Analysis of blood methylation quantitative trait loci in East Asians reveals ancestry-specific impacts on complex traits.

Methylation quantitative trait loci (mQTLs) are essential for understanding the role of DNA methylation changes in genetic predisposition, yet they have not been fully characterized in East Asians (EAs). Here we identified mQTLs in whole blood from 3,523 Chinese individuals and replicated them in additional 1,858 Chinese individuals from two cohorts. Over 9% of mQTLs displayed specificity to EAs, facilitating the fine-mapping of EA-specific genetic associations, as shown for variants associated with height. Trans-mQTL hotspots revealed biological pathways contributing to EA-specific genetic associations, including an ERG-mediated 233 trans-mCpG network, implicated in hematopoietic cell differentiation, which likely reflects binding efficiency modulation of the ERG protein complex. More than 90% of mQTLs were shared between different blood cell lineages, with a smaller fraction of lineage-specific mQTLs displaying preferential hypomethylation in the respective lineages. Our study provides new insights into the mQTL landscape across genetic ancestries and their downstream effects on cellular processes and diseases/traits.

Genome-wide epistasis study highlights genetic interactions influencing severity of COVID-19.

Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may lead to life-threatening respiratory symptoms. Understanding the genetic basis of the prognosis of COVID-19 is important for risk profiling of potentially severe symptoms. Here, we conducted a genome-wide epistasis study of COVID-19 severity in 2243 patients with severe symptoms and 12,612 patients with no or mild symptoms from the UK Biobank, followed by a replication study in an independent Spanish cohort (1416 cases, 4382 controls). Our study highlighted 3 interactions with genome-wide significance in the discovery phase, nominally significant in the replication phase, and enhanced significance in the meta-analysis. For example, the lead interaction was found between rs9792388 upstream of PDGFRL and rs3025892 downstream of SNAP25, where the composite genotype of rs3025892 CT and rs9792388 CA/AA showed higher risk of severe disease than any other genotypes (P = 2.77 × 10-12, proportion of severe cases = 0.24 ~ 0.29 vs. 0.09 ~ 0.18, genotypic OR = 1.96 ~ 2.70). This interaction was replicated in the Spanish cohort (P = 0.002, proportion of severe cases = 0.30 ~ 0.36 vs. 0.14 ~ 0.25, genotypic OR = 1.45 ~ 2.37) and showed enhanced significance in the meta-analysis (P = 4.97 × 10-14). Notably, these interactions indicated a possible molecular mechanism by which SARS-CoV-2 affects the nervous system. The first exhaustive genome-wide screening for epistasis improved our understanding of genetic basis underlying the severity of COVID-19.

Combining genome-wide association studies highlight novel loci involved in human facial variation.

Standard genome-wide association studies (GWASs) rely on analyzing a single trait at a time. However, many human phenotypes are complex and composed by multiple correlated traits. Here we introduce C-GWAS, a method for combining GWAS summary statistics of multiple potentially correlated traits. Extensive computer simulations demonstrated increased statistical power of C-GWAS compared to the minimal p-values of multiple single-trait GWASs (MinGWAS) and the current state-of-the-art method for combining single-trait GWASs (MTAG). Applying C-GWAS to a meta-analysis dataset of 78 single trait facial GWASs from 10,115 Europeans identified 56 study-wide suggestively significant loci with multi-trait effects on facial morphology of which 17 are novel loci. Using data from additional 13,622 European and Asian samples, 46 (82%) loci, including 9 (53%) novel loci, were replicated at nominal significance with consistent allele effects. Functional analyses further strengthen the reliability of our C-GWAS findings. Our study introduces the C-GWAS method and makes it available as computationally efficient open-source R package for widespread future use. Our work also provides insights into the genetic architecture of human facial appearance.

High stone-free rate immediately after suctioning flexible ureteroscopy with Intelligent pressure-control in treating upper urinary tract calculi.

BACKGROUND: The retrospective observational study aimed to evaluate the safety and efficacy of suctioning flexible ureteroscopy with Intelligent pressure-control (SFUI) on treating upper urinary tract calculi in a large cohort. METHODS: Between July 2020 and August 2021, 278 patients with upper urinary tract calculi who underwent SFUI in our hospital were enrolled. Outcomes were stone-free rate (SFR) in one session and one-month after SFUI treatment, and complications scored by the Clavien-Dindo classification. RESULTS: A total of 310 kidneys underwent SFUI were included. The median surgery time was 75 min (ranged 60-110 min). One session and one-month SFRs were 80.65% and 82.26%, respectively. The one-session SFR was ≧ 87% in patients with Guy's stone score of Grade I among stone size < 40 mm. Risk factors for unsuccessful stone-free in one session were stone history (adjusted odds ratio (aOR): 2.39, 95% confidence interval (CI): 1.21-4.73), stone size of 40-49 mm (aOR: 4.37, 95% CI: 1.16-16.45), Guy's stone score ≧ Grade II (Grade II, aOR: 3.54, 95% CI: 1.18-10.59; Grade III, aOR: 10.95, 95% CI: 2.65-45.25). The incidence of Clavien-Dindo grade II-III complication was 3.26%. Complication is associated with Guy's stone score III (aOR: 22.36, 95% CI: 1.81-276.36). CONCLUSION: SFUI shows good safety and efficiency on treating upper urinary tract calculi. Patients with stone size < 40 mm or Guy's stone score of Grade I have a high chance to reach stone-free after SFUI treatment.

Erratum: Nodal Promotes the Migration and Invasion of Bladder Cancer Cells via Regulation of Snail: Erratum.

[This corrects the article DOI: 10.7150/jca.29205.].

Trim24 prompts tumor progression via inducing EMT in renal cell carcinoma.

Renal cell carcinoma (RCC) is a malignant tumor originating from renal tubular epithelial cells with poor prognosis and high metastatic rate. Tripartite motif-containing 24 (Trim24) is a member of the tripartite motif (Trim) family and also a valuable oncogene, but its role in RCC remains unclear. We constructed the overexpression and knockdown of Trim24 cell lines to investigate its roles in RCC progression. CCK8, wound healing, and transwell assay were performed to determine the proliferation, migration, and invasion of RCC cell lines, respectively. Moreover, the expression of Trim24 and its clinicopathological significance were evaluated in a human RCC tissue microarray. From our results, Trim24 promoted the proliferation, migration, and invasion of RCC cells in vitro. Importantly, overexpression of Trim24 led to a significant increase in the expression levels of MMP-2, MMP-9, fibronectin, snail, vimentin, N-cadherin, and ß-catenin, inducing the EMT process in turn, while the expression of these proteins was significantly downregulated when Trim24 was knocked down in ACHN cells. In addition, Trim24 was significantly upregulated in RCC, and its high expression was negatively associated with the tumor size. Trim24 might operate as an oncogene in RCC progression by inducing the EMT process, suggesting that Trim24 was a potential target for human RCC.

A genome-wide association study identifies FSHR rs2300441 associated with follicle-stimulating hormone levels.

Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) play critical roles in female reproduction, while the underlying genetic basis is poorly understood. Genome-wide association studies (GWASs) of FSH and LH levels were conducted in 2590 Chinese females including 1882 polycystic ovary syndrome (PCOS) cases and 708 controls. GWAS for FSH level identified multiple variants at FSHR showing genome-wide significance with the top variant (rs2300441) located in the intron of FSHR. The A allele of rs2300441 led to a reduced level of FSH in the PCOS group (ß = -.43, P = 6.70 × 10-14 ) as well as in the control group (ß = -.35, P = 6.52 × 10-4 ). In the combined sample, this association was enhanced after adjusting for the PCOS status (before: ß = -.38, P = 1.77 × 10-13 ; after: ß = -.42, P = 3.33 × 10-16 ), suggesting the genetic effect is independent of the PCOS status. The rs2300441 explained sevenfold higher proportion of the FSH variance than the total variance explained by the two previously reported FSHR missense variants (rs2300441 R2 = 1.40% vs rs6166 R2 = 0.17%, rs6165 R2 = 0.03%). GWAS for LH did not identify any genome-wide significant associations. In conclusion, we identified genome-wide significant association between variants in FSHR and circulating FSH first, with the top associated variant rs2300441 might be a primary contributor at the population level.

Predicting adult height from DNA variants in a European-Asian admixed population.

Accurate genomic profiling for adult height is of high practical relevance in forensics genetics. Adult height is a classical reference trait in the field of human complex trait genetics characterized by highly polygenic nature and relatively high heritability. A meta-analysis of genome-wide association studies by the Genetic Investigation of Anthropocentric Traits (GIANT) consortium has identified 697 DNA variants associated with adult height in Europeans; however, whether these variants will still be informative in non-Europeans is still in question. The present study investigated the predictive power of these 697 height-associated SNPs in 687 Uyghurs of European-Asian admixed origin. Among all GIANT SNPs, 11% showed nominally significant association (6.78 × 10-4 < p < 0.05) with adult height in the Uyghur population and among the significant SNPs 77% of allele effects were in the same direction as those in Europeans reported in the GIANT study. Fitting linear and logistic models using a polygenic score consisting of all GIANT SNPs resulted in an 80-20 cross-validated mean R2 of 10.08% (95% CI 3.16-18.40%) for quantitative height prediction and a mean AUC value of 0.65 (95% CI 0.57-0.72%) for qualitative "above average" prediction. Fine-tuning the SNP set using their association p values considerably improved the prediction results (number of SNPs = 62, R2 = 15.59%, 95% CI 6.80-25.71%; AUC = 0.70, 95% CI 62-0.77) in the Uyghurs. Overall, our findings demonstrate substantial differences between the European and Asian populations in the genetics of adult height, emphasizing the importance of population heterogeneity underlying the genetic architecture of adult height.

Nodal Promotes the Migration and Invasion of Bladder Cancer Cells via Regulation of Snail.

Urinary bladder cancer is one of commonly diagnosed malignancies worldwide, especially in males. Understanding the mechanisms of advanced metastasis in bladder cell is important for therapy and drug development. Nodal, an important embryonic morphogen, has been reported to modulate tumorigenesis. We found that the expression of Nodal was upregulated in bladder cancer cells and tissues as compared to their corresponding controls. Knockdown of Nodal can suppress the migration, invasion, and epithelial-to-mesenchymal transition (EMT) of bladder cancer cells. Nodal can positively regulate the expression of Snail, one powerful EMT transcription factors, in bladder cancer cells. Overexpression of Snail can attenuate the si-Nodal suppressed cell migration and invasion. Nodal can increase the transcription and protein stability of Snail in bladder cancer cells. YY1, which can be activated by Nodal, is responsible for Nodal induced transcription of Snail. ATM, which can stabilize Snail by phosphorylation on Serine-100, was involved in Nodal upregulated protein stability of Snail. Collectively, our data showed that Nodal can trigger the malignancy of bladder cancer cells via increasing the transcription and protein stability of Snail. It indicated that Nodal might be a potential therapeutic target for bladder cancer treatment.