Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus
By J. Bentham, D. Morris, D. C. Cunninghame Graham, C. Pinder, P. Tombleson, T. Behrens, Javier Martín, B. P. Fairfax, J. Knight, Lingyan Chen and 8 more. Nature Genetics, 2015
941 citations recorded by the source corpus.
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.
Subfields: Immunology, Rheumatology
View Paper: https://www.semanticscholar.org/paper/8476e61e3185333699e3b3a5a25b473286489387
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Citations in the corpus
- Genetic Drivers of Epigenetic and Transcriptional Variation in Human Immune Cells (2016, background): “First, genetic effects on gene expression have been shown to be often context-specific (Kundaje et al., 2015) and thus are better captured in studies probing multiple primary cell types or experimental conditions (Bentham et al., 2015; Fairfax et al., 2014; Naranbhai et al., 2015).”
- Personalized Immunomonitoring Uncovers Molecular Networks That Stratify Lupus Patients (2016, positive): “We detected SNPs previously associated with SLE among numerous members of the HLA cluster on chromo- some 6, as well as ITGAM, ITGAX, IRF5, TNPO3, and BANK1 with confirmatory significance (p 0.001) (Figure 6C) (Bentham et al., 2015).”
- Bayesian weighted Mendelian randomization for causal inference based on summary statistics (2018, background): “, 2016) Immune system disorder Systemic lupus erythematosus 23,210 (Bentham et al., 2015) Immune system disorder Type 1 diabetes 14,741 (Censin et al.”