The genomics of autoimmune disease in the era of genome-wide association studies and beyond

Abstract

Recent advances in the field of genetics have dramatically changed our understanding of autoimmune disease. Candidate gene and, more recently, genome-wide association (GWA) studies have led to an explosion in the number of loci and pathways known to contribute to autoimmune phenotypes. Since the 1970s, researchers have known that several alleles in the MHC region play a role in the pathogenesis of many autoimmune diseases. More recent work has identified numerous risk loci involving both the innate and adaptive immune responses. However, much remains to be learned about the heritability of autoimmune conditions. Most regions found through GWA scans have yet to isolate the association to the causal allele(s) responsible for conferring disease risk. A role for rare variants (allele frequencies of <1%) has begun to emerge. Future research will use next-generation sequencing (NGS) technology to comprehensively evaluate the human genome for risk variants. Whole-transcriptome sequencing is now possible, which will provide much more detailed gene expression data. The dramatic drop in the cost and time required to sequence the entire human genome will ultimately make it possible for this technology to be used as a clinical diagnostic tool.

Figure 1. Typical plot of linkage disequilibrium (LD) between variants found in the human genome

LD, or correlation, occurs in the genome when variants are inherited non-randomly as units called haplotype blocks. The degree of LD between variants is typically expressed as r² values within the diamonds of the plot above where SNPs 1 and 2 have an r²=0.2 and SNPs 5 and 6 have an r²=0.99. The shading of each diamond is also proportional to the r2 value ranging from white (r²=0) to black (r²=1.0)

Figure 2. Karyogram of human autosomes depicting loci associated with autoimmune disease

This figure presents select gene/locus associations published since the beginning of the GWAS era for seven autoimmune diseases (AIDs). Genes presented within this figure either exceeded the manuscript’s criteria for significance or surpassed genome-wide significance (typically p < 5 × 10⁻⁸). Colored dots next to a gene/locus indicate an association with the corresponding AID at that chromosomal location. Regions with asterisks indicate the presence of multiple loci and Table 1 should be consulted to identify the candidate genes suggested by the authors. Some loci lie in close proximity to one another and as a result share the same chromosomal marker even though they represent distinct variants. Note the omission of the MHC region and the sex chromosomes. Like many autoimmune diseases, all seven AIDs presented here have strong associations with the MHC. In our literature search, only two associations were found on chromosome X: (rs2664170, Barrett et al.) with T1D and the association at Xq28 region containing the MECP2/IRAK1 loci with SLE (Webb et al. and Jacob et al.). CD and UC together are commonly referred to as inflammatory bowel disease (IBD); however, some studies perform meta-analysis combining CD and UC results to make an overall IBD combined p-value.