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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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Related in: MedlinePlus

p values conditional on HLA-DRB1-DQB1 together with HLA- aA, bB, cC and dDPB1, respectively. p values of a–c are generated by applying stratified Cochran–Armitage trend test on the combined dataset, whereas p values in d are generated by applying Mantel–Haenszel test on the phased T1DGC haplotypes. Significance levels were indicated in the appropriate regions under 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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Fig5: p values conditional on HLA-DRB1-DQB1 together with HLA- aA, bB, cC and dDPB1, respectively. p values of a–c are generated by applying stratified Cochran–Armitage trend test on the combined dataset, whereas p values in d are generated by applying Mantel–Haenszel test on the phased T1DGC haplotypes. Significance levels were indicated in the appropriate regions under test. The classical MHC subregions and some relevant genes are included for reference. Position is along chromosome 6, NCBI genome build 36.3

Mentions: The p values of all SNPs conditional on the different HLA genes were plotted in Figs. 5a–d. In Fig. 5a, the stratification on HLA-A almost completely ified all SNP associations in the neighborhood, while the associations of SNPs farther away remained prominent. This proves the robustness and effectiveness of our partitioning algorithm in reducing the number of HLA strata while retaining most of their confounding effects. Upon conditioning on HLA-B, the associations of rs2523619 and rs3094663 were more outstanding than other replicated SNPs in that region. A considerable level of LD was observed between Block 4 and HLA-B, even though they are about 1.8 Mb apart. In particular, the association of rs2281390 was totally gone after conditioning on HLA-B. Therefore, the SNP was not considered a novel association, despite its passing of the tests conditioned on HLA-DPB1 and -DPA1. When compared with HLA-B, conditioning on HLA-C had smaller impact on the p values and the LD with HLA-DPB1 was seemingly confined to a shorter range.Fig. 5


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 conditional on HLA-DRB1-DQB1 together with HLA- aA, bB, cC and dDPB1, respectively. p values of a–c are generated by applying stratified Cochran–Armitage trend test on the combined dataset, whereas p values in d are generated by applying Mantel–Haenszel test on the phased T1DGC haplotypes. Significance levels were indicated in the appropriate regions under 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

Fig5: p values conditional on HLA-DRB1-DQB1 together with HLA- aA, bB, cC and dDPB1, respectively. p values of a–c are generated by applying stratified Cochran–Armitage trend test on the combined dataset, whereas p values in d are generated by applying Mantel–Haenszel test on the phased T1DGC haplotypes. Significance levels were indicated in the appropriate regions under test. The classical MHC subregions and some relevant genes are included for reference. Position is along chromosome 6, NCBI genome build 36.3
Mentions: The p values of all SNPs conditional on the different HLA genes were plotted in Figs. 5a–d. In Fig. 5a, the stratification on HLA-A almost completely ified all SNP associations in the neighborhood, while the associations of SNPs farther away remained prominent. This proves the robustness and effectiveness of our partitioning algorithm in reducing the number of HLA strata while retaining most of their confounding effects. Upon conditioning on HLA-B, the associations of rs2523619 and rs3094663 were more outstanding than other replicated SNPs in that region. A considerable level of LD was observed between Block 4 and HLA-B, even though they are about 1.8 Mb apart. In particular, the association of rs2281390 was totally gone after conditioning on HLA-B. Therefore, the SNP was not considered a novel association, despite its passing of the tests conditioned on HLA-DPB1 and -DPA1. When compared with HLA-B, conditioning on HLA-C had smaller impact on the p values and the LD with HLA-DPB1 was seemingly confined to a shorter range.Fig. 5

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