title: Statistical colocalization of monocyte gene expression and genetic risk variants for type 1 diabetes.
abstract: One mechanism by which disease-associated DNA variation can alter disease risk is altering gene expression. However, linkage disequilibrium (LD) between variants, mostly single-nucleotide polymorphisms (SNPs), means it is not sufficient to show that a particular variant associates with both disease and expression, as there could be two distinct causal variants in LD. Here, we describe a formal statistical test of colocalization and apply it to type 1 diabetes (T1D)-associated regions identified mostly through genome-wide association studies and expression quantitative trait loci (eQTLs) discovered in a recently determined large monocyte expression data set from the Gutenberg Health Study (1370 individuals), with confirmation sought in an additional data set from the Cardiogenics Transcriptome Study (558 individuals). We excluded 39 out of 60 overlapping eQTLs in 49 T1D regions from possible colocalization and identified 21 coincident eQTLs, representing 21 genes in 14 distinct T1D regions. Our results reflect the importance of monocyte (and their derivatives, macrophage and dendritic cell) gene expression in human T1D and support the candidacy of several genes as causal factors in autoimmune pancreatic beta-cell destruction, including AFF3, CD226, CLECL1, DEXI, FKRP, PRKD2, RNLS, SMARCE1 and SUOX, in addition to the recently described GPR183 (EBI2) gene.
authors.affiliation: Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK. chris.wallace@cimr.cam.ac.uk
authors.forename: Chris
authors.initials: C
authors.lastname: Wallace
authors.forename: Maxime
authors.initials: M
authors.lastname: Rotival
authors.forename: Jason D
authors.initials: JD
authors.lastname: Cooper
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Rice
authors.forename: Jennie H M
authors.initials: JH
authors.lastname: Yang
authors.forename: Mhairi
authors.initials: M
authors.lastname: McNeill
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Smyth
authors.forename: David
authors.initials: D
authors.lastname: Niblett
authors.forename: François
authors.initials: F
authors.lastname: Cambien
authors.forename: Laurence
authors.initials: L
authors.lastname: Tiret
authors.forename: John A
authors.initials: JA
authors.lastname: Todd
authors.forename: David G
authors.initials: DG
authors.lastname: Clayton
authors.forename: Stefan
authors.initials: S
authors.lastname: Blankenberg
mesh_terms: D000328:Adult; D000368:Aged; D000465:Algorithms; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D009000:Monocytes / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000235:genetics; D012307:Risk Factors; D059467:Transcriptome