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Refined mapping of autoimmune disease associated genetic variants with gene expression suggests an important role for non-coding RNAs

View Article: PubMed Central - PubMed

ABSTRACT

Genome-wide association and fine-mapping studies in 14 autoimmune diseases (AID) have implicated more than 250 loci in one or more of these diseases. As more than 90% of AID-associated SNPs are intergenic or intronic, pinpointing the causal genes is challenging. We performed a systematic analysis to link 460 SNPs that are associated with 14 AID to causal genes using transcriptomic data from 629 blood samples. We were able to link 71 (39%) of the AID-SNPs to two or more nearby genes, providing evidence that for part of the AID loci multiple causal genes exist. While 54 of the AID loci are shared by one or more AID, 17% of them do not share candidate causal genes. In addition to finding novel genes such as ULK3, we also implicate novel disease mechanisms and pathways like autophagy in celiac disease pathogenesis. Furthermore, 42 of the AID SNPs specifically affected the expression of 53 non-coding RNA genes. To further understand how the non-coding genome contributes to AID, the SNPs were linked to functional regulatory elements, which suggest a model where AID genes are regulated by network of chromatin looping/non-coding RNAs interactions. The looping model also explains how a causal candidate gene is not necessarily the gene closest to the AID SNP, which was the case in nearly 50% of cases.

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Examples of long non-coding RNAs as candidate causal genes for AIDs. (A) The locus on chromosome 2q32.3 is associated to AD (rs12615545) and CeD (rs1018326), and both SNPs are in strong LD (r2 = 0.96, D′ = 1). The CeD-associated risk allele, rs1018326*C is associated with higher levels of expression of the AC104820.2 lncRNA (similar results were observed for AD risk allele at rs12615545). The function prediction based on co-expression (GO biological processes) suggested this lncRNA is involved in alpha-beta T-cell proliferation. The right-hand panel shows the expression pattern for AC1048202 lncRNA across seven different immune cell types (obtained from two individuals and the average expression levels are shown), which indicates its strong expression in CD8+ T-cells. (B) The locus on chromosome 11q23.3 is associated to CeD (rs10892258), MS (rs533646) and RA (rs10790268). The MS-associated risk allele rs533646*G is associated with lower levels of expression of the AP002954.4 lncRNA (eQTL P = 6.41 × 10−80; similar results were also observed for the CeD and RA risk alleles). The expression patterns across seven cell types were obtained from two individuals and the average expression levels are shown as a heatmap, which confirms the strong expression of AP002954.4 in monocytes. The function prediction based on co-expression (GO biological processes) was obtained from the RNA network (http://genenetwork.nl/)7.
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Figure 4: Examples of long non-coding RNAs as candidate causal genes for AIDs. (A) The locus on chromosome 2q32.3 is associated to AD (rs12615545) and CeD (rs1018326), and both SNPs are in strong LD (r2 = 0.96, D′ = 1). The CeD-associated risk allele, rs1018326*C is associated with higher levels of expression of the AC104820.2 lncRNA (similar results were observed for AD risk allele at rs12615545). The function prediction based on co-expression (GO biological processes) suggested this lncRNA is involved in alpha-beta T-cell proliferation. The right-hand panel shows the expression pattern for AC1048202 lncRNA across seven different immune cell types (obtained from two individuals and the average expression levels are shown), which indicates its strong expression in CD8+ T-cells. (B) The locus on chromosome 11q23.3 is associated to CeD (rs10892258), MS (rs533646) and RA (rs10790268). The MS-associated risk allele rs533646*G is associated with lower levels of expression of the AP002954.4 lncRNA (eQTL P = 6.41 × 10−80; similar results were also observed for the CeD and RA risk alleles). The expression patterns across seven cell types were obtained from two individuals and the average expression levels are shown as a heatmap, which confirms the strong expression of AP002954.4 in monocytes. The function prediction based on co-expression (GO biological processes) was obtained from the RNA network (http://genenetwork.nl/)7.

Mentions: Our study identified 27 ncRNAs at 25 AID-loci as candidate causal genes as these were the only affected transcripts in PBMCs (Table 1). Although previous microarray-based eQTL studies suggested UBE2E3 as the causal gene at 2q31.3, a locus associated with CeD and AS [35], our analysis indicates that the AS (rs12615545)-and CeD (rs1018326)-associated SNPs are not in LD with the eQTL SNP that affects UBE2E3 expression (r2 = 0.16). Instead, both the AD and CeD index SNPs (r2 = 0.94) affect the expression of long non-coding RNA (lncRNA) AC104820.2 (P = 9.22 × 10−8). AC104820.2 is strongly expressed in CD8+ T-cells (Fig. 4A) and is suggested to function in alpha-beta T-cell proliferation (P = 4.1 × 10−6), which is a crucial process in autoimmunity [38]. AC104820.2 was also found to be up-regulated in intestinal biopsies of patients with active CeD [39]. Another example is lncRNA AP002954.4 at 11q23.3, whose expression was significantly affected by three unrelated SNPs associated to three different AIDs (MS, RA and CeD). AP002954.4 is expressed specifically in monocytes and may function in regulating cytokine responses (P = 5.95 × 10−6) and defence against fungal infection (P = 3.79 × 10−5) (Fig. 4B). Indeed, the cytokine levels produced by fungus-stimulated, human PBMCs [27,28] were dependent on SNP rs533646, with the risk allele G causing higher IL-6 and TNF-alpha levels (Supplemental Fig. 3). Both examples highlight the potential functional role of lncRNAs in AID.


Refined mapping of autoimmune disease associated genetic variants with gene expression suggests an important role for non-coding RNAs
Examples of long non-coding RNAs as candidate causal genes for AIDs. (A) The locus on chromosome 2q32.3 is associated to AD (rs12615545) and CeD (rs1018326), and both SNPs are in strong LD (r2 = 0.96, D′ = 1). The CeD-associated risk allele, rs1018326*C is associated with higher levels of expression of the AC104820.2 lncRNA (similar results were observed for AD risk allele at rs12615545). The function prediction based on co-expression (GO biological processes) suggested this lncRNA is involved in alpha-beta T-cell proliferation. The right-hand panel shows the expression pattern for AC1048202 lncRNA across seven different immune cell types (obtained from two individuals and the average expression levels are shown), which indicates its strong expression in CD8+ T-cells. (B) The locus on chromosome 11q23.3 is associated to CeD (rs10892258), MS (rs533646) and RA (rs10790268). The MS-associated risk allele rs533646*G is associated with lower levels of expression of the AP002954.4 lncRNA (eQTL P = 6.41 × 10−80; similar results were also observed for the CeD and RA risk alleles). The expression patterns across seven cell types were obtained from two individuals and the average expression levels are shown as a heatmap, which confirms the strong expression of AP002954.4 in monocytes. The function prediction based on co-expression (GO biological processes) was obtained from the RNA network (http://genenetwork.nl/)7.
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Related In: Results  -  Collection

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Figure 4: Examples of long non-coding RNAs as candidate causal genes for AIDs. (A) The locus on chromosome 2q32.3 is associated to AD (rs12615545) and CeD (rs1018326), and both SNPs are in strong LD (r2 = 0.96, D′ = 1). The CeD-associated risk allele, rs1018326*C is associated with higher levels of expression of the AC104820.2 lncRNA (similar results were observed for AD risk allele at rs12615545). The function prediction based on co-expression (GO biological processes) suggested this lncRNA is involved in alpha-beta T-cell proliferation. The right-hand panel shows the expression pattern for AC1048202 lncRNA across seven different immune cell types (obtained from two individuals and the average expression levels are shown), which indicates its strong expression in CD8+ T-cells. (B) The locus on chromosome 11q23.3 is associated to CeD (rs10892258), MS (rs533646) and RA (rs10790268). The MS-associated risk allele rs533646*G is associated with lower levels of expression of the AP002954.4 lncRNA (eQTL P = 6.41 × 10−80; similar results were also observed for the CeD and RA risk alleles). The expression patterns across seven cell types were obtained from two individuals and the average expression levels are shown as a heatmap, which confirms the strong expression of AP002954.4 in monocytes. The function prediction based on co-expression (GO biological processes) was obtained from the RNA network (http://genenetwork.nl/)7.
Mentions: Our study identified 27 ncRNAs at 25 AID-loci as candidate causal genes as these were the only affected transcripts in PBMCs (Table 1). Although previous microarray-based eQTL studies suggested UBE2E3 as the causal gene at 2q31.3, a locus associated with CeD and AS [35], our analysis indicates that the AS (rs12615545)-and CeD (rs1018326)-associated SNPs are not in LD with the eQTL SNP that affects UBE2E3 expression (r2 = 0.16). Instead, both the AD and CeD index SNPs (r2 = 0.94) affect the expression of long non-coding RNA (lncRNA) AC104820.2 (P = 9.22 × 10−8). AC104820.2 is strongly expressed in CD8+ T-cells (Fig. 4A) and is suggested to function in alpha-beta T-cell proliferation (P = 4.1 × 10−6), which is a crucial process in autoimmunity [38]. AC104820.2 was also found to be up-regulated in intestinal biopsies of patients with active CeD [39]. Another example is lncRNA AP002954.4 at 11q23.3, whose expression was significantly affected by three unrelated SNPs associated to three different AIDs (MS, RA and CeD). AP002954.4 is expressed specifically in monocytes and may function in regulating cytokine responses (P = 5.95 × 10−6) and defence against fungal infection (P = 3.79 × 10−5) (Fig. 4B). Indeed, the cytokine levels produced by fungus-stimulated, human PBMCs [27,28] were dependent on SNP rs533646, with the risk allele G causing higher IL-6 and TNF-alpha levels (Supplemental Fig. 3). Both examples highlight the potential functional role of lncRNAs in AID.

View Article: PubMed Central - PubMed

ABSTRACT

Genome-wide association and fine-mapping studies in 14 autoimmune diseases (AID) have implicated more than 250 loci in one or more of these diseases. As more than 90% of AID-associated SNPs are intergenic or intronic, pinpointing the causal genes is challenging. We performed a systematic analysis to link 460 SNPs that are associated with 14 AID to causal genes using transcriptomic data from 629 blood samples. We were able to link 71 (39%) of the AID-SNPs to two or more nearby genes, providing evidence that for part of the AID loci multiple causal genes exist. While 54 of the AID loci are shared by one or more AID, 17% of them do not share candidate causal genes. In addition to finding novel genes such as ULK3, we also implicate novel disease mechanisms and pathways like autophagy in celiac disease pathogenesis. Furthermore, 42 of the AID SNPs specifically affected the expression of 53 non-coding RNA genes. To further understand how the non-coding genome contributes to AID, the SNPs were linked to functional regulatory elements, which suggest a model where AID genes are regulated by network of chromatin looping/non-coding RNAs interactions. The looping model also explains how a causal candidate gene is not necessarily the gene closest to the AID SNP, which was the case in nearly 50% of cases.

No MeSH data available.


Related in: MedlinePlus