The Causal Relationship between Lipid Metabolites and Multiple Myeloma Risk: A Mendelian Randomization Study

Background:To understand a causal role of modifiable lifestyle factors in angiotensin-converting enzyme 2 (ACE2) expression (a putative severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] receptor) across 44 human tissues/organs, and in coronavirus disease 2019 (COVID-19) susceptibility and severity, we conducted a phenome-wide two-sample Mendelian randomization (MR) study.Methods:More than 500 genetic variants were used as instrumental variables to predict smoking and alcohol consumption. Inverse-variance weighted approach was adopted as the primary method to estimate a causal association, while MR-Egger regression, weighted median, and MR pleiotropy residual sum and outlier (MR-PRESSO) were performed to identify potential horizontal pleiotropy.Results:We found that genetically predicted smoking intensity significantly increased ACE2 expression in thyroid (β=1.468, p=1.8×10−8), and increased ACE2 expression in adipose, brain, colon, and liver with nominal significance. Additionally, genetically predicted smoking initiation significantly increased the risk of COVID-19 onset (odds ratio=1.14, p=8.7×10−5). No statistically significant result was observed for alcohol consumption.Conclusions:Our work demonstrates an important role of smoking, measured by both status and intensity, in the susceptibility to COVID-19.Funding:XJ is supported by research grants from the Swedish Research Council (VR-2018–02247) and Swedish Research Council for Health, Working Life and Welfare (FORTE-2020–00884).

Decision letter: Mendelian randomization analysis provides causality of smoking on the expression of ACE2, a putative SARS-CoV-2 receptor

BackgroundPrimary ovarian insufficiency (POI) is a common clinical endocrine disorder with a high heterogeneity in both endocrine hormones and etiological phenotypes. However, the etiology of POI remains unclear. Herein, we unraveled the causality of genetically determined metabolites (GDMs) on POI through Mendelian randomization (MR) study with the overarching goal of disclosing underlying mechanisms.MethodsGenetic links with 486 metabolites were retrieved from GWAS data of 7824 European participants as exposures, while GWAS data concerning POI were utilized as the outcome. Via MR analysis, we selected inverse-variance weighted (IVW) method for primary analysis and several additional MR methods (MR-Egger, weighted median, and MR-PRESSO) for sensitivity analyses. MR-Egger intercept and Cochran’s Q statistical analysis were conducted to assess potential heterogeneity and pleiotropy. In addition, genetic variations in the key target metabolite were scrutinized further. We conducted replication, meta-analysis, and linkage disequilibrium score regression (LDSC) to reinforce our findings. The MR Steiger test and reverse MR analysis were utilized to assess the robustness of genetic directionality. Furthermore, to deeply explore causality, we performed colocalization analysis and metabolic pathway analysis.ResultsVia IVW methods, our study identified 33 metabolites that might exert a causal effect on POI development. X-11437 showed a robustly significant relationship with POI in four MR analysis methods (PIVW=0.0119; Pweighted-median =0.0145; PMR-Egger =0.0499; PMR-PRESSO =0.0248). Among the identified metabolites, N-acetylalanine emerged as the most significant in the primary MR analysis using IVW method, reinforcing its pivotal status as a serum biomarker indicative of an elevated POI risk with the most notable P-value (PIVW=0.0007; PMR-PRESSO =0.0022). Multiple analyses were implemented to further demonstrate the reliability and stability of our deduction of causality. Reverse MR analysis did not provide evidence for the causal effects of POI on 33 metabolites. Colocalization analysis revealed that some causal associations between metabolites and POI might be driven by shared genetic variants.ConclusionBy incorporating genomics with metabolomics, this study sought to offer a comprehensive analysis in causal impact of serum metabolome phenotypes on risks of POI with implications for underlying mechanisms, disease screening and prevention.

Background: Multiple myeloma (MM) is a hematologic malignancy closely associated with diets and metabolic disorders, showing an increasing incidence trend. Genome-wide association studies (GWAS) contribute to exploring the causal relationships between diets, metabolites, and MM, thereby revealing biological mechanisms underlying cancer progression. Methods: This study included large-scale GWAS data for two diets, four metabolomics, and MM. The two-sample Mendelian randomization (MR) analysis was conducted to assess causalities between these dietary patterns, metabolites, and MM. The MR analysis primarily employed the inverse variance weighted (IVW) method, supported by multiple sensitivity analysis and reverse MR analysis to validate significant associations. Mediation analysis identified specific metabolites mediating the causal relationships between diets and MM. Results: Univariate MR analysis suggested that coffee consumption (ORIVW = 2.72; 95% CI: 1.21-6.10; PIVW = 0.015, P_fdr = 0.022), decaffeinated coffee consumption (ORIVW = 7.10; 95% CI: 1.33-37.87; PIVW = 0.022, P_fdr = 0.022), ground coffee consumption (ORIVW = 4.04; 95% CI: 1.25-13.02; PIVW = 0.019, P_fdr = 0.022), instant coffee consumption (ORIVW = 6.13; 95% CI: 1.95-19.34; PIVW = 0.002, P_fdr = 0.008), and coffee max liking (ORIVW = 2.94; 95% CI: 1.23-7.03; PIVW = 0.015, P_fdr = 0.035) were associated with increased MM risk. Metabolomic MR analysis identified 19 plasma metabolites, 1 blood and urine biomarker, and 4 plasma lipids with significant association with MM. Mediation analysis indicated that hippurate and cinnamoylglycine mediated 35.55% (P < 0.001) and 21.85% (P = 0.002) of the genetically predicted effect of coffee consumption on MM risk, respectively. Cinnamoylglycine contributed 12.63% (P = 0.042) to the total causal effect of ground coffee consumption on MM. Hippurate (21.43%, P < 0.001), 3-hydroxyhippurate (4.39%, P = 0.031), and cinnamoylglycine (8.79%, P = 0.010) mediated the genetically predicted impact of instant coffee consumption on MM risk. Metabolic pathway analysis suggested that glutathione metabolism significantly contributes to MM pathogenesis (P = 0.002, FDR < 0.05). Conclusions: Our findings support the adverse causal effects of various coffee consumption on MM risk, identifying hippurate, 3-hydroxyhippurate, and cinnamoylglycine as key mediators, driving the relationship potentially through the glutathione metabolism pathway.

Impact of serum calcium levels on total body bone mineral density: A mendelian randomization study in five age strata

Background: Previous observational studies have suggested a potential association between Epstein-Barr virus (EBV) infection and the development of multiple myeloma (MM), but this relationship is not clear. Therefore, we conducted a systematic Mendelian randomization (MR) analysis to investigate the causal relationship between EBV infection and the risk of MM, while exploring the possible mediating role of immune cells in this association. Methods: The study first conducted a two-sample MR analysis using the MM R11 dataset from the FinnGen Consortium to evaluate the causal relationship between five EBV infection-related antibodies (AEB-IgG, EA-D, EBNA-1, VCA-p18, and ZEBRA) and MM, with validation in the MM R10 dataset. A reverse MR analysis was then performed. For significant results, multivariable MR (MVMR) was used to adjust for the effects of confounding risk factors. Next, a two-step MR mediation analysis was applied to investigate the potential mediating role of 731 immune cell types between positive exposure and MM. Multiple sensitivity analyses were conducted to assess the robustness of the findings. Results: A two-sample MR study found that EBNA-1 antibodies (OR = 1.36, 95% CI: 1.06–1.73; P = 0.015) were associated with an increased risk of MM, with similar results observed in the FinnGen Consortium R10 replication study. Although the association did not remain statistically significant after false discovery rate (FDR) adjustment (P_fdr = 0.075), further adjustment for relevant confounders using multivariable MR (MVMR) demonstrated that EBNA-1 antibodies (OR = 1.33, 95% CI: 1.01–1.75; P = 0.041) were still significantly associated with an increased risk of MM. Reverse MR analysis indicated no causal effect of MM on EBV-related antibodies. A two-sample MR analysis involving 731 immune cell phenotypes identified 27 potential mediating cell types. Ultimately, two-step MR confirmed that HLA-DR on myeloid dendritic cells (HLA-DR⁺ mDC) serves as a mediating factor, with EBNA-1 antibodies downregulating HLA-DR⁺ mDC, thereby increasing MM risk. Multiple sensitivity analyses supported the robustness of these findings. Conclusion: The findings of this study suggest that EBNA-1 antibodies may increase the risk of MM by downregulating HLA-DR⁺ mDC. This indicates that chronic EBV infection may contribute to an elevated risk of MM. We hope these results provide new insights for future research on the prevention and treatment of MM.

Observational studies showed possible associations between systemic lupus erythematosus and multiple myeloma. However, whether there is a casual relationship between different types of autoimmune diseases (type 1 diabetes mellitus, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, multiple sclerosis, primary sclerosing cholangitis, primary biliary cirrhosis, and juvenile idiopathic arthritis) and multiple myeloma (MM) is not well known. We performed a two-sample Mendelian randomization (MR) study to estimate the casual relationship. Summary-level data of autoimmune diseases were gained from published genome-wide association studies while data of MM was obtained from UKBiobank. The Inverse-Variance Weighted (IVW) method was used as the primary analysis method to interpret the study results, with MR-Egger and weighted median as complementary methods of analysis. There is causal relationship between primary sclerosing cholangitis [OR = 1.00015, 95% CI 1.000048–1.000254, P = 0.004] and MM. Nevertheless, no similar causal relationship was found between the remaining seven autoimmune diseases and MM. Considering the important role of age at recruitment and body mass index (BMI) in MM, we excluded these relevant instrument variables, and similar results were obtained. The accuracy and robustness of these findings were confirmed by sensitivity tests. Overall, MR analysis suggests that genetic liability to primary sclerosing cholangitis could be causally related to the increasing risk of MM. This finding may serve as a guide for clinical attention to patients with autoimmune diseases and their early screening for MM.

Currently, the precise interplay between autoimmune thyroiditis, particularly Hashimoto thyroiditis, and thyroid cancer remains ambiguous. While certain observational studies suggest autoimmune thyroiditis (including Hashimoto thyroiditis) as a predisposing factor for thyroid cancer. Nevertheless, it is still uncertain whether autoimmune thyroiditis is independently associated with thyroid cancer. We employed Mendelian randomization (MR) study methodology, a genetic analysis approach, to evaluate the causal impact of autoimmune thyroiditis on the occurrence of thyroid cancer. We obtained and synthesized statistical data by utilizing public available genome-wide association studies (GWAS). Our study utilized GWAS summary statistics datasets associated with autoimmune thyroiditis (including Hashimoto thyroiditis) as the exposure data source and selected GWAS summary statistics datasets related to thyroid cancer as the outcome data source. Single nucleotide polymorphisms closely associated with autoimmune thyroiditis were chosen as instrumental variables. We conducted 2-sample MR analyses to elucidate the causal association between autoimmune thyroiditis and thyroid cancer. The inverse variance-weighted (IVW) method was employed as the primary methodology, supplemented by additional MR methods including MR-Egger regression, weighted median, simple mode, and weighted mode analyses, to bolster the robustness of our findings. The MR analysis conducted using the IVW method did not confirm a causal relationship between autoimmune thyroiditis and thyroid cancer (odds ratio [OR] = 0.8554, 95% confidence interval [CI]: 0.7193 to 1.0172, P = .0772; OR = 0.8477, 95% CI: 0.7159 to 1.0039, P = .0555; and OR = 1.1324, 95% CI: 0.9342 to 1.3725, P = .2052, from 3 eligible dataset analyses, respectively). Additionally, MR analysis did not observe a causal association between Hashimoto thyroiditis and thyroid cancer (OR = 1.0449, 95% CI: 0.9400 to 1.1615, P = .4155; and OR = 0.9897, 95% CI: 0.8174 to 1.1984, P = .9159, from 2 eligible dataset analyses, respectively). Consistency in results across alternative MR methods was observed. This study employing MR methodology indicates the absence of significant causal relationship between exposure to autoimmune thyroiditis (including Hashimoto thyroiditis) and thyroid cancer. Further validation through larger-scale studies with increased sample sizes is warranted in future investigations.

Background: Prospective cohort studies have shown a positive association between body mass index (BMI) and the risk of colorectal cancer (CRC). However, limitations inherent in traditional observational studies, such as reverse causality and residual confounding, might explain the association. To overcome these limitations, Mendelian randomization (MR) studies of the BMI-CRC association have been conducted in European and U.S. groups, but the association remains to be clarified in East Asians. Purpose: We performed MR analyses to investigate the causal association between BMI and CRC in Japanese populations. Methods: Our study design consisted of 4 steps. (1) Based on a previous Genome-Wide Association Study in Japanese populations, we selected 68 BMI-associated single nucleotide polymorphisms (SNPs), which explained about 2.0% of the BMI variance, as instruments. (2) We examined the associations between 68 SNPs and BMI among general Japanese populations in the Japanese Consortium of Genetic Epidemiology studies (N=36,253). (3) We performed a fixed-effect meta-analysis to investigate associations between 68 SNPs and CRC using individual-level data and publicly available summary-statistic data of Japanese populations (cases=7,473, controls=33,322). (4) Finally, we used the inverse-variance weighted (IVW) method to calculate MR estimates. Several sensitivity analyses were applied to assess robustness or horizontal pleiotropy using weighted median, weighted mode, MR-Egger regression, and MR-Pleiotropy Residual Sum and Outlier (PRESSO) methods. Results: In the main analysis using the IVW method, a one-unit increase in BMI was associated with an odds ratio of 1.12 (95% confidence interval [CI]: 1.06-1.20) for CRC. Sensitivity analyses consistently showed increased odds ratios for CRC per one-unit increase in BMI. The odds ratios for weighted median, weighted mode, and MR-Egger regression were 1.16 (95% CI: 1.06-1.27), 1.14 (95% CI: 1.05-1.24), and 1.10(95% CI: 0.98-1.23), respectively. The MR-Egger intercept P-value was 0.63. No outlier was detected using the MR-PRESSO method. Conclusions: Our MR analyses provide evidence that BMI is positively associated with CRC in Japanese populations. Our findings seem to suggest that MR estimates for the BMI-CRC association may be consistent across different ethnicities. Citation Format: Shiori Suzuki, Atsushi Goto, Masahiro Nakatochi, Akira Narita, Taiki Yamaji, Norie Sawada, Ryoko Katagiri, Tsuyoshi Hachiya, Yoichi Sutoh, Isao Oze, Yuriko Koyanagi, Yumiko Kasugai, Hidemi Ito, Hiroaki Ikezaki, Keitaro Tanaka, Takashi Tamura, Haruo Mikami, Toshiro Takezaki, Sadao Suzuki, Nagato Kuriyama, Kiyonori Kuriki, Yoshikuni Kita, Kokichi Arisawa, Kenji Takeuchi, Kozo Tanno, Atsushi Shimizu, Gen Tamiya, Atsushi Hozawa, Kengo Kinoshita, Kenji Wakai, Makoto Sasaki, Masayuki Yamamoto, Keitaro Matsuo, Shoichiro Tsugane, Motoki Iwasaki. Body mass index and colorectal cancer risk in Japanese populations: a Mendelian randomization study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3486.

Decision letter: Common genetic variations in telomere length genes and lung cancer: a Mendelian randomisation study and its novel application in lung tumour transcriptome

Editor's evaluation: Common genetic variations in telomere length genes and lung cancer: a Mendelian randomisation study and its novel application in lung tumour transcriptome

Genetic liability to acne is associated with increased risk of inflammatory bowel disease: A Mendelian randomization study

BackgroundAlthough previous observational studies have shown an association between venous thromboembolism (VTE) and atrial fibrillation (AF), the underlying causal relationship between them remains uncertain.Methods and resultsThis two-sample bidirectional Mendelian randomization (MR) analysis was performed to investigate the causal relationship between VTE and AF. The VTE dataset were obtained from FinnGen, including 9,176 cases and 209,616 controls. Meanwhile a genome-wide association study (GWAS) of 60,620 individuals with AF and 970,216 control subjects identified genetic variations associated with AF. The principal MR analytic approach used in this study is the inverse-variance weighting (IVW) method. Furthermore, we performed complementary MR analyses, including the MR-Egger, Weighted median (WM), and Weighted Mode. MR pleiotropy residual sum was applied to identify pleiotropy. The MR analysis showed suggestive causal associations between VTE and the risk of AF (p = 0.0245, OR [95%CI]: 1.027 [1.003, 1.051]). The reverse MR analysis found that genetic susceptibility to AF was not significantly associated with VTE, as determined by the IVW method (p = 0.7773). The robustness of these findings was corroborated through MR sensitivity analyses.ConclusionsThere is a unidirectional causal relationship between VTE and AF, meaning that VTE is a causal risk factor for AF, whereas no effect of AF on VTE was identified.

Objectives: Asthma contributes to a significant global disease burden. Coffee has been linked to a reduced risk of asthma in several epidemiological studies. However, conflicting findings create confusion regarding the role of coffee in asthma management. We executed a consolidated analysis in conjunction with a Mendelian randomization (MR) study with the aim of scrutinizing the potential correlation between coffee intake and the susceptibility to asthma development. Furthermore, we analyzed the dose-response relationship between coffee intake and the onset of asthma. Methods: In this meta-analysis, we searched online to identify studies involving coffee consumption on the risk of asthma. The primary outcome was the risk of asthma development. We used RevMan and R language to calculate the pooled results and create plots. A meta-package dosresmeta was used for dose-response analysis. In the MR analyses, we obtained data from public databases. MR studies were conducted using genome-wide association data for coffee intake. Independent genetic instrumental variants strongly associated with each exposure (P &lt; 5*10^-8) were considered as instruments. The inverse variance-weighted method was used in the primary analysis. Sensitivity analyses were also conducted. Results: We ultimately incorporated four publications into our meta-analysis. Our study encompassed 671,417 participants and elucidated a negative correlation between the intake of ground coffee and the incidence of asthma (pooled odds ratios [OR] = 0.86, 95% confidence interval [CI] = 0.82–0.91, I2 = 66.2%). A potential nonlinear relationship between coffee and asthma was discovered. A J-shaped dose-response association was found between ground coffee consumption and the risk of asthma development, with the lowest risk of asthma occurring at approximately 2–3 cups per day. In the MR study, the findings suggest a decrease in asthma risk associated with ground coffee consumption (OR = 0.982, 95% CI 0.972–0.992; P = 0.000). Sensitivity analyses revealed that the causality estimations were robust. Conclusion: A comprehensive analysis of epidemiological studies and an MR analysis indicate a correlation between coffee intake and a decreased risk of asthma. Furthermore, dose-response analysis of observational studies reveals that consuming an optimal amount of 2–3 cups of coffee every day is associated with the lowest risk of asthma, as opposed to abstaining from coffee or consuming more than four cups daily.

This study investigates the causal relationships between plasma metabolites, immune cell phenotypes, and diabetic foot ulcer (DFU). A Mendelian randomization (MR) study was conducted, which included 731 immune cell phenotypes, 1400 metabolites, and DFU. The primary analytical approach was the inverse variance-weighted method. Sensitivity analyses were performed to assess heterogeneity and pleiotropy, and MR analyses in the reverse direction were conducted to examine the possibility of reverse causation. In addition, a mediation analysis was performed to reveal how metabolites mediate the impact of immune cells on DFU. Through MR, reverse MR and sensitivity analysis, the casualty was found in 17 immune cell phenotypes and 18 metabolites. A total of 15 mediating relationships were identified through mediation analysis, including 9 metabolites and 10 immune cell phenotypes. Among them, the highest mediation proportion was citrulline levels mediating CD24+ CD27+ AC (absolute count, B cell panel) to DFU, with a proportion of 11.60%. In conclusion, the study identified causal relationships between 10 immune cell phenotypes mediated by 9 metabolites. These discoveries offered fresh perspectives on the processes behind DFU and laid the groundwork for subsequent studies to create specific treatments for DFU.