Data_Sheet_1_Exploring the causal relationship between gut microbiota and multiple myeloma risk based on Mendelian randomization and biological annotation.PDF

IntroductionThe microbial genome-wide association studies (mbGWAS) have highlighted significant host-microbiome interactions based on microbiome heritability. However, establishing causal relationships between particular microbiota and multiple myeloma (MM) remains challenging due to limited sample sizes.MethodsGut microbiota data from a GWAS with 18,340 participants and MM summary statistics from 456,348 individuals. The inverse variance-weighted (IVW) method was used as the main bidirectional Mendelian randomization (MR) analysis. To assess the robustness of our results, we further performed supplementary analyses, including MR pleiotropy residual sum and outlier (MR-PRESSO) test, MR-Egger, Weighted median, Simple mode, and Weighted mode. Moreover, a backward MR analysis was conducted to investigate the potential for reverse causation. Finally, gene and gene-set-based analyses were then conducted to explore the common biological factors connecting gut microbiota and MM.ResultsWe discovered that 10 gut microbial taxa were causally related to MM risk. Among them, family Acidaminococcaceae, Bacteroidales family S24-7, family Porphyromonadaceae, genus Eubacterium ruminantium group, genus Parabacteroides, and genus Turicibacter were positively correlated with MM. Conversely, class Verrucomicrobia, family Verrucomicrobiaceae, genus Akkermansia, and order Verrucomicrobiales were negatively correlated with MM. The heterogeneity test revealed no Heterogeneity. MR-Egger and MR-PRESSO tests showed no significant horizontal pleiotropy. Importantly, leave-one-out analysis confirmed the robustness of MR results. In the backward MR analysis, no statistically significant associations were discovered between MM and 10 gut microbiota taxa. Lastly, we identified novel host-microbiome shared genes (AUTS2, CDK2, ERBB3, IKZF4, PMEL, SUOX, and RAB5B) that are associated with immunoregulation and prognosis in MM through biological annotation.DiscussionOverall, this study provides evidence supporting a potential causal relationship between gut microbiota and MM risk, while also revealing novel host-microbiome shared genes relevant to MM immunoregulation and clinical prognosis.

引言：基于微生物组可遗传性的微生物基因组广谱关联研究（mbGWAS）突显了宿主-微生物组之间的重要相互作用。然而，由于样本量有限，确定特定微生物群与多发性骨髓瘤（MM）之间的因果关系仍然颇具挑战。方法：本研究收集了来自一项包含18,340名参与者的GWAS的肠道微生物组数据以及来自456,348个人的MM汇总统计数据。主要采用逆方差加权（IVW）方法作为双向孟德尔随机化（MR）分析。为了评估结果的稳健性，我们还进行了补充分析，包括MR多效性残差和离群值（MR-PRESSO）测试、MR-Egger、加权中位数、简单模式和加权模式。此外，还进行了逆向MR分析，以探究反向因果关系的可能性。最后，通过基因和基因集分析，探索连接肠道微生物组与MM的共同生物学因素。结果：我们发现10种肠道微生物类群与MM风险存在因果关系。其中，酸氨酸球菌科、拟杆菌目S24-7科、梭杆菌科、瘤胃真杆菌属、拟杆菌属和土里克菌属与MM呈正相关。相反，疣微菌门、疣微菌科、阿克曼氏菌属和疣微菌目与MM呈负相关。异质性测试未发现异质性。MR-Egger和MR-PRESSO测试未显示显著的横向多效性。重要的是，留一法分析证实了MR结果的稳健性。在逆向MR分析中，未发现MM与10种肠道微生物类群之间存在统计学上的显著关联。最后，我们通过生物注释确定了与MM免疫调节和临床预后相关的新的宿主-微生物组共享基因（AUTS2、CDK2、ERBB3、IKZF4、PMEL、SUOX和RAB5B）。讨论：总体而言，本研究提供了支持肠道微生物组与MM风险之间潜在因果关系的证据，同时揭示了与MM免疫调节和临床预后相关的新的宿主-微生物组共享基因。