Genetics of Sjögren's syndrome in the genome-wide association era

Abstract

While Sjögren's syndrome (SS) is more common than related autoimmune disorders, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), scientific and medical research in SS has lagged behind significantly. This is especially true in the field of SS genetics, where efforts to date have relied heavily on candidate gene approaches. Within the last decade, the advent of the genome-wide association (GWA) scan has altered our understanding of disease pathogenesis in hundreds of disorders through the successful identification of novel risk loci. With strong evidence for a genetic component in SS as evidenced by familial aggregation of SS as well as similarities between SS and SLE and RA, the application of GWA approaches would likely yield numerous novel risk loci in SS. Here we review the fundamental scientific principles employed in GWA scans as well as the limitations of this tool, and we discuss the application of GWA scans in determining genetic variants at play in complex disease. We also examine the successful application of GWA scans in SLE, which now has more than 40 confirmed risk loci, and consider the possibility for a similar trajectory of SS genetic discovery in the era of GWA scans. Ultimately, the GWA studies that will be performed in SS have the potential to identify a myriad of novel genetic loci that will allow scientists to begin filling in the gaps in our understanding of the SS pathogenesis.

Figure 1.1. Number of genetics publications since 1970 for Sjögren’s syndrome and several autoimmune diseases

This figure illustrates the differences in the number of genetics publications generated since 1970 for a variety of autoimmune diseases. Data was generated by searching PubMed for the autoimmune disease and the term “genetics” (e.g. “rheumatoid arthritis [AND] genetics”), while restricting the publications to those written in English and published between January 1 and December 31 for the year in question. Note that Sjögren’s syndrome consistently has the fewest genetics publications per year when compared with several other well-studied autoimmune diseases.

Figure 1.2. Linkage disequilibrium (LD) between SNPs within the human genome

LD (or correlation) is present between variants within the genome where portions of sequence are inherited non-randomly as units, and is typically expressed as r² values. An example is shown with regions of strong LD and weak LD. Each diamond represents the r² values between any 2 SNPs with the shading of each diamond being proportional to the r² value (e.g. black is r² =1.0). In this example, the r² value between SNP1, SNP2, and SNP3 is r² =0.99. The r² between SNP8 and SNP9 is 0.05.

Figure 1.3. Power to detect association

This graph illustrates 3 different scenarios for studies with sample sizes of 100 cases-100 controls (blue line; majority of manuscripts published to date in SS), 1000 cases-1000 controls (green dashed line; most current GWA scans), and 5000 cases-5000 controls (gold dashed line; future GWA scans and some current meta-analysis between multiple GWA studies). Power to detect genetic association is a function of not only sample size, but also the allele frequency and the odds ratio (or increase in disease risk of an allele) of causal alleles can influence the ability to detect association.