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Conditional meta-analysis stratifying on detailed HLA genotypes identifies a novel type 1 diabetes locus around TCF19 in the MHC.

Cheung YH, Watkinson J, Anastassiou D - Hum. Genet. (2010)

Bottom Line: Additional loci in the major histocompatibility complex (MHC) are difficult to identify due to the region's high gene density and complex linkage disequilibrium (LD).Screening and replication were performed on two large and independent datasets: the Wellcome Trust Case-Control Consortium (WTCCC) dataset of 2,000 cases and 1,504 controls, and the T1D Genetics Consortium (T1DGC) dataset of 2,300 nuclear families.A subsequent LD analysis established TCF19, POU5F1, CCHCR1 and PSORS1C1 as potential causal genes for the observed association.

View Article: PubMed Central - PubMed

Affiliation: Department of Electrical Engineering, Center for Computational Biology and Bioinformatics, Columbia University, 1300 S.W. Mudd, 500 West 120th Street, New York, NY 10027, USA.

ABSTRACT
The human leukocyte antigen (HLA) class II genes HLA-DRB1, -DQA1 and -DQB1 are the strongest genetic factors for type 1 diabetes (T1D). Additional loci in the major histocompatibility complex (MHC) are difficult to identify due to the region's high gene density and complex linkage disequilibrium (LD). To facilitate the association analysis, two novel algorithms were implemented in this study: one for phasing the multi-allelic HLA genotypes in trio families, and one for partitioning the HLA strata in conditional testing. Screening and replication were performed on two large and independent datasets: the Wellcome Trust Case-Control Consortium (WTCCC) dataset of 2,000 cases and 1,504 controls, and the T1D Genetics Consortium (T1DGC) dataset of 2,300 nuclear families. After imputation, the two datasets have 1,941 common SNPs in the MHC, of which 22 were successfully tested and replicated based on the statistical testing stratifying on the detailed DRB1 and DQB1 genotypes. Further conditional tests using the combined dataset confirmed eight novel SNP associations around 31.3 Mb on chromosome 6 (rs3094663, p = 1.66 × 10(-11) and rs2523619, p = 2.77 × 10(-10) conditional on the DR/DQ genotypes). A subsequent LD analysis established TCF19, POU5F1, CCHCR1 and PSORS1C1 as potential causal genes for the observed association.

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p values of the T1DGC dataset conditional on the HLA-DRB1-DQA1-DQB1 haplotypes based on Mantel–Haenszel test. The classical MHC subregions and some relevant genes are included for reference. Position is along chromosome 6, NCBI genome build 36.3
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Fig3: p values of the T1DGC dataset conditional on the HLA-DRB1-DQA1-DQB1 haplotypes based on Mantel–Haenszel test. The classical MHC subregions and some relevant genes are included for reference. Position is along chromosome 6, NCBI genome build 36.3

Mentions: To capture those SNPs showing stronger associations in the T1DGC dataset than in the WTCCC dataset, the conditional analysis was carried out again with the roles of the two datasets switched: T1DGC dataset for initial screening and WTCCC dataset for replication. Out of the 1,941 common SNPs under test, 29 were able to pass the Bonferroni’s-corrected 5% significance level, of which 7 were successfully replicated at 5% FDR (p < 7 × 0.05/29 ≈ 0.0121). It was expected that a fewer number of SNPs passed the screening, since the T1DGC dataset is smaller in size and hence less powerful statistically. The seven newly replicated SNPs were all different from the 15 obtained in the previous round of analysis, making a total of 22 replicated SNPs. These SNPs, together with their conditional p values for the two datasets, are listed in Table 2. Plots of the conditional p values of all SNPs with respect to their chromosome positions are shown in Figs. 2 and 3, respectively, for the two datasets.Table 2


Conditional meta-analysis stratifying on detailed HLA genotypes identifies a novel type 1 diabetes locus around TCF19 in the MHC.

Cheung YH, Watkinson J, Anastassiou D - Hum. Genet. (2010)

p values of the T1DGC dataset conditional on the HLA-DRB1-DQA1-DQB1 haplotypes based on Mantel–Haenszel test. The classical MHC subregions and some relevant genes are included for reference. Position is along chromosome 6, NCBI genome build 36.3
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3020293&req=5

Fig3: p values of the T1DGC dataset conditional on the HLA-DRB1-DQA1-DQB1 haplotypes based on Mantel–Haenszel test. The classical MHC subregions and some relevant genes are included for reference. Position is along chromosome 6, NCBI genome build 36.3
Mentions: To capture those SNPs showing stronger associations in the T1DGC dataset than in the WTCCC dataset, the conditional analysis was carried out again with the roles of the two datasets switched: T1DGC dataset for initial screening and WTCCC dataset for replication. Out of the 1,941 common SNPs under test, 29 were able to pass the Bonferroni’s-corrected 5% significance level, of which 7 were successfully replicated at 5% FDR (p < 7 × 0.05/29 ≈ 0.0121). It was expected that a fewer number of SNPs passed the screening, since the T1DGC dataset is smaller in size and hence less powerful statistically. The seven newly replicated SNPs were all different from the 15 obtained in the previous round of analysis, making a total of 22 replicated SNPs. These SNPs, together with their conditional p values for the two datasets, are listed in Table 2. Plots of the conditional p values of all SNPs with respect to their chromosome positions are shown in Figs. 2 and 3, respectively, for the two datasets.Table 2

Bottom Line: Additional loci in the major histocompatibility complex (MHC) are difficult to identify due to the region's high gene density and complex linkage disequilibrium (LD).Screening and replication were performed on two large and independent datasets: the Wellcome Trust Case-Control Consortium (WTCCC) dataset of 2,000 cases and 1,504 controls, and the T1D Genetics Consortium (T1DGC) dataset of 2,300 nuclear families.A subsequent LD analysis established TCF19, POU5F1, CCHCR1 and PSORS1C1 as potential causal genes for the observed association.

View Article: PubMed Central - PubMed

Affiliation: Department of Electrical Engineering, Center for Computational Biology and Bioinformatics, Columbia University, 1300 S.W. Mudd, 500 West 120th Street, New York, NY 10027, USA.

ABSTRACT
The human leukocyte antigen (HLA) class II genes HLA-DRB1, -DQA1 and -DQB1 are the strongest genetic factors for type 1 diabetes (T1D). Additional loci in the major histocompatibility complex (MHC) are difficult to identify due to the region's high gene density and complex linkage disequilibrium (LD). To facilitate the association analysis, two novel algorithms were implemented in this study: one for phasing the multi-allelic HLA genotypes in trio families, and one for partitioning the HLA strata in conditional testing. Screening and replication were performed on two large and independent datasets: the Wellcome Trust Case-Control Consortium (WTCCC) dataset of 2,000 cases and 1,504 controls, and the T1D Genetics Consortium (T1DGC) dataset of 2,300 nuclear families. After imputation, the two datasets have 1,941 common SNPs in the MHC, of which 22 were successfully tested and replicated based on the statistical testing stratifying on the detailed DRB1 and DQB1 genotypes. Further conditional tests using the combined dataset confirmed eight novel SNP associations around 31.3 Mb on chromosome 6 (rs3094663, p = 1.66 × 10(-11) and rs2523619, p = 2.77 × 10(-10) conditional on the DR/DQ genotypes). A subsequent LD analysis established TCF19, POU5F1, CCHCR1 and PSORS1C1 as potential causal genes for the observed association.

Show MeSH
Related in: MedlinePlus