An epidemiological association between multiple sclerosis (MS) and inflammatory bowel disease (IBD) is well established, but whether this reflects a shared genetic aetiology, and whether consistent genetic relationships exist between MS and the two predominant IBD subtypes, ulcerative colitis (UC) and Crohn’s disease (CD), remains unclear. Here, we use large-scale genome-wide association study summary data to investigate the shared genetic architecture between MS and IBD overall and UC and CD independently. We find a significantly greater genetic correlation between MS and UC than between MS and CD, and identify three SNPs shared between MS and IBD (rs13428812), UC (rs116555563) and CD (rs13428812, rs9977672) in cross-trait meta-analyses. We find suggestive evidence for a causal effect of MS on UC and IBD using Mendelian randomization, but no or weak and inconsistent evidence for a causal effect of IBD or UC on MS. We observe largely consistent patterns of tissue-specific heritability enrichment for MS and IBDs in lung, spleen, whole blood and small intestine, and identify cell-type-specific enrichment for MS and IBDs in CD4⁺ T cells in lung and CD8⁺ cytotoxic T cells in lung and spleen. Our study sheds light on the biological basis of comorbidity between MS and IBD.

多发性硬化症 (MS) 和炎症性肠病 (IBD) 之间的流行病学关联已得到很好的证实，但这是否反映了共同的遗传病因，以及 MS 与两种主要 IBD 亚型、溃疡性结肠炎 (UC) 和克罗恩病 (CD) 尚不清楚。在这里，我们使用大规模的全基因组关联研究汇总数据来独立研究 MS 和 IBD 以及 UC 和 CD 之间的共享遗传结构。我们发现 MS 和 UC 之间的遗传相关性显着高于 MS 和 CD 之间的遗传相关性，并在跨性状荟萃分析中确定了 MS 和 IBD (rs13428812)、UC (rs116555563) 和 CD (rs13428812, rs9977672) 之间共享的三个 SNP。我们使用孟德尔随机化发现了 MS 对 UC 和 IBD 因果关系的暗示性证据，但没有证据表明 IBD 或 UC 对 MS 有因果关系，或者证据很弱且不一致。我们观察到肺、脾、全血和小肠中 MS 和 IBD 的组织特异性遗传富集模式基本一致，并确定了 CD4 中 MS 和 IBD 的细胞类型特异性富集⁺肺中的 T 细胞和 CD8 ⁺肺和脾中的细胞毒性 T 细胞。我们的研究阐明了 MS 和 IBD 共病的生物学基础。