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. 2017 Mar 15;26(6):1205-1216.
doi: 10.1093/hmg/ddx026.

Confirmation of five novel susceptibility loci for systemic lupus erythematosus (SLE) and integrated network analysis of 82 SLE susceptibility loci

Julio E Molineros  1 , Wanling Yang  2 , Xu-Jie Zhou  3 , Celi Sun  1 , Yukinori Okada  4   5 , Huoru Zhang  2 , Kek Heng Chua  6 , Yu-Lung Lau  2 , Yuta Kochi  7 , Akari Suzuki  7 , Kazuhiko Yamamoto  7   8 , Jianyang Ma  9 , So-Young Bang  10 , Hye-Soon Lee  10 , Kwangwoo Kim  11 , Sang-Cheol Bae  10 , Hong Zhang  3 , Nan Shen  9 , Loren L Looger  12 , Swapan K Nath  1
Affiliations

Confirmation of five novel susceptibility loci for systemic lupus erythematosus (SLE) and integrated network analysis of 82 SLE susceptibility loci

Julio E Molineros et al. Hum Mol Genet. .

Abstract

We recently identified ten novel SLE susceptibility loci in Asians and uncovered several additional suggestive loci requiring further validation. This study aimed to replicate five of these suggestive loci in a Han Chinese cohort from Hong Kong, followed by meta-analysis (11,656 cases and 23,968 controls) on previously reported Asian and European populations, and to perform bioinformatic analyses on all 82 reported SLE loci to identify shared regulatory signatures. We performed a battery of analyses for these five loci, as well as joint analyses on all 82 SLE loci. All five loci passed genome-wide significance: MYNN (rs10936599, Pmeta = 1.92 × 10-13, OR = 1.14), ATG16L2 (rs11235604, Pmeta = 8.87 × 10 -12, OR = 0.78), CCL22 (rs223881, Pmeta = 5.87 × 10-16, OR = 0.87), ANKS1A (rs2762340, Pmeta = 4.93 × 10-15, OR = 0.87) and RNASEH2C (rs1308020, Pmeta = 2.96 × 10-19, OR = 0.84) and co-located with annotated gene regulatory elements. The novel loci share genetic signatures with other reported SLE loci, including effects on gene expression, transcription factor binding, and epigenetic characteristics. Most (56%) of the correlated (r2 > 0.8) SNPs from the 82 SLE loci were implicated in differential expression (9.81 × 10-198 < P < 5 × 10-3) of cis-genes. Transcription factor binding sites for p53, MEF2A and E2F1 were significantly (P < 0.05) over-represented in SLE loci, consistent with apoptosis playing a critical role in SLE. Enrichment analysis revealed common pathways, gene ontology, protein domains, and cell type-specific expression. In summary, we provide evidence of five novel SLE susceptibility loci. Integrated bioinformatics using all 82 loci revealed that SLE susceptibility loci share many gene regulatory features, suggestive of conserved mechanisms of SLE etiopathogenesis.

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Figures

Figure 1
Figure 1
Meta-analysis of all studies for five novel loci. We carried out meta-analysis for our five novel loci on nine independent cohorts. P-values and odds ratios (ORs) are presented for each cohort, as well as heterogeneity statistics for each locus. *Sun et al. 2016; **this study; ***Morris et al. 2016; ****Bentham et al. 2016. (a) ATG16L2; (b) MYNN; (c)CCL22; (d)ANKS1A; (e) RNASEH2C.
Figure 1
Figure 1
Meta-analysis of all studies for five novel loci. We carried out meta-analysis for our five novel loci on nine independent cohorts. P-values and odds ratios (ORs) are presented for each cohort, as well as heterogeneity statistics for each locus. *Sun et al. 2016; **this study; ***Morris et al. 2016; ****Bentham et al. 2016. (a) ATG16L2; (b) MYNN; (c)CCL22; (d)ANKS1A; (e) RNASEH2C.
Figure 2
Figure 2
Variant set enrichment analysis of 76 transcription factors (TFs) in GM12878. (a) Number of SLE loci enriched in each TF (x-axis). (b) Enrichment score for each TF, boxplots for all permutations of enrichment analysis. Dots represent enrichment score for each TF. Empty circles represent all TFs that passed 5 × 10−8 enrichment P-value.
Figure 3
Figure 3
Cell-specific enrichment was carried out in SNPsea. Enrichment P-value is presented as –log10P, significantly enriched categories pass the multiple testing threshold (vertical line). Correlation between categories is presented to the left of each plot. (a) Gene ontology; (b) FANTOM5; (c) Gene Atlas; (d) ImmVar.
See this image and copyright information in PMC

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