title: Conditional meta-analysis stratifying on detailed HLA genotypes identifies a novel type 1 diabetes locus around TCF19 in the MHC.
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.
authors.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.
authors.forename: Yee Him
authors.initials: YH
authors.lastname: Cheung
authors.forename: John
authors.initials: J
authors.lastname: Watkinson
authors.forename: Dimitris
authors.initials: D
authors.lastname: Anastassiou
mesh_terms: D016022:Case-Control Studies; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D050814:Octamer Transcription Factor-3 / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C412616:CCHCR1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; C484393:PSORS1C1 protein, human; D011506:Proteins; C098583:TCF19 protein, human; D014157:Transcription Factors