We applied Mendelian randomization analyses to investigate the potential causality between blood minerals (calcium, magnesium, iron, copper, and zinc) and osteoporosis (OP), gout, rheumatoid arthritis (RA), type 2 diabetes (T2D), Alzheimer’s disease (AD), bipolar disorder (BD), schizophrenia, Parkinson’s disease and major depressive disorder. Single nucleotide polymorphisms (SNPs) that are independent (r² < 0.01) and are strongly related to minerals (p < 5 × 10⁻⁸) are selected as instrumental variables. Each standard deviation increase in magnesium (0.16 mmol/L) is associated with an 8.94-fold increase in the risk of RA (p = 0.044) and an 8.78-fold increase in BD (p = 0.040) but a 0.10 g/cm² increase in bone density related to OP (p = 0.014). Each per-unit increase in copper is associated with a 0.87-fold increase in the risk of AD (p = 0.050) and BD (p = 0.010). In addition, there is suggestive evidence that calcium is positively correlated (OR = 1.36, p = 0.030) and iron is negatively correlated with T2D risk (OR = 0.89, p = 0.010); both magnesium (OR = 0.26, p = 0.013) and iron (OR = 0.71, p = 0.047) are negatively correlated with gout risk. In the sensitivity analysis, causal estimation is not affected by pleiotropy. This study supports the long-standing hypothesis that magnesium supplementation can increase RA and BD risks and decrease OP risk and that copper intake can reduce AD and BD risks. This study will be helpful to address some controversial debates on the relationships between minerals and chronic diseases.

Tuberculosis is a chronic infectious disease caused by Mycobacterium tuberculosis (Mtb). Due to the extensive use of anti-tuberculosis drugs and the development of mutations, the emergence and spread of multidrug-resistant tuberculosis is recognized as one of the most dangerous threats to global tuberculosis control. Some single mutations have been identified to be significantly linked with drug resistance. However, the prior research did not take gene-gene interactions into account, and the emergence of transmissible drug resistance is connected with multiple genetic mutations. In this study we use the bioinformatics software GBOOST (The Hong Kong University, Clear Water Bay, Kowloon, Hong Kong, China) to calculate the interactions of Single Nucleotide Polymorphism (SNP) pairs and identify gene pairs associated with drug resistance. A large part of the non-synonymous mutations in the drug target genes that were included in the screened gene pairs were confirmed by previous reports, which lent sound solid credits to the effectiveness of our method. Notably, most of the identified gene pairs containing drug targets also comprise Pro-Pro-Glu (PPE) family proteins, suggesting that PPE family proteins play important roles in the drug resistance of Mtb. Therefore, this study provides deeper insights into the mechanisms underlying anti-tuberculosis drug resistance, and the present method is useful for exploring the drug resistance mechanisms for other microorganisms.

Motivation: One of the major findings in systems biomedicine is that both pathogenesis of diseases and drug mode of action have a module basis. However, the transcription factors (TFs) regulating the modules remain largely unknown. Results: In this study, by using biclustering approach FABIA (factor analysis for bicluster acquisition), we generate 49 modules for gene expression profiles on 1309 agent treatments. These modules are of biological relevance in terms of functional enrichment, drug–drug interactions and 3D proximity in chromatins. By using the information of drug targets (some of which are TFs) and biological regulation, the links between 28 modules and 12 specific TFs, such as estrogen receptors (ERs), nuclear factor-like 2 and peroxisome proliferator-activated receptor gamma, can be established. Some of the links are supported by 3D transcriptional regulation data [derived from ChIA-PET (chromatin interaction analysis using paired-end tags) experiments] and drug mode of action as well. The relationships between modules and TFs provide new clues to interpreting biological regulation mechanisms, in particular, the lipid metabolism regulation by ERα. In addition, the links between natural products (e.g. polyphenols) and their associated modules and TFs are helpful to elucidate their polypharmacological effects in terms of activating specific TFs, such as ERs, nuclear factor-like 2 and peroxisome proliferator-activated receptor gamma. Contact:zhy630@mail.hzau.edu.cn Supplementary Information: Supplementary data are available at Bioinformatics online.

Genome-wide association studies (GWAS) have identified tens of genetic variants associated with Parkinson’s disease (PD). Nevertheless, the genes or DNA elements that affect traits through these genetic variations are usually undiscovered. This study was the first to combine meta-analysis GWAS data and expression data to identify PD risk genes. Four known genes, CRHR1, KANSL1, NSF and LRRC37A, and two new risk genes, STX4 and BST1, were identified. Among them, CRHR1 is a known drug target, indicating that hydrocortisone may become a potential drug for the treatment of PD. Furthermore, the potential pathogenesis of CRHR1 and LRRC37A was explored by applying DNA methylation (DNAm) data, indicating a pathogenesis whereby the effect of a genetic variant on PD is mediated by genetic regulation of transcription through DNAm. Overall, this research identified the risk genes and pathogenesis that affect PD through genetic variants, which has significance for the diagnosis and treatment of PD.

Recent observational studies have reported associations between serum mineral nutrient levels, gut microbiota composition, and neurological, psychiatric, and metabolic diseases. However, the causal effects of mineral nutrients on gut microbiota and their causal associations with diseases remain unclear and require further investigation. This study aimed to identify the associations between serum mineral nutrients, gut microbiota, and risk of neurological, psychiatric, and metabolic diseases using Mendelian randomization (MR). We conducted an MR study using the large-scale genome-wide association study (GWAS) summary statistics of 5 serum mineral nutrients, 196 gut microbes at the phylum, order, family, and genus levels, and a variety of common neurological, psychiatric, and metabolic diseases. Initially, the independent causal associations of mineral nutrients and gut microbiota with diseases were examined by MR. Subsequently, the causal effect of mineral nutrients on gut microbiota was estimated to investigate whether specific gut microbes mediated the association between mineral nutrients and diseases. Finally, we performed sensitivity analyses to assess the robustness of the study results. After correcting for multiple testing, we identified a total of 33 causal relationships among mineral nutrients, gut microbiota, and diseases. Specifically, we found 4 causal relationships between 3 mineral nutrition traits and 3 disease traits, 15 causal associations between 14 gut microbiota traits and 6 disease traits, and 14 causal associations involving 4 mineral nutrition traits and 15 gut microbiota traits. Meanwhile, 118 suggestive associations were identified. The current study reveals multiple causal associations between serum mineral nutrients, gut microbiota, risk of neurological, psychiatric, and metabolic diseases, and potentially provides valuable insights for subsequent nutritional therapies.

Background: Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is one of the oldest known and most dangerous diseases. Although the spread of TB was controlled in the early 20th century using antibiotics and vaccines, TB has again become a threat because of increased drug resistance. There is still a lack of effective treatment regimens for a person who is already infected with multidrug-resistant Mtb (MDR-Mtb) or extensively drug-resistant Mtb (XDRMtb). In the past decades, many research groups have explored the drug resistance profiles of Mtb based on sequence data by GWAS, which identified some mutations that were significantly linked with drug resistance, and attempted to explain the resistance mechanisms. However, they mainly focused on several significant mutations in drug targets (e.g. rpoB, katG). Some genes which are potentially associated with drug resistance may be overlooked by the GWAS analysis. Objective: In this article, our motivation is to detect potential drug resistance genes of Mtb using a heat diffusion model. Methods: All sequencing data, which contained 127 samples of Mtb, i.e. 34 ethambutol-, 65 isoniazid-, 53 rifampicin- and 45 streptomycin-resistant strains. The raw sequence data were preprocessed using Trimmomatic software and aligned to the Mtb H37Rv reference genome using Bowtie2. From the resulting alignments, SAMtools and VarScan were used to filter sequences and call SNPs. The GWAS was performed by the PLINK package to obtain the significant SNPs, which were mapped to genes. The P-values of genes calculated by GWAS were transferred into a heat vector. The heat vector and the Mtb protein-protein interactions (PPI) derived from the STRING database were inputted into the heat diffusion model to obtain significant subnetworks by HotNet2. Finally, the most significant (P < 0.05) subnetworks associated with different phenotypes were obtained. To verify the change of binding energy between the drug and target before and after mutation, the method of molecular dynamics simulation was performed using the AMBER software. Results: We identified significant subnetworks in rifampicin-resistant samples. Excitingly, we found rpoB and rpoC, which are drug targets of rifampicin. From the protein structure of rpoB, the mutation location was extremely close to the drug binding site, with a distance of only 3.97 Å. Molecular dynamics simulation revealed that the binding energy of rpoB and rifampicin decreased after D435V mutation. To a large extent, this mutation can influence the affinity of drug-target binding. In addition, topA and pyrG were reported to be linked with drug resistance, and might be new TB drug targets. Other genes that have not yet been reported are worth further study. Conclusion: Using a heat diffusion model in combination with GWAS results and protein-protein interactions, the significantly mutated subnetworks in rifampicin-resistant samples were found. The subnetwork not only contained the known targets of rifampicin (rpoB, rpoC), but also included topA and pyrG, which are potentially associated with drug resistance. Together, these results offer deeper insights into drug resistance of Mtb, and provides potential drug targets for finding new antituberculosis drugs.