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[Preprint]. 2024 Jul 3:2024.07.01.24309721.
doi: 10.1101/2024.07.01.24309721.

Cross-Phenotype GWAS Supports Shared Genetic Susceptibility to Systemic Sclerosis and Primary Biliary Cholangitis

Yiming Luo  1 , Atlas Khan  2 , Lili Liu  2 , Cue Hyunkyu Lee  3 , Gabriel J Perreault  4 , Sydney F Pomenti  4 , Pravitt Gourh  5 , Krzysztof Kiryluk  2 , Elana J Bernstein  1
Affiliations

Cross-Phenotype GWAS Supports Shared Genetic Susceptibility to Systemic Sclerosis and Primary Biliary Cholangitis

Yiming Luo et al. medRxiv. .

Update in

Abstract

Objective: An increased risk of primary biliary cholangitis (PBC) has been reported in patients with systemic sclerosis (SSc). Our study aims to investigate the shared genetic susceptibility between the two disorders and to define candidate causal genes using cross-phenotype GWAS meta-analysis.

Methods: We performed cross-phenotype GWAS meta-analysis and colocalization analysis for SSc and PBC. We performed both genome-wide and locus-based analysis, including tissue and pathway enrichment analyses, fine-mapping, colocalization analyses with expression quantitative trait loci (eQTL) and protein quantitative trait loci (pQTL) datasets, and phenome-wide association studies (PheWAS). Finally, we used an integrative approach to prioritize candidate causal genes from the novel loci.

Results: We detected a strong genetic correlation between SSc and PBC (rg = 0.84, p = 1.7 × 10-6). In the cross-phenotype GWAS meta-analysis, we identified 44 non-HLA loci that reached genome-wide significance (p < 5 × 10-8). Evidence of shared causal variants between SSc and PBC was found for nine loci, five of which were novel. Integrating multiple sources of evidence, we prioritized CD40, ERAP1, PLD4, SPPL3, and CCDC113 as novel candidate causal genes. The CD40 risk locus colocalized with trans-pQTLs of multiple plasma proteins involved in B cell function.

Conclusion: Our study supports a strong shared genetic susceptibility between SSc and PBC. Through cross-phenotype analyses, we have prioritized several novel candidate causal genes and pathways for these disorders.

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Figures

Figure 1
Figure 1
Flowchart for the overview of the study. We performed multiple cross-phenotype GWAS analyses to identify the shared genetic susceptibility between SSc and PBC. Additionally, we also performed a single-center retrospective chart review to evaluate the prevalence of PBC, including potentially undiagnosed cases, in patients with SSc. SSc: systemic sclerosis. PBC: primary biliary cholangitis. GWAS: genome-wide association studies. PLEIO: Pleiotropic Locus Exploration and Interpretation using Optimal test. eQTL: expression quantitative trait loci. PheWAS: phenome-wide association studies.
Figure 2
Figure 2
Pairwise genetic correlation in SSc, PBC, RA and SLE. We performed genetic correlation analyses using linkage disequilibrium score regression pairwise among SSc, PBC, RA and SLE. The effect estimates of genetic correlation between SSc and PBC, and between SSc and SLE, were both 0.84, higher than other pairwise estimates.
Figure 3
Figure 3
Manhattan plot of the cross-phenotype GWAS meta-analysis in SSc and PBC using the fixed-effect model. We performed a cross-phenotype GWAS meta-analysis in SSc and PBC using the fixed-effect model. We identified 44 significant genomic loci (p < 5 × 10−8). We found 9 loci that colocalized between SSc and PBC and did not show evidence of heterogeneity (indicated in red), among which five were novel (indicated with an asterisk). SNPs with evidence of heterogeneity (Phet < 0.05) were excluded.
Figure 4
Figure 4
Tissue and pathway enrichment analyses. a Tissue enrichment analysis using MAGMA prioritized tissues related to the immune system (spleen, whole blood and EBV-transformed lymphocytes), respiratory system (lung) and digestive system (terminal ileum). b Tissue enrichment analysis using DEPICT prioritized multiple tissues and cells related to the immune system, respiratory system and musculoskeletal system. c Significant enrichment of multiple immune-related pathways associated with SSc and PBC using MAGMA.
Figure 5
Figure 5
Colocalization analysis with expression quantitative trait loci (eQTL) in blood, skin, lung, liver and immune cells. Out of the nine loci that were significant in the fixed-model cross-phenotype meta-analysis, showed no evidence of heterogeneity, and colocalized between SSc and PBC, seven colocalized with expressed genes in at least one of the examined tissues.
Figure 6
Figure 6
Integrative prioritization of novel candidate causal genes We prioritized five novel candidate causal genes based on a priority score integrating nine criteria: CD40, ERAP1, PLD4, SPPL3 and CCDC113
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