Swedish Research Council. We would like to express our gratitude to Lyle Weimerslage, Ph.D. for assisting with the writing of the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that there are no conflicts of interest.

Supplementary material

439_2015_1599_MOESM1_ESM.pdf (1 mb)
Supplementary material 1 (PDF 1062 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  1. 1.Department of Neuroscience, Division of Functional PharmacologyUppsala University, Biomedical Center (BMC)UppsalaSweden
  2. 2.Department of Medical Biochemistry and MicrobiologyUppsala University, BMCUppsalaSweden

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