Background Accumulating evidences have suggested that high body fat percentage (BF%) often occurs in parallel with cardiovascular diseases (CVDs), implying a common etiology between them. However, the shared genetic etiology underlying BF% and CVDs remains unclear. Methods Using large-scale genome-wide association study (GWAS) data, we investigated shared genetics between BF% (N = 100,716) and 10 CVD-related traits (n = 6968-977,323) with linkage disequilibrium score regression, multi-trait analysis of GWAS, and transcriptome-wide association analysis, and evaluated causal associations using Mendelian randomization. Results We found strong positive genetic correlations between BF% and heart failure (HF) (Rg = 0.47, P = 1.27 × 10− 22) and coronary artery disease (CAD) (Rg = 0.22, P = 3.26 × 10− 07). We identified 5 loci and 32 gene-tissue pairs shared between BF% and HF, as well as 16 loci and 28 gene-tissue pairs shared between BF% and CAD. The loci were enriched in blood vessels and brain tissues, while the gene-tissue pairs were enriched in the nervous, cardiovascular, and exo-/endocrine system. In addition, we observed that BF% was causally related with a higher risk of HF (odds ratio 1.63 per 1-SD increase in BF%, P = 4.16 × 10–04) using a MR approach. Conclusions Our findings suggest that BF% and CVDs have shared genetic etiology and targeted reduction of BF% may improve cardiovascular outcomes. This work advances our understanding of the genetic basis underlying co-morbid obesity and CVDs and opens up a new way for early prevention of CVDs.
Coronavirus Disease (COVID-19) may cause a dysregulation of the immune system and has complex relationships with multiple autoimmune diseases, including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). However, little is known about their common genetic architecture. Using the latest data from COVID-19 host genetics consortium and consortia on RA and SLE, we conducted a genome-wide cross-trait analysis to examine the shared genetic etiology between COVID-19 and RA/SLE and evaluated their causal associations using bidirectional Mendelian randomization (MR). The cross-trait meta-analysis identified 23, 28, and 10 shared genetic loci for severe COVID-19, COVID-19 hospitalization, and SARS-CoV-2 infection with RA, and 14, 17, and 7 shared loci with SLE, respectively.Co-localization analysis identified five causal variants in TYK2, IKZF3, PSORS1C1, and COG6 for COVID-19 with RA, and four in CRHR1, FUT2, and NXPE3 for COVID-19 with SLE, involved in immune function, angiogenesis and coagulation. Bidirectional MR analysis suggested RA is associated with a higher risk of COVID-19 hospitalization, and COVID-19 is not related to RA or SLE. Our novel findings improved the understanding of the genetic etiology shared by COVID-19, RA and SLE, and suggested an increased risk of COVID-19 hospitalization in people with higher genetic liability to RA.
Motivation It is of scientific interest to identify DNA methylation CpG sites that might mediate the effect of an environmental exposure on a survival outcome in high-dimensional mediation analysis. However, there is a lack of powerful statistical methods that can provide a guarantee of false discovery rate (FDR) control in finite-sample settings. Results In this article, we propose a novel method called CoxMKF, which applies aggregation of multiple knockoffs to a Cox proportional hazards model for a survival outcome with high-dimensional mediators. The proposed CoxMKF can achieve FDR control even in finite-sample settings, which is particularly advantageous when the sample size is not large. Moreover, our proposed CoxMKF can overcome the randomness of the unstable model-X knockoffs. Our simulation results show that CoxMKF controls FDR well in finite samples. We further apply CoxMKF to a lung cancer data set from The Cancer Genome Atlas (TCGA) project with 754 subjects and 365 306 DNA methylation CpG sites, and identify four DNA methylation CpG sites that might mediate the effect of smoking on the overall survival among lung cancer patients. Availability The R package CoxMKF is publicly available at https://github.com/MinhaoYaooo/CoxMKF. Supplementary information Supplementary data are available at Bioinformatics online.
Head smut, caused by the fungus Sporisorium reilianum, is a devastating global disease of maize (Zea mays). In the present study, maize seedlings were artificially inoculated with compatible mating-type strains of S. reilianum by needle inoculation of mesocotyls (NIM) or by soaking inoculation of radicles (SIR). After NIM or SIR, Huangzao4 mesocotyls exhibited severe damage with brownish discoloration and necrosis, whereas Mo17 mesocotyls exhibited few lesions. Fluorescence and electron microscopy showed that S. reilianum infected maize within 0.5 day after SIR and mainly colonized the phloem. With longer incubation, the density of S. reilianum hyphae increased in the vascular bundles, concentrated mainly in the phloem. In Mo17, infected cells exhibited apoptosis-like features, and hyphae became sequestered within dead cells. In contrast, in Huangzao4, pathogen invasion resulted in autophagy that failed to prevent hyphal spreading. The growth of S. reilianum hyphae diminished at 6 days after inoculation when expression of the R genes ZmWAK and ZmNL peaked. Thus, 6 days after SIR inoculation might be an important time for inhibiting the progress of S. reilianum infection in maize. The results of this study will provide a basis for further analysis of the mechanisms of maize resistance to S. reilianum.
Rice black-streaked dwarf virus (RBSDV), a ds-RNA virus in Fijivirus genus with family Reoviridae, which is transmitted by the small brown planthopper, is responsible for incidence of maize rough dwarf disease (MRDD) and rice black-streaked dwarf disease (RBSDD). To understand the variation and evolution of S5, a unique fragment in the genome of RBSDV which encodes two partially overlapping ORFs (ORF5-1 and ORF5-2), we analyzed 127 sequences from maize and rice exhibiting symptoms of dwarfism. The nucleotide diversity of both ORF5-1 (π = 0.039) and ORF5-2 (π = 0.027) was higher than that of the overlapping region (π = 0.011) (P < 0.05). ORF5-2 was under the greatest selection pressure based on codon bias analysis, and its activation was possibly influenced by the overlapping region. The recombinant fragments of three recombinant events (14NM23, 14BM20, and 14NM17) cross the overlapping region. Based on neighbor-joining tree analysis, the overlapping region could represent the evolutionary basis of the full-length S5, which was classified into three main groups. RBSDV populations were expanding and haplotype diversity resulted mainly from the overlapping region. The genetic differentiation of combinations (T127-B35, T127-J34, A58-B35, A58-J34, and B35-J34) reached significant or extremely significant levels. Gene flow was most frequent between subpopulations A58 and B35, with the smallest |Fst| (0.02930). We investigated interactions between 13 RBSDV proteins by two-hybrid screening assays and identified interactions between P5-1/P6, P6/P9-1, and P3/P6. We also observed self-interactive effects of P3, P6, P7-1, and P10. In short, we have proven that RBSDV populations were expanding and the overlapping region plays an important role in the genetic variation and evolution of RBSDV S5. Our results enable ongoing research into the evolutionary history of RBSDV-S5 with two partly overlapping ORFs.
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