High-density genotyping of immune-related loci identifies new SLE risk variants in individuals with Asian ancestry

Abstract

Systemic lupus erythematosus (SLE) has a strong but incompletely understood genetic architecture. We conducted an association study with replication in 4,492 SLE cases and 12,675 controls from six East-Asian cohorts, to identify novel and better localize known SLE susceptibility loci. We identified 10 novel loci as well as 20 known loci with genome-wide significance. Among the novel loci, the most significant was GTF2IRD1-GTF2I at 7q11.23 (rs73366469, Pmeta=3.75×10−117, OR=2.38), followed by DEF6, IL12B, TCF7, TERT, CD226, PCNXL3, RASGRP1, SYNGR1 and SIGLEC6. We localized the most likely functional variants for each locus by analyzing epigenetic marks and gene regulation data. Ten putative variants are known to alter cis- or trans-gene expression. Enrichment analysis highlights the importance of these loci in B- and T-cell biology. Together with previously known loci, the explained heritability of SLE increases to 24%. Novel loci share functional and ontological characteristics with previously reported loci, and are possible drug targets for SLE therapeutics.

Confirmation of five novel susceptibility loci for Systemic Lupus Erythematosus (SLE) and integrated network analysis of 82 SLE susceptibility loci

“…We recently reported ten novel loci associated with SLE susceptibility in individuals of Korean, Han Chinese, Japanese and Malaysian Chinese descent (2). Additionally, we uncovered several novel loci that either fell just below genome-wide significance (P < 5Â10 À8 ) or were not independently replicated.…”

“…In summary, the five replicated loci have functional involvement in transcription and gene expression, particularly in B-and T-cells. We also investigated whether these loci were pleiotropic, as is the case with many other autoimmune disease (AD)-related loci (2). MYNN, CCL22 and ATG16L2 have previous reported association with AD.…”

“…Disease severity, morbidity and mortality are highest in individuals of non-European descent (1). To date, more than ten genome-wide association studies (GWAS) and historical candidate gene studies have identified diverse risk loci (2)(3)(4). However, these SLE candidate genes taken together are insufficient to explain the entire heritability of SLE.…”

“…Our approach used a logistic regression model choosing the strongest associated SNP as an iterative process starting with the strongest SNP and adding additional SNPs to the model until no more variants passed the P < 5Â10 À5 threshold of significance (2).…”

“…However, these SLE candidate genes taken together are insufficient to explain the entire heritability of SLE. We recently determined that an aggregate of 47 SLE risk loci explain only $24% of SLE heritability (2). Thus, many more SLE loci and genetic variants are yet to be discovered.…”