title: Long-range DNA looping and gene expression analyses identify DEXI as an autoimmune disease candidate gene.
abstract: The chromosome 16p13 region has been associated with several autoimmune diseases, including type 1 diabetes (T1D) and multiple sclerosis (MS). CLEC16A has been reported as the most likely candidate gene in the region, since it contains the most disease-associated single-nucleotide polymorphisms (SNPs), as well as an imunoreceptor tyrosine-based activation motif. However, here we report that intron 19 of CLEC16A, containing the most autoimmune disease-associated SNPs, appears to behave as a regulatory sequence, affecting the expression of a neighbouring gene, DEXI. The CLEC16A alleles that are protective from T1D and MS are associated with increased expression of DEXI, and no other genes in the region, in two independent monocyte gene expression data sets. Critically, using chromosome conformation capture (3C), we identified physical proximity between the DEXI promoter region and intron 19 of CLEC16A, separated by a loop of >150 kb. In reciprocal experiments, a 20 kb fragment of intron 19 of CLEC16A, containing SNPs associated with T1D and MS, as well as with DEXI expression, interacted with the promotor region of DEXI but not with candidate DNA fragments containing other potential causal genes in the region, including CLEC16A. Intron 19 of CLEC16A is highly enriched for transcription-factor-binding events and markers associated with enhancer activity. Taken together, these data indicate that although the causal variants in the 16p13 region lie within CLEC16A, DEXI is an unappreciated autoimmune disease candidate gene, and illustrate the power of the 3C approach in progressing from genome-wide association studies results to candidate causal genes.
authors: Lucy J
authors: LJ
authors: Davison
authors: Chris
authors: C
authors: Wallace
authors: Jason D
authors: JD
authors: Cooper
authors: Nathan F
authors: NF
authors: Cope
authors: Nicola K
authors: NK
authors: Wilson
authors: Deborah J
authors: DJ
authors: Smyth
authors: Joanna M M
authors: JM
authors: Howson
authors: Nada
authors: N
authors: Saleh
authors: Abdullah
authors: A
authors: Al-Jeffery
authors: Karen L
authors: KL
authors: Angus
authors: Helen E
authors: HE
authors: Stevens
authors: Sarah
authors: S
authors: Nutland
authors: Simon
authors: S
authors: Duley
authors: Richard M R
authors: RM
authors: Coulson
authors: Neil M
authors: NM
authors: Walker
authors: Oliver S
authors: OS
authors: Burren
authors: Catherine M
authors: CM
authors: Rice
authors: Francois
authors: F
authors: Cambien
authors: Tanja
authors: T
authors: Zeller
authors: Thomas
authors: T
authors: Munzel
authors: Karl
authors: K
authors: Lackner
authors: Stefan
authors: S
authors: Blakenberg
authors: Peter
authors: P
authors: Fraser
authors: Berthold
authors: B
authors: Gottgens
authors: John A
authors: JA
authors: Todd
authors: Tony
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authors: Attwood
authors: Stephanie
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authors: Belz
authors: Peter
authors: P
authors: Braund
authors: François
authors: F
authors: Cambien
authors: Jason
authors: J
authors: Cooper
authors: Abi
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authors: Crisp-Hihn
authors: Patrick
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authors: Diemert
authors: Panos
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authors: Deloukas
authors: Nicola
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authors: Foad
authors: Jeanette
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authors: Erdmann
authors: Alison H
authors: AH
authors: Goodall
authors: Jay
authors: J
authors: Gracey
authors: Emma
authors: E
authors: Gray
authors: Rhian G
authors: RG
authors: Williams
authors: Susanne
authors: S
authors: Heimerl
authors: Christian
authors: C
authors: Hengstenberg
authors: Jennifer
authors: J
authors: Jolley
authors: Unni
authors: U
authors: Krishnan
authors: Heather
authors: H
authors: Lloyd-Jones
authors: Ingrid
authors: I
authors: Lugauer
authors: Per
authors: P
authors: Lundmark
authors: Seraya
authors: S
authors: Maouche
authors: Jasbir S
authors: JS
authors: Moore
authors: David
authors: D
authors: Muir
authors: Elizabeth
authors: E
authors: Murray
authors: Chris P
authors: CP
authors: Nelson
authors: Jessica
authors: J
authors: Neudert
authors: David
authors: D
authors: Niblett
authors: Karen
authors: K
authors: O'Leary
authors: Willem H
authors: WH
authors: Ouwehand
authors: Helen
authors: H
authors: Pollard
authors: Angela
authors: A
authors: Rankin
authors: Catherine M
authors: CM
authors: Rice
authors: Hendrik
authors: H
authors: Sager
authors: Nilesh J
authors: NJ
authors: Samani
authors: Jennifer
authors: J
authors: Sambrook
authors: Gerd
authors: G
authors: Schmitz
authors: Michael
authors: M
authors: Scholz
authors: Laura
authors: L
authors: Schroeder
authors: Heribert
authors: H
authors: Schunkert
authors: Ann-Christine
authors: AC
authors: Syvannen
authors: Stefanie
authors: S
authors: Tennstedt
authors: Chris
authors: C
authors: Wallace
mesh_terms: D001327:Autoimmune Diseases / Q000235:genetics*; D002885:Chromosomes, Human, Pair 16; D004247:DNA / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D009000:Monocytes / Q000378:metabolism; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci
chemical_list: C433368:DEXI protein, human; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D004247:DNA