Autoimmune diseases affect up to approximately 10% of the population. While rare Mendelian autoimmunity syndromes can result from monogenic mutations disrupting essential mechanisms of central and peripheral tolerance, more common human autoimmune diseases are complex disorders that arise from the interaction between polygenic risk factors and environmental factors. Although the risk attributable to most individual nucleotide variants is modest, genome-wide association studies (GWAS) have the potential to provide an unbiased view of biological pathways that drive human autoimmune diseases. Interpretation of GWAS requires integration of multiple genomic datasets including dense genotyping,
Alexander Marson, William J. Housley, David A. Hafler
Moving from GWAS loci to cellular pathways.
The causal SNPs that contribute to autoimmune disease risk are often inherited along with neighboring neutral SNPs as a result of linkage disequilibrium. The index SNPs that are genotyped and associated with disease risk in GWAS implicate genomic loci — linkage disequilibrium blocks — composed of multiple linked SNPs (gray boxes). GWAS loci associated with autoimmune disease are enriched in genes (rectangles) that are preferentially expressed in particular immune cell subsets (autoimmune disease cell signatures; bottom left) (