Shared genetic architecture between autoimmune disorders and B-cell acute lymphoblastic leukemia: insights from large-scale genome-wide cross-trait analysis

Abstract

Background: To study the shared genetic structure between autoimmune diseases and B-cell acute lymphoblastic leukemia (B-ALL) and identify the shared risk loci and genes and genetic mechanisms involved.

Methods: Based on large-scale genome-wide association study (GWAS) summary-level data sets, we observed genetic overlaps between autoimmune diseases and B-ALL, and cross-trait pleiotropic analysis was performed to detect shared pleiotropic loci and genes. A series of functional annotation and tissue-specific analysis were performed to determine the influence of pleiotropic genes. The heritability enrichment analysis was used to detect crucial immune cells and tissues. Finally, bidirectional Mendelian randomization (MR) methods were utilized to investigate the casual associations.

Results: Our research highlighted shared genetic mechanisms between seven autoimmune disorders and B-ALL. A total of 73 pleiotropic loci were identified at the genome-wide significance level (P < 5 × 10^-8), 16 of which had strong evidence of colocalization. We demonstrated that several loci have been previously reported (e.g., 17q21) and discovered some novel loci (e.g., 10p12, 5p13). Further gene-level identified 194 unique pleiotropic genes, for example IKZF1, GATA3, IKZF3, GSDMB, and ORMDL3. Pathway analysis determined the key role of cellular response to cytokine stimulus, B cell activation, and JAK-STAT signaling pathways. SNP-level and gene-level tissue enrichment suggested that crucial role pleiotropic mechanisms involved in the spleen, whole blood, and EBV-transformed lymphocytes. Also, hyprcoloc and stratified LD score regression analyses revealed that B cells at different developmental stages may be involved in mechanisms shared between two different diseases. Finally, two-sample MR analysis determined causal effects of asthma and rheumatoid arthritis on B-ALL.

Conclusions: Our research proved shared genetic architecture between autoimmune disorders and B-ALL and shed light on the potential mechanism that might involve in.

Keywords: Autoimmune disease; B-cell acute lymphoblastic leukemia; Genetic overlap; Mendelian randomization.

Fig. 1

Study workflow

Fig. 2

The circular diagram presents pleiotropic loci and genes identified by PLACO among seven trait pairs. Note: Shared loci identified by colocalization analysis are highlighted in orange; shared genes identified by MAGMA analysis are highlighted in blue. B-ALL B-cell acute lymphoblastic leukemia, AOA adult-onset asthma, HT hypothyroidism, PBC primary biliary cirrhosis, IBD inflammatory bowel disease, CD Crohn’s disease, RA rheumatoid arthritis, MS multiple sclerosis

Fig. 3

Bar plot of MAGMA gene-set (A) and tissue-specific (B) analysis for genome-wide pleiotropic results. Note: The red dotted line represents the significance of 0.05 after multiple corrections, and the blue represents the significance of 0.05. B-ALL B-cell acute lymphoblastic leukemia, AOA adult-onset asthma, HT hypothyroidism, PBC primary biliary cirrhosis, IBD inflammatory bowel disease, CD Crohn’s disease, RA rheumatoid arthritis, MS multiple sclerosis

Fig. 4

Overview of pleiotropic genes (highlighted in all three signals) for the autoimmune disorders and B-ALL. Note: The signals represent hits of genes across different trait pairs. eQTL expression quantitative trait loci, SMR summary-based Mendelian randomization, AD autoimmune disorders, B-ALL B-cell acute lymphoblastic leukemia, AOA adult-onset asthma, HT hypothyroidism, PBC primary biliary cirrhosis, IBD inflammatory bowel disease, CD Crohn’s disease, RA rheumatoid arthritis, MS multiple sclerosis

Fig. 5

A Pathway enrichments for identified pleiotropic genes (KEGG, GO, Wiki pathways). B Cell-type enrichments for identified pleiotropic genes. C Immune signatures enrichments for identified pleiotropic genes. D Protein–protein interaction analysis based on identified pleiotropic genes

Fig. 6

A The forest plot shows causal associations between autoimmune disorders and B-ALL by using one-directional MR analysis. Note: Causal effects were estimated by using IVW method. B Forest plot shows causal effects of AOA and RA on B-ALL risk estimated by using different methods. C Scatter plot shows significant causal association between AOA and B-ALL risk. D Funnel plot shows significant causal association between AOA and B-ALL risk. E Scatter plot shows significant causal association between RA and B-ALL risk. F Funnel plot shows significant causal association between RA and B-ALL risk. Associations highlighted with red represent that associations were significant in more than three main MR methods