Long-range DNA looping and gene expression analyses identify DEXI as an autoimmune disease candidate gene

TY - JOUR

T1 - Long-range DNA looping and gene expression analyses identify DEXI as an autoimmune disease candidate gene

AU - Davison, Lucy J

AU - Wallace, Chris

AU - Cooper, Jason D

AU - Cope, Nathan F

AU - Wilson, Nicola K

AU - Smyth, Deborah J

AU - Howson, Joanna M M

AU - Saleh, Nada

AU - Al-Jeffery, Abdullah

AU - Angus, Karen L

AU - Stevens, Helen E

AU - Nutland, Sarah

AU - Duley, Simon

AU - Coulson, Richard M R

AU - Walker, Neil M

AU - Burren, Oliver S

AU - Rice, Catherine M

AU - Cambien, Francois

AU - Zeller, Tanja

AU - Munzel, Thomas

AU - Lackner, Karl

AU - Blakenberg, Stefan

AU - Fraser, Peter

AU - Gottgens, Berthold

AU - Todd, John A

AU - Attwood, Tony

AU - Belz, Stephanie

AU - Braund, Peter

AU - Cambien, François

AU - Cooper, Jason

AU - Crisp-Hihn, Abi

AU - Diemert, Patrick

AU - Deloukas, Panos

AU - Foad, Nicola

AU - Erdmann, Jeanette

AU - Goodall, Alison H

AU - Gracey, Jay

AU - Gray, Emma

AU - Williams, Rhian G

AU - Heimerl, Susanne

AU - Hengstenberg, Christian

AU - Jolley, Jennifer

AU - Krishnan, Unni

AU - Lloyd-Jones, Heather

AU - Lugauer, Ingrid

AU - Lundmark, Per

AU - Maouche, Seraya

AU - Moore, Jasbir S

AU - Muir, David

AU - Murray, Elizabeth

AU - Nelson, Chris P

AU - Neudert, Jessica

AU - Niblett, David

AU - O'Leary, Karen

AU - Ouwehand, Willem H

AU - Pollard, Helen

AU - Rankin, Angela

AU - Rice, Catherine M

AU - Sager, Hendrik

AU - Samani, Nilesh J

AU - Sambrook, Jennifer

AU - Schmitz, Gerd

AU - Scholz, Michael

AU - Schroeder, Laura

AU - Schunkert, Heribert

AU - Syvannen, Ann-Christine

AU - Tennstedt, Stefanie

AU - Wallace, Chris

AU - CardioGenics Consortium

N1 - © The Author 2011. Published by Oxford University Press.

PY - 2012/1/15

Y1 - 2012/1/15

N2 - 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.

AB - 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.

KW - Autoimmune Diseases/genetics

KW - Chromosomes, Human, Pair 16

KW - DNA/genetics

KW - DNA-Binding Proteins/genetics

KW - Humans

KW - Membrane Proteins/genetics

KW - Monocytes/metabolism

KW - Polymerase Chain Reaction

KW - Polymorphism, Single Nucleotide

KW - Quantitative Trait Loci

U2 - 10.1093/hmg/ddr468

DO - 10.1093/hmg/ddr468

M3 - SCORING: Journal article

C2 - 21989056

VL - 21

SP - 322

EP - 333

JO - HUM MOL GENET

JF - HUM MOL GENET

SN - 0964-6906

IS - 2

ER -