caa a22 4500 445861886 CHVBK 20180317145446.0 cr unu---uuuuu 170323e20110201xx s 000 0 eng 10.1007/s00439-010-0908-2 doi (NATIONALLICENCE)springer-10.1007/s00439-010-0908-2 Conditional meta-analysis stratifying on detailed HLA genotypes identifies a novel type 1 diabetes locus around TCF19 in the MHC [Elektronische Daten] [Yee Cheung, John Watkinson, Dimitris Anastassiou] 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 31.3Mb 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. The Author(s), 2010 Cheung Yee Department of Electrical Engineering, Center for Computational Biology and Bioinformatics, Columbia University, 1300 S.W. Mudd, 500 West 120th Street, 10027, New York, NY, USA aut Watkinson John Department of Electrical Engineering, Center for Computational Biology and Bioinformatics, Columbia University, 1300 S.W. Mudd, 500 West 120th Street, 10027, New York, NY, USA aut Anastassiou Dimitris Department of Electrical Engineering, Center for Computational Biology and Bioinformatics, Columbia University, 1300 S.W. Mudd, 500 West 120th Street, 10027, New York, NY, USA aut Human Genetics Springer-Verlag 129/2(2011-02-01), 161-176 0340-6717 129:2<161 2011 129 439 https://doi.org/10.1007/s00439-010-0908-2 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s00439-010-0908-2 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Cheung Yee Department of Electrical Engineering, Center for Computational Biology and Bioinformatics, Columbia University, 1300 S.W. Mudd, 500 West 120th Street, 10027, New York, NY, USA aut NATIONALLICENCE 700 1- Watkinson John Department of Electrical Engineering, Center for Computational Biology and Bioinformatics, Columbia University, 1300 S.W. Mudd, 500 West 120th Street, 10027, New York, NY, USA aut NATIONALLICENCE 700 1- Anastassiou Dimitris Department of Electrical Engineering, Center for Computational Biology and Bioinformatics, Columbia University, 1300 S.W. Mudd, 500 West 120th Street, 10027, New York, NY, USA aut NATIONALLICENCE 773 0- Human Genetics Springer-Verlag 129/2(2011-02-01), 161-176 0340-6717 129:2<161 2011 129 439 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer