Statistical colocalization of monocyte gene expression and genetic risk variants for type 1 diabetes
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Statistical colocalization of monocyte gene expression and genetic risk variants for type 1 diabetes. / Wallace, Chris; Rotival, Maxime; Cooper, Jason D; Rice, Catherine M; Yang, Jennie H M; McNeill, Mhairi; Smyth, Deborah J; Niblett, David; Cambien, François; Tiret, Laurence; Todd, John A; Clayton, David G; Blankenberg, Stefan; CardioGenics Consortium.
in: HUM MOL GENET, Jahrgang 21, Nr. 12, 15.06.2012, S. 2815-2824.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Statistical colocalization of monocyte gene expression and genetic risk variants for type 1 diabetes
AU - Wallace, Chris
AU - Rotival, Maxime
AU - Cooper, Jason D
AU - Rice, Catherine M
AU - Yang, Jennie H M
AU - McNeill, Mhairi
AU - Smyth, Deborah J
AU - Niblett, David
AU - Cambien, François
AU - Tiret, Laurence
AU - Todd, John A
AU - Clayton, David G
AU - Blankenberg, Stefan
AU - CardioGenics Consortium
PY - 2012/6/15
Y1 - 2012/6/15
N2 - 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.
AB - 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.
KW - Adult
KW - Aged
KW - Algorithms
KW - Diabetes Mellitus, Type 1/genetics
KW - Female
KW - Genetic Predisposition to Disease/genetics
KW - Genome-Wide Association Study
KW - Genotype
KW - Humans
KW - Linkage Disequilibrium
KW - Male
KW - Middle Aged
KW - Models, Genetic
KW - Monocytes/metabolism
KW - Polymorphism, Single Nucleotide
KW - Quantitative Trait Loci/genetics
KW - Risk Factors
KW - Transcriptome
U2 - 10.1093/hmg/dds098
DO - 10.1093/hmg/dds098
M3 - SCORING: Journal article
C2 - 22403184
VL - 21
SP - 2815
EP - 2824
JO - HUM MOL GENET
JF - HUM MOL GENET
SN - 0964-6906
IS - 12
ER -