RUNX2 Phase Separation Mediates Long-Range Regulation Between Osteoporosis-Susceptibility Variant and XCR1 to Promote Osteoblast Differentiation.

GWASs have identified many loci associated with osteoporosis, but the underlying genetic regulatory mechanisms and the potential drug target need to be explored. Here, a new regulatory mechanism is found that a GWAS intergenic SNP (rs4683184) functions as an enhancer to influence the binding affinity of transcription factor RUNX2, whose phase separation can mediate the long-range chromatin interaction between enhancer and target gene XCR1 (a member of the GPCR family), leading to changes of XCR1 expression and osteoblast differentiation. Bone-targeting AAV of Xcr1 can improve bone formation in osteoporosis mice, suggesting that XCR1 can be a new susceptibility gene for osteoporosis.

Synovial transcriptome-wide association study implicates novel genes underlying rheumatoid arthritis risk.

Objectives: This study aimed to address the lack of gene expression regulation data in synovial tissues and to identify conditionally independent genes associated with rheumatoid arthritis (RA) in the synovium, a primary target tissue for RA.

Methods: Gene expression prediction models were built for synovial tissue using matched genotype and gene expression data from 202 subjects. Using this model, we conducted transcriptome-wide association study (TWAS), utilizing the largest RA genome-wide association study (GWAS) meta-analysis data (n = 276 020).

Revealing brain cell-stratified causality through dissecting causal variants according to their cell-type-specific effects on gene expression.

The human brain has been implicated in the pathogenesis of several complex diseases. Taking advantage of single-cell techniques, genome-wide association studies (GWAS) have taken it a step further and revealed brain cell-type-specific functions for disease loci. However, genetic causal associations inferred by Mendelian randomization (MR) studies usually include all instrumental variables from GWAS, which hampers the understanding of cell-specific causality.

Unveiling Promising Neuroimaging Biomarkers for Schizophrenia Through Clinical and Genetic Perspectives.

Schizophrenia is a complex and serious brain disorder. Neuroscientists have become increasingly interested in using magnetic resonance-based brain imaging-derived phenotypes (IDPs) to investigate the etiology of psychiatric disorders. IDPs capture valuable clinical advantages and hold biological significance in identifying brain abnormalities.

Two-sample Mendelian randomization analysis reveals causal relationships between blood lipids and venous thromboembolism.

Venous thromboembolism (VTE) is a complex disease that can be classified into two subtypes: deep vein thrombosis (DVT) and pulmonary embolism (PE). Previous observational studies have shown associations between lipids and VTE, but causality remains unclear. Hence, by utilizing 241 lipid-related traits as exposures and data from the FinnGen consortium on VTE, DVT, and PE as outcomes, we conducted two-sample Mendelian randomization (MR) analysis to investigate causal relationships between lipids and VTE, DVT and PE.

The Causal Relationships Between Gut Microbiota, Brain Volume, and Intelligence: A Two-Step Mendelian Randomization Analysis.

Background: Growing evidence indicates that dynamic changes in gut microbiome can affect intelligence; however, whether these relationships are causal remains elusive. We aimed to disentangle the poorly understood causal relationship between gut microbiota and intelligence.

Methods: We performed a 2-sample Mendelian randomization (MR) analysis using genetic variants from the largest available genome-wide association studies of gut microbiota (N = 18,340) and intelligence (N = 269,867).

A landscape of gene expression regulation for synovium in arthritis.

The synovium is an important component of any synovial joint and is the major target tissue of inflammatory arthritis. However, the multi-omics landscape of synovium required for functional inference is absent from large-scale resources. Here we integrate genomics with transcriptomics and chromatin accessibility features of human synovium in up to 245 arthritic patients, to characterize the landscape of genetic regulation on gene expression and the regulatory mechanisms mediating arthritic diseases predisposition.

Integrative high-throughput enhancer surveying and functional verification divulges a YY2-condensed regulatory axis conferring risk for osteoporosis.

The precise roles of chromatin organization at osteoporosis risk loci remain largely elusive. Here, we combined chromatin interaction conformation (Hi-C) profiling and self-transcribing active regulatory region sequencing (STARR-seq) to qualify enhancer activities of prioritized osteoporosis-associated single-nucleotide polymorphisms (SNPs). We identified 319 SNPs with biased allelic enhancer activity effect (baaSNPs) that linked to hundreds of candidate target genes through chromatin interactions across 146 loci.

Multi-tissue transcriptome-wide association study reveals susceptibility genes and drug targets for insulin resistance-relevant phenotypes.

Aim: Genome-wide association studies (GWAS) have identified multiple susceptibility loci associated with insulin resistance (IR)-relevant phenotypes. However, the genes responsible for these associations remain largely unknown. We aim to identify susceptibility genes for IR-relevant phenotypes via a transcriptome-wide association study.

High-throughput functional dissection of noncoding SNPs with biased allelic enhancer activity for insulin resistance-relevant phenotypes.

Most of the single-nucleotide polymorphisms (SNPs) associated with insulin resistance (IR)-relevant phenotypes by genome-wide association studies (GWASs) are located in noncoding regions, complicating their functional interpretation. Here, we utilized an adapted STARR-seq to evaluate the regulatory activities of 5,987 noncoding SNPs associated with IR-relevant phenotypes. We identified 876 SNPs with biased allelic enhancer activity effects (baaSNPs) across 133 loci in three IR-relevant cell lines (HepG2, preadipocyte, and A673), which showed pervasive cell specificity and significant enrichment for cell-specific open chromatin regions or enhancer-indicative markers (H3K4me1, H3K27ac).

Assessment of bidirectional relationships between brain imaging-derived phenotypes and stroke: a Mendelian randomization study.

Background: Stroke is a major cause of mortality and long-term disability worldwide. Whether the associations between brain imaging-derived phenotypes (IDPs) and stroke are causal is uncertain.

Methods: We performed two-sample bidirectional Mendelian randomization (MR) analyses to explore the causal associations between IDPs and stroke.

Application of Hi-C technology in three-dimensional genomics research and disease pathogenesis analysis.

3D genomics aims to investigate the spatial structure of chromatin in the nucleus on the basis of genomic sequences, gene structures and relevant regulatory elements. The spatial organization of chromosomes is fundamental for gene expression regulation. Recent advances of high-throughput chromosome conformation capture (Hi-C) technology and its derivatives, has enabled capture of chromatin architecture with high resolution.

Lineage-selective super enhancers mediate core regulatory circuitry during adipogenic and osteogenic differentiation of human mesenchymal stem cells.

Human mesenchymal stem cells (hMSCs) can be differentiated into osteoblasts and adipocytes. During these processes, super enhancers (SEs) play important roles. Here, we performed comprehensive characterization of the SEs changes associated with adipogenic and osteogenic differentiation of hMSCs, and revealed that SEs changed more dramatically compared with typical enhancers.

Mendelian randomization analyses support causal relationships between brain imaging-derived phenotypes and risk of psychiatric disorders.

Observational studies have reported the correlations between brain imaging-derived phenotypes (IDPs) and psychiatric disorders; however, whether the relationships are causal is uncertain. We conducted bidirectional two-sample Mendelian randomization (MR) analyses to explore the causalities between 587 reliable IDPs (N = 33,224 individuals) and 10 psychiatric disorders (N = 9,725 to 161,405). We identified nine IDPs for which there was evidence of a causal influence on risk of schizophrenia, anorexia nervosa and bipolar disorder.

Associations of genetic variations in NEDD4L with salt sensitivity, blood pressure changes and hypertension incidence in Chinese adults.

Neural precursor cell expressed developmentally downregulated 4-like (NEDD4L), a member of the E3 ubiquitin-protein ligases, encoded by NEDD4L gene, was found to be involved in in salt sensitivity by regulating sodium reabsorption in salt-sensitive rats. The authors aimed to explore the associations of NEDD4L genetic variants with salt sensitivity, blood pressure (BP) changes and hypertension incidence in Chinese adults. Participants from 124 families in Northern China in the Baoji Salt-Sensitive Study Cohort in 2004, who received the chronic salt intake intervention, including a 7-day low-salt diet (3.

Lineage-specific rearrangement of chromatin loops and epigenomic features during adipocytes and osteoblasts commitment.

Human mesenchymal stem cells (hMSCs) can be differentiated into adipocytes and osteoblasts. The processes are driven by the rewiring of chromatin architectures and transcriptomic/epigenomic changes. Here, we induced hMSCs to adipogenic and osteogenic differentiation, and performed 2 kb resolution Hi-C experiments for chromatin loops detection.

Bidirectional two-sample Mendelian randomization analysis identifies causal associations between relative carbohydrate intake and depression.

Growing evidence suggests that relative carbohydrate intake affects depression; however, the association between carbohydrates and depression remains controversial. To test this, we performed a two-sample bidirectional Mendelian randomization (MR) analysis using genetic variants associated with relative carbohydrate intake (N = 268,922) and major depressive disorder (N = 143,265) from the largest available genome-wide association studies. MR evidence suggested a causal relationship between higher relative carbohydrate intake and lower depression risk (odds ratio, 0.

ExsgRNA: reduce off-target efficiency by on-target mismatched sgRNA.

Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing technology has been widely used to facilitate efficient genome editing. Current popular sgRNA design tools only consider the sgRNA perfectly matched to the target site and provide the results without any on-target mismatch. We suppose taking on-target gRNA-DNA mismatches into consideration might provide better sgRNA with similar binding activity and reduced off-target sites.

Individualized pathway activity algorithm identifies oncogenic pathways in pan-cancer analysis.

Background: Accumulative evidences have shown that dysregulation of biological pathways contributed to the initiation and progression of malignant tumours. Several methods for pathway activity measurement have been proposed, but they are restricted to making comparisons between groups or sensitive to experimental batch effects.

Methods: We introduced a novel method for individualized pathway activity measurement (IPAM) that is based on the ranking of gene expression levels in individual sample.