Identification of T1D susceptibility genes within the MHC region by combining protein interaction networks and SNP genotyping data.
OBJECTIVE
To develop novel methods for identifying new genes that contribute to the risk of developing type 1 diabetes within the Major Histocompatibility Complex (MHC) region on chromosome 6, independently of the known linkage disequilibrium (LD) between human leucocyte antigen (HLA)-DRB1, -DQA1, -DQB1 genes.


METHODS
We have developed a novel method that combines single nucleotide polymorphism (SNP) genotyping data with protein-protein interaction (ppi) networks to identify disease-associated network modules enriched for proteins encoded from the MHC region. Approximately 2500 SNPs located in the 4 Mb MHC region were analysed in 1000 affected offspring trios generated by the Type 1 Diabetes Genetics Consortium (T1DGC). The most associated SNP in each gene was chosen and genes were mapped to ppi networks for identification of interaction partners. The association testing and resulting interacting protein modules were statistically evaluated using permutation.


RESULTS
A total of 151 genes could be mapped to nodes within the protein interaction network and their interaction partners were identified. Five protein interaction modules reached statistical significance using this approach. The identified proteins are well known in the pathogenesis of T1D, but the modules also contain additional candidates that have been implicated in beta-cell development and diabetic complications.


CONCLUSIONS
The extensive LD within the MHC region makes it important to develop new methods for analysing genotyping data for identification of additional risk genes for T1D. Combining genetic data with knowledge about functional pathways provides new insight into mechanisms underlying T1D.
Brorsson
C
C
Steno Diabetes Center, Gentofte, Denmark.
Hansen
N T
NT
Lage
K
K
Bergholdt
R
R
Brunak
S
S
Pociot
F
F
D001053:Apolipoproteins / Q000235:genetics; D000075243:Apolipoproteins M; D015704:CD4 Antigens / Q000235:genetics; D002135:Calcium-Binding Proteins; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics*; D024243:HMGB1 Protein / Q000235:genetics; D006801:Humans; D054834:Lipocalins; D008285:Major Histocompatibility Complex / Q000235:genetics*; D008840:Microfilament Proteins; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D025941:Protein Interaction Mapping; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics
C112986:AIF1 protein, human; C400523:APOM protein, human; D001053:Apolipoproteins; D000075243:Apolipoproteins M; D015704:CD4 Antigens; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D006680:HLA Antigens; D024243:HMGB1 Protein; D054834:Lipocalins; D008840:Microfilament Proteins; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic