Zhang Jingjing, Yan Yuqing, Han Liqin, Qiao Rui, Niu Xiaohui, Li Peiluan
School of Mathematics and Statistics, Henan University of Science and Technology, No. 263 Kaiyuan Avenue, Luolong District, Luoyang, Henan 471000, China.
Longmen Laboratory, Henan University of Science and Technology, No. 263 Kaiyuan Avenue, Luolong District, Luoyang, Henan 471003, China.
Brief Funct Genomics. 2025 Jan 15;24. doi: 10.1093/bfgp/elaf013.
Comorbidities and genetic correlations between gastrointestinal tract diseases and psychiatric disorders have been widely reported, but the underlying intrinsic link between Alzheimer's disease (AD) and inflammatory bowel disease (IBD) is not adequately understood.
To identify pathogenic cell types of AD and IBD and explore their shared genetic architecture, we developed Pathogenic Cell types and shared Genetic Loci (PCGL) framework, which studied AD and IBD and its two subtypes of ulcerative colitis (UC) and Crohn's disease (CD).
We found that monocytes and CD8 T cells were the enriched pathogenic cell types of AD and IBDs, respectively. By PCGL framework, there was a significant global genetic correlation between AD and each of IBD, UC, and CD. Especially, local genetic correlations between AD and IBD showed strong signals in chr6. Bidirectional two-sample MR Analyses also validated these. Cross-trait meta-analysis identified two key genetic loci rs660895 (on chr6) and rs917117 (on chr7), which have not been previously reported. Two loci are located on the genes HLA-DRB1 and JAZF1, respectively. MAGMA genome-wide gene-based analysis identified six overlapping genes including HLA-DRB1. Subsequently, for one thing, SMR analyses further validated six shared genes in specific tissues and monocytes. For another, pathway enrichment analysis revealed shared genes were enriched in several natural killer cell mediated cytotoxicity and chemokine signaling pathways.
PCGL not only revealed the significant genetic correlations underlying AD and IBDs but also identified enriched pathogenic cell types and new shared loci and genes. We highlighted the mediation of HLA-DRB1 effects in the comorbidity mechanisms.
胃肠道疾病与精神障碍之间的共病情况及遗传相关性已有广泛报道，但阿尔茨海默病（AD）与炎症性肠病（IBD）之间潜在的内在联系尚未得到充分理解。
为了确定AD和IBD的致病细胞类型并探索它们共同的遗传结构，我们开发了致病细胞类型和共享遗传位点（PCGL）框架，该框架研究了AD和IBD及其两个亚型溃疡性结肠炎（UC）和克罗恩病（CD）。
我们发现单核细胞和CD8 T细胞分别是AD和IBD的富集致病细胞类型。通过PCGL框架，AD与IBD、UC和CD中的每一种之间都存在显著的全局遗传相关性。特别是，AD和IBD之间的局部遗传相关性在6号染色体上显示出强烈信号。双向两样本孟德尔随机化分析也验证了这些结果。跨性状荟萃分析确定了两个关键遗传位点rs660895（位于6号染色体上）和rs917117（位于7号染色体上），这两个位点此前尚未被报道。这两个位点分别位于基因HLA - DRB1和JAZF1上。MAGMA全基因组基于基因的分析确定了六个重叠基因，包括HLA - DRB1。随后，一方面，SMR分析进一步在特定组织和单核细胞中验证了六个共享基因。另一方面，通路富集分析表明共享基因在几种自然杀伤细胞介导的细胞毒性和趋化因子信号通路中富集。
PCGL不仅揭示了AD和IBD潜在的显著遗传相关性，还确定了富集的致病细胞类型以及新的共享位点和基因。我们强调了HLA - DRB1效应在共病机制中的介导作用。
