3.1 Analysis and comparison of causal immune cells in different types of lymphoma
After conducting MR analysis and applying BH correction, we identified a series of distinct immune cell types that exhibited causal relationships with six lymphomas (Fig. 2A-F). Supplementary Table 1 provides detailed information on these specific immune cell types. Our findings demonstrated that Hodgkin lymphoma was causally associated with 11 immune cells, DLBCL with 19 immune cells, other and unspecified non-Hodgkin lymphomas with 19 immune cells, mature T/NK-cell lymphomas with 14 immune cells, non-follicular lymphoma with 18 immune cells, and follicular lymphoma with 15 immune cells. Moreover, both the MR-Egger truncation test and the MR-PRESSO global test effectively ruled out pleiotropy at the level of causal immune cell associations across different lymphomas. Sensitivity analyses further confirmed the robustness of our observed causal relationships. Comprehensive information can be found in Supplementary Table 2. The heterogeneity analysis revealed that the majority of results exhibited homogeneity, while those with heterogeneity demonstrated only mild levels (I2 < 25%). A small subset of findings displayed moderate heterogeneity (25%<I2<75%), and Significant heterogeneity was observed in a limited number of findings (mature T/NK-cell lymphomas: CD3 on CD4, I2 = 75.7%; non-follicular lymphoma: HLA DR on CD33dim HLA DR+ CD11b+, I2 = 75.7%, IgD on IgD+ CD38br, I2 = 76%), thus indicating the robustness of our analytical findings. Additionally, to investigate whether there existed a causal relationship between lymphomas and aforementioned immune cell types, we conducted inverse Mendelian randomization analysis as an extension to our study. The corresponding results are provided in Supplementary Table 3. Our analysis revealed a unidirectional association between these specific immune cell types and lymphoma rather than a bidirectional relationship.
3.2 Analysis and comparison of causal immune cells in different types of lymphoma
To further explore the causal relationship between immune cells and various subtypes of lymphoma at the genetic level, we conducted an architectural analysis and employed a Manhattan plot (Fig. 3A) to identify effector genes. Our findings exhibited significant correlations in Hodgkin's lymphoma between CD247, CMTM6, CD25, ENTPD1, MBL2, and CD40. In non-Hodgkin lymphoma, including unspecified types, FCGR2A, ENTPD1, LYZ, CIITA, and rs709589 were found to be significantly associated. Notably, LYZ displayed a pronounced association specifically with follicular lymphoma but was also observed in non-follicular lymphoma. Additionally, robust associations of CD247, HLADR-DQ, and CIITA were evident. Furthermore, in DLBCL cases, CD247, FCGR2A, LYZ, and CD40 demonstrated significant associations. In mature T/NK cell lymphomas, a significant association was observed between CD247 and ENTPD1. Figure 3B highlights the co-occurrence of immune cells that are causally linked to different types of lymphoma. A total of 28 immune cells were identified as being causally associated with two or more distinct lymphomas. Among these, 20 immune cells were associated with two lymphomas, seven immune cells were associated with three lymphomas, and notably, one immune cell was implicated in four lymphoma subtypes (including unspecified non-Hodgkin lymphoma, DLBCL, follicular lymphoma, and non-follicular lymphoma). Figure 3C further illustrates the specific directionality exhibited by these immune cells in relation to the six aforementioned lymphomas. Surprisingly, all immune cells exhibit consistent directional activity across the six different lymphomas, including CD28− CD25++ CD8br%CD8br, which is identified as a risk factor for the four lymphomas.
3.3 LDSC results causally associated with lymphoma
Furthermore, to delve deeper into the correlation between different immune cell populations and lymphoma, we conducted LDSC analysis. Detailed results can be found in the supplementary materials Table 4. Notably, the association of CD28−CD25++ CD8br%CD8br immune cells with all four lymphoma types is particularly noteworthy (p = 0.0343 with other and unspecified non-Hodgkin lymphoma, p = 0.0294 with follicular lymphoma, p = 0.0306 with non-follicular lymphoma, p = 0.0247 with DLBCL). This finding significantly strengthens the reliability of our previous Mendelian randomization (MR) results. Moreover, certain immune cell populations, such as CD8br%leukocyte and CD25 on secreting Treg cells, were observed to be associated with three types of lymphoma simultaneously.
3.4 Immune cell SMR results and LDSC results causally associated with lymphoma
The associations between immune cells from the lymphoid tissue that were causal for different lymphomas were obtained by SMR analysis (Fig. 4A). Through SMR analysis, we identified genes that exhibited a significant association with lymphoma-associated immune cells (PFDR < 0.05, PHIED > 0.05). Detailed genetic information can be found in supplementary materials Table 5. As showed in Fig. 4. we focused on immune cells (CD28−CD25++ CD8br%CD8br) that were causally associated with all four lymphomas, and found WARS2(betaSMR[SE]=-0.13[0.04], PSMR=8.37×10− 04, PFDR=0.026, PHEID=0.77, Fig. 4A), PTPN7(betaSMR[SE] = 0.19[0.05], PSMR=9.81×10− 04, PFDR=0.026, PHEID=0.69, Fig. 4B). Additionally, we have also identified associations between several genes (HLA-DRB5, TSPAN32, SLC25A11, MRPL28, L3MBTL2, etc.) and diverse immune cell populations, suggesting their potential involvement in the regulation of multiple immune cell types simultaneously.