ObjectiveAn 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.MethodsWe performed cross‐phenotype GWAS meta‐analysis and Bayesian colocalization analysis for SSc and PBC. We performed both genome‐wide and locus‐based analysis, including tissue and pathway enrichment analyses, fine‐mapping, Bayesian 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.ResultsWe detected a strong genetic correlation between SSc and PBC (rg = 0.84, p = 1.7 x 10‐6). In the cross‐phenotype GWAS meta‐analysis, we identified 44 non‐HLA loci that reached genome‐wide significance (p < 5 x 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.ConclusionOur 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.

中文翻译：

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跨表型全基因组关联研究支持对系统性硬化症和原发性胆汁性胆管炎的共同遗传易感性


目的据报道，系统性硬化症 （SSc） 患者发生原发性胆汁性胆管炎 （PBC） 的风险增加。我们的研究旨在调查两种疾病之间共有的遗传易感性，并使用跨表型 GWAS 荟萃分析定义候选致病基因。方法我们对 SSc 和 PBC 进行了跨表型 GWAS meta 分析和贝叶斯共定位分析。我们进行了全基因组和基于基因座的分析，包括组织和通路富集分析、精细定位、与表达数量性状位点 （eQTL） 和蛋白质数量性状位点 （pQTL） 数据集的贝叶斯共定位分析，以及表型组范围关联研究 （PheWAS）。最后，我们使用综合方法从新基因座中确定候选致病基因的优先级。结果我们检测到 SSc 和 PBC 之间存在很强的遗传相关性 （rg = 0.84，p = 1.7 x 10-6）。在交叉表型 GWAS meta 分析中，我们确定了 44 个达到全基因组意义的非 HLA 基因座 （p < 5 x 10-8）。发现 9 个位点存在 SSc 和 PBC 之间共同因果变异的证据，其中 5 个是新的。整合多个证据来源，我们将 CD40 、 ERAP1 、 PLD4 、 SPPL3 和 CCDC113 作为新的候选致病基因。CD40 风险位点与参与 B 细胞功能的多种血浆蛋白的反式 pQTL 共定位。结论本研究支持 SSc 和 PBC 之间存在很强的共同遗传易感性。通过交叉表型分析，我们优先考虑了这些疾病的几个新的候选致病基因和通路。