Chr
SNP
Best p value
OR
SNP position
PTPN22a
1
rs6679677
3.2 × 10−25
1.59
Intergenic
ATP8B2-IL6R
1
11265608
2.8 × 10−8
1.33
Intergenic
STAT4
2
Rs10174238
1.3 × 10−13
1.29
Intron
IL2-IL21
4
1479924
6.2 × 10−11
0.79
Intergenic
ANKRD55
5
71624119
4.4 × 10−11
0.78
Intron
ERAP2-LNPEP
5
27290
7.5 × 10−9
1.32
Intron
C5orf56-IRF1
5
4705862
1.0 × 10−8
0.84
Intergenic
HLA DQB1-DQA2a
6
rs7775055
3.1 × 10−174
6.01
Intergenic
IL2RA
10
7909519
8.0 × 10−10
0.72
Intron
FAS
10
7069750
2.9 × 10−8
1.18
Intron
SH2B3-ATXN2
12
3184504
2.6 × 10−9
1.20
Coding
ZFP36L1
14
12434551
1.6 × 10−8
0.77
Intergenic
PTPN2a
18
Rs2847293
1.4 × 10−12
1.31
Intergenic
TYK2
19
34536443
1.0 × 10−10
0.56
Coding
RUNX1
21
Rs9979383
1.1 × 10−8
0.78
Intergenic
UBE2L3
22
2266959
6.2 × 10−9
1.24
Intron
Il2RB
22
2284033
1.6 × 10−8
0.84
Intron
The cumulative data from genetic studies of rheumatic disease allow us to draw several conclusions. While some discovered that genetic associations of rheumatic diseases are very strong (e.g., HLA variants provide ~13 % of genetic risk in RA compared to ~4 % of the validated alleles outside the MHC), these remain the minority [37]. The risk alleles identified in genomic screens are common in the general population, have a modest effect on risk, and together explain only a small part of the variance in disease risk. Whereas the actual causal variants for most risk loci identified to date remain to be determined, some themes have emerged: most variants are located in intronic or intergenic regions, many risk loci and variants are associated with more than one autoimmune disease, and many genes are associated with discrete biological pathways [62]. Finally, it is clear that identifying the numerous risk factors for complex rheumatic diseases in general and pediatric rheumatic diseases in particular requires international collaboration to investigate large cohorts.
The Shared Genetics of Autoimmunity
Several studies have demonstrated that children with JIA have an increased prevalence of other autoimmune disorders including thyroiditis or celiac disease [63–66]. Furthermore, relatives of children with JIA have an increased prevalence of autoimmunity [7], and this is pronounced in maternal aunts and grandmothers compared to paternal aunts and grandmothers, demonstrating a parent of origin effect [67]. Familial clustering of autoimmunity is also observed in families of adults with RA or idiopathic inflammatory myopathies [68, 69]. Together, these observations suggest that clinically distinct autoimmune phenotypes share common genetic risk factors. Recent genomic studies have confirmed that many genetic variants predispose to multiple autoimmune phenotypes [45, 70, 71]. Emerging data indicate that while some genes confer a predisposition to autoimmunity in general, other disease specific genes and other factors including smoking or infections might influence susceptibility to individual autoimmune diseases. This is illustrated by the observations that mutations in PTPN22 and STAT4 appear to influence susceptibility to multiple autoimmune phenotypes, whereas NOD2 and ATG16L1 variants only seem to influence the risk of IBD. Similarly PADI4 variants are specific to RA, whereas ITGAM variants are specific to SLE [72]. Meta-analyses of genome-wide studies of clinically distinct autoimmune phenotypes will likely enhance our understanding of common pathways that will be targets for treatment across diseases.
Role of Whole-Exome Sequencing Studies
In spite of the success in identifying common variants predisposing to rheumatic diseases, a substantial proportion of heritability to rheumatic diseases is still unexplained. Rare disease-associated variants, in part, have been postulated to explain the missing heritability [28]. Current GWAS assays do not effectively capture low frequency and rare variants associated with disease. One common strategy to identify rare variants predisposing to phenotypes of interest is to catalog variants present in affected individuals, since it is anticipated that they will be enriched for such rare variants. Although sequencing costs are rapidly decreasing, sequencing the entire human genome on a large scale is still not cost effective. Hence investigations have focused on sequencing the entire coding exome in individuals and their families to identify disease-causing mutations. Thus, whole-exome sequencing has helped to identify causal variants in extremely early-onset cases of inflammatory bowel disease [73, 74]. In rheumatology, Belot et al. investigated three siblings with juvenile SLE from consanguineous kindred by whole-exome sequencing and identified a functional homozygous mutation in the PRKCD gene which resulted in reduced expression of a protein involved in deletion of autoreactive B cells [75]. These examples show that rare variants with large effects can predispose to complex traits, and it is possible to identify such variants using whole-exome sequencing. In the next decade, whole genome sequencing might complement our efforts to discover additional genomic variation underlying most phenotypes with substantial heritability.