Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a genetically complex autoimmune disease characterized by loss of immune tolerance to nuclear and cell surface antigens. Previous genome-wide association studies (GWAS) had modest sample sizes, reducing their scope and reliability. Our study comprised 7,219 cases and 15,991 controls of European ancestry, constituting a new GWAS, a meta-analysis with a published GWAS and a replication study. We have mapped 43 susceptibility loci, including ten new associations. Assisted by dense genome coverage, imputation provided evidence for missense variants underpinning associations in eight genes. Other likely causal genes were established by examining associated alleles for cis-acting eQTL effects in a range of ex vivo immune cells. We found an over-representation (n = 16) of transcription factors among SLE susceptibility genes. This finding supports the view that aberrantly regulated gene expression networks in multiple cell types in both the innate and adaptive immune response contribute to the risk of developing SLE.

Figure 1

Heat map for cis-acting gene expression RTC scores from ex vivo cells. The heat map includes all genes with evidence of cis-regulatory (+/– 1Mb) action by SLE associated SNPs in at least one cell type. The color represents a signed-RTC-score: a positive score indicates that the associated allele in the GWAS is positively correlated with gene expression; a negative score indicates that the associated allele in the GWAS is negatively correlated with gene expression. We set the RTC score to zero if the P-value for association was > 0.001. Colors represent the RTC-scores as follows: blue, RTC < –0.9 (GWAS risk allele reduces expression); green, RTC < –0.5 (GWAS risk allele reduces expression); yellow –0.5 < RTC < 0.5; orange, RTC > 0.5 (GWAS risk allele increases expression); red, RTC > 0.9 (GWAS risk allele increases expression). A white block indicates that data were not available for this cell type (see Supplementary Figure 4 for results on lymphoblastoid cell lines), either because the probe data failed QC or the probe was not present in the experiment platform. Clustering was performed on cell types, including only genes with data observed for all cell types (i.e., missing data did not inform cell clustering). Genes were clustered using all available data across cells (missing data were not included when determining distance between pairs of genes if eQTL results were not observed for one of the pairs).

Figure 2

Summary of functional role of likely causal genes in SLE and other autoimmune diseases. The concentric rings in the figure show several layers of evidence to support the functional annotation of likely causal genes for SLE listed in Table 2. The genes are illustrated clockwise in chromosomal order with the grey arcs delineating those loci for which several genes are implicated. Inner Ring 1 - the gene’s functional category, taken from Ingenuity Pathway Analysis; Middle Ring 2 - the presence of a cis-acting eQTL (Figure 1) and/or coding variant and Innermost Ring 3 - the number of autoimmune diseases (excluding SLE) in Immunobase - Type 1 diabetes (T1D), Celiac disease (CEL), Multiple Sclerosis (MS), Crohn’s Disease (CRO), Primary Billiary Cirrhosis (PBC), Psoriasis (PSO), Rheumatoid Arthritis (RA), Ulcerative Colitis (UC), Ankylosing Spondylitis (AS), Autoimmune Thyroid Disease (ATD), Juvenile Idiopathic Arthritis (JIA), Alopecia Areata (AA), Inflammatory Bowel Disease (IBD), Narcolepsy (NAR), Primary Sclerosing Cholangitis (PSC), Sjögren's Syndrome (SJO), Systemic Scleroderma (SSc), Vitiligo (VIT) - previously reported to be associated with the gene.