title: Complete re-sequencing of a 2Mb topological domain encompassing the FTO/IRXB genes identifies a novel obesity-associated region upstream of IRX5.
abstract: BACKGROUND
  Association 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.
  
  
  METHODS
  Here, 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.
  
  
  RESULTS
  We 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.
  
  
  CONCLUSIONS
  Our 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.
authors.affiliation: The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, Mill Hill, London, NW7 1AA, UK.
authors.forename: Lilian E
authors.initials: LE
authors.lastname: Hunt
authors.affiliation: The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, Mill Hill, London, NW7 1AA, UK.
authors.forename: Boris
authors.initials: B
authors.lastname: Noyvert
authors.affiliation: Genomics Facility, The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, Mill Hill, London, NW7 1AA, UK.
authors.forename: Leena
authors.initials: L
authors.lastname: Bhaw-Rosun
authors.affiliation: Genomics Facility, The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, Mill Hill, London, NW7 1AA, UK.
authors.forename: Abdul K
authors.initials: AK
authors.lastname: Sesay
authors.affiliation: MRC Integrative Epidemiology Unit (IEU) at the University of Bristol, University of Bristol, Bristol, UK.
authors.forename: Lavinia
authors.initials: L
authors.lastname: Paternoster
authors.affiliation: Research Unit for Gynecology and Obstetrics, Institute of Clinical Research, University of Southern Denmark, Odense, Denmark.
authors.forename: Ellen A
authors.initials: EA
authors.lastname: Nohr
authors.affiliation: MRC Integrative Epidemiology Unit (IEU) at the University of Bristol, University of Bristol, Bristol, UK.
authors.forename: George
authors.initials: G
authors.lastname: Davey Smith
authors.affiliation: Willhelm Johannsen Centre for Functional Genome Research, Department of Cellular and Molecular Medicine, The Faculty of Health Sciences, The University of Copenhagen, Blegdamsvej 3B, DK-2200, Copenhagen N, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Tommerup
authors.affiliation: MRC Integrative Epidemiology Unit (IEU) at the University of Bristol, University of Bristol, Bristol, UK.|The Novo Nordisk Foundation Centre for Basic Metabolic Research, Section on Metabolic genetics, The Faculty of Health and Medical Sciences, University of Copenhagen, DK2100, Copenhagen Ø, Denmark.|Institute of Preventive Medicine, Bispebjerg and Frederiksberg Hospitals, The Capital Region, DK2000, Frederiksberg, Denmark.
authors.forename: Thorkild I A
authors.initials: TI
authors.lastname: Sørensen
authors.affiliation: The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, Mill Hill, London, NW7 1AA, UK. Greg.Elgar@crick.ac.uk.
authors.forename: Greg
authors.initials: G
authors.lastname: Elgar
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000328:Adult; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D016022:Case-Control Studies; D042002:Chromatin Assembly and Disassembly; D002874:Chromosome Mapping; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006239:Haplotypes; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007438:Introns; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D005810:Multigene Family; D009765:Obesity / Q000235:genetics*; D050177:Overweight / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018398:Homeodomain Proteins; C501600:IRX5 protein, human; D011506:Proteins; C532826:RPGRIP1L protein, human; D014157:Transcription Factors; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human