Download Fine-mapping the MHC region in autoimmune diseases

Fine-mapping the MHC region in autoimmune diseases
Soumya Raychaudhuri MD/PhD
Associate Professor of Medicine and Biomedical Informatics, Harvard Medical School
Associate Member, Broad Institute
Professor in Genetics, University of Manchester
The major histocompatibility complex is the single locus that explains more disease risk than
all other loci combined for a large number of autoimmune diseases, include psoriasis, type I
diabetes, rheumatoid arthritis, and ankylosing spondylitis. Here we describe efforts to finemap the MHC locus in a range of these different diseases. For these efforts we have been
using HLA imputation based on a panel of over 5,000 HLA typed individuals to infer HLA
genotypes into large pre-existing genome-wide association (GWAS) data sets. We describe
how we identified the individual amino acid positions for rheumatoid arthritis, type I diabetes,
and other diseases that drive autoimmune disease risk. Most of these individual positions are
within the binding groove and interact directly with antigens that may be triggering disease
risk. We focus specifically on DRB1 position 13, which drives risk of multiple diseases. Next
we demonstrate how HLA alleles interact with each other in a non-additive fashion to confer
unexpectedly high or low risk of disease. Finally, we will go onto describe efforts to finemap disease alleles in other loci outside of the MHC, where power is more limited, using
complementary approaches integrating functional genomic data with genetic data.