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PubMed2025

DNA O-MAP uncovers the molecular neighborhoods associated with specific genomic loci.

The accuracy of crucial nuclear processes such as transcription, replication, and repair, depends on the local composition of chromatin and the regulatory proteins that reside there. Understanding these DNA-protein interactions at the level of specific genomic loci has remained challenging due to technical limitations. Here, we introduce a method termed "DNA O-MAP", which uses programmable peroxidase-conjugated oligonucleotide probes to biotinylate nearby proteins. We show that DNA O-MAP can be coupled with sample multiplexed quantitative proteomics, targeted chemical perturbations, and next-generation sequencing to quantify DNA-protein and DNA-DNA interactions at specific genomic loci. Furthermore, we establish that DNA O-MAP \ is applicable to both repetitive and unique genomic loci of varying sizes (kilobases to megabases), and that DNA O-MAP can measure proximal molecular effectors in a homolog-specific manner.

Journal Article↗

PubMed2025

A genome-wide association study identified 10 novel genomic loci associated with intrinsic capacity.

BACKGROUND: Intrinsic capacity (IC) is a multidimensional concept within the World Health Organization framework for healthy aging. It refers to the composite of an individual's physical and mental capacities that enable them to maintain well-being, functional ability, and engagement in valued activities throughout life. While substantial evidence supports the biological basis of IC and its subdomains, the extent to which genetic factors influence IC remains largely unexplored, with no studies currently available. METHODS: Using datasets from the UK Biobank (UKB; N = 44 631) and the Canadian Longitudinal Study on Aging (CLSA; N = 13 085), we implemented the restricted maximum likelihood method to estimate SNP-based heritability (h2snp), followed by a Genome-Wide Association Study (GWAS) to identify genetic variants associated with IC, and post-GWAS analyses to pinpoint biological implications. RESULTS: The h2snp for IC was estimated at 25.2% in UKB and 19.5% in CLSA. Our GWAS identified 38 independent SNPs for IC across 10 genomic loci and 4289 candidate SNPs, mapped to 197 genes. Post-GWAS analysis revealed the role of these genes in cellular processes such as cell proliferation, immune function, metabolism, and neurodegeneration, with high expression in muscle, heart, brain, adipose, and nerve tissues. Of the 52 traits tested, 23 showed significant genetic correlations with IC, and a higher genetic loading for IC was associated with higher IC scores. CONCLUSIONS: Overall, this study provides comprehensive evidence on the genetic architecture of IC, identifying novel genetic variants and biological pathways, advancing our current knowledge and laying the foundation for ongoing and future research on healthy aging.

Adult↗

PubMed2025

Genetic crosses reveal genomic loci responsible for virulence in Cryptosporidium parvum infection.

The relationship between parasite genotype and pathogenesis is largely unknown for Cryptosporidium, a leading cause of diarrheal disease in children. An array of parasites with similar genomes produces varied disease outcomes in different hosts. Here, we isolate and characterize Cryptosporidium parvum strains that show marked differences in virulence and persistence in mice. Taking advantage of the sexual life cycle of this eukaryotic pathogen, we use genetic crosses to discover the underlying chromosomal loci. Whole-genome sequencing and bulk segregant analysis of infection-selected progeny mapped three loci on chromosomes 2, 6, and 7 associated with the ability to colonize and persist in mice and the positions of drug resistance genes. The chromosome 6 locus encodes the hyper-polymorphic surface glycoprotein GP60. Reverse genetic studies in both parental strains demonstrate that GP60 controls parasite burden and virulence, but not persistence, and reveal the dominance of the less virulent allele, suggesting it restricts virulence.

Cryptosporidium parvum↗

PubMed2026

Integrative haplotype and SNP-based GWAS supports the identification of stable genomic loci controlling yield-related traits in soybean.

Soybean yield is vulnerable to environmental variation, therefore, it is important to detect and implement stable genomic regions associated with yield-related traits in soybean breeding programs. In this study, SNP and haplotype-based GWAS were conducted to reveal important candidate genomic regions and putative candidate genes associated with soybean yield-related traits. This study demonstrates that the integration of haplotype and SNP-based GWAS could improve the detection of genomic regions associated with complex traits, enhance statistical power, and facilitate the identification of biologically relevant candidate genes. Ten stable haplotype blocks and six stable SNPs were detected based on the integration of haplotype and SNP-based GWAS, respectively. Furthermore, multiple candidate genes associated with the yield-related traits were identified. For instance, six genes were identified as transporters, including Glyma.15G092800, encoding serine-type endopeptidase activity, Glyma.15G203300 encoding a major facilitator superfamily (MFS) sugar transporter, Glyma.04G163000, transmembrane transporter, and Glyma.04G164100, leucine-rich repeat receptor-like protein kinase (LRR-RLK), as the most promising candidate genes. Additionally, three genes involved in signaling and pathways of various phytohormones can be promising candidates for increasing seed yield through improving plant architecture in soybean plants. The identified superior haplotypes with favourable alleles will be useful for marker-assisted selection in future breeding programs in soybean.

DArT markers↗

PubMed2025

Genomic loci and molecular genetic mechanisms for hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is a common, chronic and debilitating inflammatory disease that most commonly affects intertriginous skin. Despite its high heritability, the genetic underpinnings of HS remain poorly understood. OBJECTIVES: To identify genetic signals associated with HS, determine genetic relationships with other diseases and investigate potential molecular genetic mechanisms. METHODS: We performed a genome-wide association meta-analysis of six studies, totalling 4540 patients with HS and > 1 million control participants, and identified genetic correlations with other common diseases. We integrated the HS data with expression quantitative trait loci from 10 trait-relevant tissues, epigenomic and transcriptomic data from human scalp, differential expression data from HS lesions vs. adjacent skin and mesenchymal Hi-C chromatin looping data. To identify functional noncoding variants, we performed transcriptional reporter assays for signals near KLF5 and SOX9. RESULTS: We identified 11 significant HS signals across 7 loci: 4 corresponded to previously reported associations, 4 represented novel signals within known loci and 3 were signals in newly implicated loci. We identified significant genetic correlations between HS and other inflammatory conditions, particularly inflammatory bowel disease, rheumatoid arthritis, type 2 diabetes mellitus and asthma. We prioritized candidate genes for the 11 signals. The risk allele at KLF5 exhibited 10-fold greater transcriptional activity than the nonrisk allele, while risk alleles at SOX9 showed significantly reduced transcriptional activity. CONCLUSIONS: Our results provide insights into potential genetic mechanisms underlying HS and suggest potential therapeutic targets for this challenging condition.

Humans↗

PubMed2025

dCas-Based Tools to Visualize Chromatin or Modify Epigenetic Marks at Specific Plant Genomic Loci.

Development of locus-specific approaches targeting precise regions on chromatin, for locus/transcription visualization or transcription/epigenetic marks editing, is a critical challenge in functional genetics and epigenetics. Systems engineered from the clustered regularly interspaced short palindromic repeats (CRISPR) and its associated endonuclease (Cas) operate through DNA sequence-specific recognition by so-called guide RNAs, which provides high flexibility and modularity for precise chromatin visualization or edition. Here, we provide an overview of the CRISPR/Cas-derived tools developed for visualization of chromatin loci in live imaging or for effective modification of gene expression. These tools make use of effector modules that combine activators, repressors, and epigenetic modifiers with a deactivated Cas protein (dCas). We present how their use in plants brought advances in visualizing or manipulating the expression of loci involved in agronomically interesting traits such as flowering time and response to drought or heat. We also discuss the limitations and future improvements of the dCas-related technologies, such as more compact and combinatorial systems, spatiotemporal targeting for fine-tuning of gene expression, and live visualization of chromatin dynamics.

Chromatin↗

PubMed2024

Inverted triplications formed by iterative template switches generate structural variant diversity at genomic disorder loci.

The duplication-triplication/inverted-duplication (DUP-TRP/INV-DUP) structure is a complex genomic rearrangement (CGR). Although it has been identified as an important pathogenic DNA mutation signature in genomic disorders and cancer genomes, its architecture remains unresolved. Here, we studied the genomic architecture of DUP-TRP/INV-DUP by investigating the DNA of 24 patients identified by array comparative genomic hybridization (aCGH) on whom we found evidence for the existence of 4 out of 4 predicted structural variant (SV) haplotypes. Using a combination of short-read genome sequencing (GS), long-read GS, optical genome mapping, and single-cell DNA template strand sequencing (strand-seq), the haplotype structure was resolved in 18 samples. The point of template switching in 4 samples was shown to be a segment of ∼2.2-5.5 kb of 100% nucleotide similarity within inverted repeat pairs. These data provide experimental evidence that inverted low-copy repeats act as recombinant substrates. This type of CGR can result in multiple conformers generating diverse SV haplotypes in susceptible dosage-sensitive loci.

Humans↗

PubMed2025

Foxh1 is a locus-specific PRC2 recruiter governing germ layer silencing.

Polycomb Repressive Complex 2 (PRC2) establishes H3K27me3 marks to shape spatiotemporal gene expression during embryogenesis. While its dysregulation is linked to developmental disorders, cancer, and aging, the mechanisms guiding PRC2 to specific genomic loci remain a subject of ongoing debate. A prevailing model proposes that PRC2 recruitment occurs via its intrinsic affinity for chromatin rather than through sequence-specific transcription factors. Here, we provide evidence that the maternally deposited pioneer transcription factor Foxh1 plays a critical role in directing PRC2 to specific genomic loci during zygotic genome activation in Xenopus. Foxh1 is a critical transcription factor mediating Nodal signaling, but it also plays an earlier role by pre-binding enhancers prior to signaling activation. This pre-binding is essential for forming enhanceosome complexes that trigger mesendodermal gene expression and drive gastrulation, in cooperation with other maternal transcription factors. Using maternal Foxh1-null embryos, we demonstrate that Foxh1 directly recruits Ezh2, the catalytic subunit of PRC2, to Foxh1-bound loci. Loss of Foxh1 impairs Ezh2 recruitment, leading to a global reduction in H3K27me3. These findings support a dual-function model in which Foxh1 not only activates endodermal gene expression in endoderm, but also recruits PRC2 to silence the same genes in ectoderm. This dual activity of Foxh1 allows the spatially coordinated epigenetic states of the endodermal gene regulatory program during early embryogenesis.

CRISPR/Cas9↗

PubMed2025

Simultaneous Visualization of Protein and Genomic Regions in Plant Nuclei.

Immunohistostaining (IHS) is a widely used technique in diagnostic and research laboratories in which specific antibodies are used to detect and visualize a protein of interest in cells or tissues. Similarly, with specific oligonucleotide probes, the fluorescence in situ hybridization (FISH) method allows one to visualize genomic regions and to analyze its localization in the nuclear space. Here, we describe a combined FISH-IHS technique that enables researchers to determine the localization of protein and genomic loci in plant nuclei simultaneously. This method can be applied to extracted nuclei and sections of paraffin-embedded tissues. It provides a valuable tool to improve our understanding of nuclear dynamics by revealing the spatial relationship between specific genomic loci and target proteins.

In Situ Hybridization, Fluorescence↗

PubMed2026

Learning a pairwise epigenomic and transcription factor binding association score across the human genome.

MOTIVATION: Identifying pairwise associations between genomic loci is an important challenge for which large and diverse collections of epigenomic and transcription factor (TF) binding data can potentially be informative. RESULTS: We developed Learning Evidence of Pairwise Association from Epigenomic and TF binding data (LEPAE). LEPAE uses neural networks to quantify evidence of association for pairs of genomic windows from large-scale epigenomic and TF binding data along with distance information. We applied LEPAE using thousands of human datasets. We show using additional data that LEPAE captures biologically meaningful pairwise relationships between genomic loci, and we expect LEPAE scores to be a resource. AVAILABILITY AND IMPLEMENTATION: The LEPAE scores and the software are available at https://github.com/ernstlab/LEPAE.

Humans↗

PubMed2025

Epistasis of ERAP1 With 4 Major Histocompatibility Complex Class I Alleles in Frontal Fibrosing Alopecia: A Genome-Wide Association Study Meta-Analysis.

IMPORTANCE: Frontal fibrosing alopecia (FFA) is an inflammatory and scarring form of hair loss of increasing prevalence that most commonly affects women. An improved understanding of the genetic basis of FFA will support the identification of pathogenic mechanisms and therapeutic targets. OBJECTIVE: To identify novel genomic loci at which common genetic variation affects FFA susceptibility and assess nonadditive effects on genetic risk between susceptibility loci. DESIGN, SETTING, AND PARTICIPANTS: Four genome-wide association studies were combined using an SE-weighted meta-analysis. Within the major histocompatibility complex (MHC) locus, stepwise conditional analysis was undertaken to determine independently associated classical MHC class I alleles. Statistical tests for epistatic interaction were performed between risk alleles at the MHC and endoplasmic reticulum aminopeptidase 1 (ERAP1) loci. MAIN OUTCOMES AND MEASURES: Genome-wide significant locus associated with FFA and nonadditive effects on genetic risk between susceptibility loci. RESULTS: Of 6668 included patients, there were 1585 European female individuals with FFA and 5083 controls. Genome-wide significant associations were identified at 4 genomic loci, including a novel susceptibility locus at 5q15, and the association signal could be fine-mapped to a single nucleotide substitution (rs10045403) in the 5' untranslated region of ERAP1 (rs10045403; odds ratio, 1.30; 95% CI, 1.19-1.43; P = 3.6 × 10-8). Within the MHC, FFA risk was statistically independently associated with HLA-A*11:01, HLA-A*33:01, HLA-B*07:02, and HLA-B*35:01. FFA risk was affected by genetic variation at the ERAP1 locus only in individuals who carried at least 1 of the MHC class I risk alleles. CONCLUSIONS AND RELEVANCE: In this genome-wide meta-analysis, a supra-additive effect of genetic variation was found that affected peptide trimming and antigen presentation on FFA susceptibility. Patients with FFA may benefit from emerging therapeutic approaches that modulate ERAP-mediated processes.

Female↗

PubMed2025

Optimized phenotyping of complex morphological traits: enhancing discovery of common and rare genetic variants.

Genotype-phenotype (G-P) analyses for complex morphological traits typically utilize simple, predetermined anatomical measures or features derived via unsupervised dimension reduction techniques (e.g. principal component analysis (PCA) or eigen-shapes). Despite the popularity of these approaches, they do not necessarily reveal axes of phenotypic variation that are genetically relevant. Therefore, we introduce a framework to optimize phenotyping for G-P analyses, such as genome-wide association studies (GWAS) of common variants or rare variant association studies (RVAS) of rare variants. Our strategy is two-fold: (i) we construct a multidimensional feature space spanning a wide range of phenotypic variation, and (ii) within this feature space, we use an optimization algorithm to search for directions or feature combinations that are genetically enriched. To test our approach, we examine human facial shape in the context of GWAS and RVAS. In GWAS, we optimize for phenotypes exhibiting high heritability, estimated from either family data or genomic relatedness measured in unrelated individuals. In RVAS, we optimize for the skewness of phenotype distributions, aiming to detect commingled distributions that suggest single or few genomic loci with major effects. We compare our approach with eigen-shapes as baseline in GWAS involving 8246 individuals of European ancestry and in gene-based tests of rare variants with a subset of 1906 individuals. After applying linkage disequilibrium score regression to our GWAS results, heritability-enriched phenotypes yielded the highest SNP heritability, followed by eigen-shapes, while commingling-based traits displayed the lowest SNP heritability. Heritability-enriched phenotypes also exhibited higher discovery rates, identifying the same number of independent genomic loci as eigen-shapes with a smaller effective number of traits. For RVAS, commingling-based traits resulted in more genes passing the exome-wide significance threshold than eigen-shapes, while heritability-enriched phenotypes lead to only a few associations. Overall, our results demonstrate that optimized phenotyping allows for the extraction of genetically relevant traits that can specifically enhance discovery efforts of common and rare variants, as evidenced by their increased power in facial GWAS and RVAS.

Humans↗

PubMed2026

CRISPR/Cas- and Argonaute-Based In Vivo Nucleic-Acid Imaging Technologies: Strategies, Challenges, and Perspectives.

Live-cell monitoring of sequence-specific nucleic acids is essential to understanding genome organization, RNA regulation, and disease progression. Clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein (Cas) and Argonaute (Ago) systems provide programmable, guide-directed recognition of DNA or RNA and are increasingly used as platforms for in vivo bioimaging. This review summarizes the structural and mechanistic features of representative CRISPR and Ago effectors and discusses design strategies for sensitive, specific, and multiplexed imaging of genomic loci, extrachromosomal DNA, and endogenous RNA in living cells. We compare the analytical performance and limitations of CRISPR- and Ago-based imaging, with particular emphasis on the major technical and biological challenges affecting their accuracy, applicability, and reliability. Finally, this review offers insights into developing high-resolution and user-friendly bioimaging platforms for fundamental biology and future translational applications.

CRISPR↗

PubMed2025

The role of the brain-bone axis in skeletal degenerative diseases and psychiatric disorders, A genome-wide pleiotropic analysis.

INTRODUCTION: Skeletal degenerative diseases and psychiatric disorders often coexist clinically. However, the genetic correlations and underlying biological mechanisms between these two types of diseases remain unclear. OBJECTIVES: To investigate the genetic correlations between skeletal degenerative diseases and psychiatric disorders and to identify shared genomic loci, genes, and pathways. METHODS: This comprehensive genome-wide pleiotropic association study utilized summary statistics from publicly available genome-wide association data. Various statistical genetic correlation methods were employed, including LDSC, HDL, PLACO, Coloc, Hyprcoloc, and Mendelian randomization (MR) analysis, along with immune cell colocalization analysis. The study aimed to identify potential shared genetic factors among three skeletal degenerative diseases (osteoarthritis, intervertebral disc degeneration, and osteoporosis) and three psychiatric disorders (schizophrenia, anxiety disorder, and major depressive disorder). RESULTS: Analyses using LDSC, HDL, and Bonferroni corrections revealed significant genetic correlations between intervertebral disc degeneration (IVDD) and anxiety disorder (ANX); fractures, IVDD, and arthritis with major depressive disorder (MDD); and arthritis with schizophrenia (SCZ). Significant genetic correlations were also observed between VDD and ANX, fractures, IVDD, hip osteoarthritis (HipOA), knee osteoarthritis (KneeOA) and MDD, and KneeOA and SCZ. Pleiotropy analysis using PLACO, MAGMA, and multitrait colocalization Hyprcoloc identified 65 pleiotropic loci, 27 shared causal loci, and 9 shared risk loci involving immune cells related to both psychiatric and bone-related diseases. Additionally, tissue-specific enrichment analysis showed that genes mapped to these loci were enriched in brain, cardiovascular, pancreatic, and other tissues. The IVW method demonstrated that MDD increased the risk of IVDD and KneeOA, while IVDD increased the risk of ANX and MDD. Conversely, SCZ was associated with a reduced risk of KneeOA. Multiple sensitivity analyses further supported a positive causal effect of IVDD on MDD. CONCLUSION: These findings suggest significant genetic correlations between skeletal degenerative diseases and psychiatric disorders, highlighting multiple shared comorbid genes and key immune cell types. Importantly, the study supports the role of the brain-bone axis in the regulation of skeletal degenerative diseases and psychiatric disorders, which could provide valuable insights for potential therapeutic targets and interventions for these conditions.

Humans↗

PubMed2017

Rapid and reversible epigenome editing by endogenous chromatin regulators.

Understanding the causal link between epigenetic marks and gene regulation remains a central question in chromatin biology. To edit the epigenome we developed the FIRE-Cas9 system for rapid and reversible recruitment of endogenous chromatin regulators to specific genomic loci. We enhanced the dCas9-MS2 anchor for genome targeting with Fkbp/Frb dimerizing fusion proteins to allow chemical-induced proximity of a desired chromatin regulator. We find that mSWI/SNF (BAF) complex recruitment is sufficient to oppose Polycomb within minutes, leading to activation of bivalent gene transcription in mouse embryonic stem cells. Furthermore, Hp1/Suv39h1 heterochromatin complex recruitment to active promoters deposits H3K9me3 domains, resulting in gene silencing that can be reversed upon washout of the chemical dimerizer. This inducible recruitment strategy provides precise kinetic information to model epigenetic memory and plasticity. It is broadly applicable to mechanistic studies of chromatin in mammalian cells and is particularly suited to the analysis of endogenous multi-subunit chromatin regulator complexes.Understanding the link between epigenetic marks and gene regulation requires the development of new tools to directly manipulate chromatin. Here the authors demonstrate a Cas9-based system to recruit chromatin remodelers to loci of interest, allowing rapid, reversible manipulation of epigenetic states.

CRISPR-Cas Systems↗

PubMed2026

Synergistic engineering of Casδ nuclease for robust genome editing.

Casδ is a recently identified evolutionary transitional CRISPR system characterized by its compact size (~900 amino acids), broad temperature tolerance, and guidance by a short crRNA without the requirement of a tracrRNA. However, the low editing efficiency of Casδ in eukaryotic cells limits its application. Here, we have developed a hierarchical engineering strategy to improve the genome editing activity of Casδ-1, with optimization focused on enhancing its interactions with the crRNA, the protospacer adjacent motif (PAM) duplex, the single-stranded DNA substrate, and the RNA-DNA heteroduplex. Through this strategy, we successfully generated an activity-enhanced Casδ-1 variant, designated enCasδ, which harbors 9 amino acid substitutions that synergistically augment its editing efficiency. In human cell lines, enCasδ showed 1.3- to 29.3-fold higher editing activity than the wild-type Casδ-1 across ten tested genomic loci, with an average editing efficiency of 54.6%. In addition, enCasδ also mediated robust genome editing in maize; its editing efficiency increased by an average of 5.3-fold relative to Casδ-1, and reached up to an average of 80% at the TS4 and PSY1 loci in stable transgenic lines. The overall editing performance of enCasδ was comparable to that of Streptococcus pyogenes Cas9 (SpCas9) and other Cas12 nucleases. Collectively, enCasδ represents a highly optimized Casδ-1 variant that broadens the applicability of the Casδ CRISPR system and facilitates robust genome editing in both animal cells and plants.

Gene Editing↗

PubMed2026

SeqQC-former: A sequence-quality fusion framework for QC-aware review prioritization of candidate somatic SNVs in cancer genomics.

The accurate prioritization of candidate somatic single-nucleotide variants (SNVs) remains a challenge due to the substantial variability in sequencing quality across genomic loci. SeqQC-Former is a sequence-quality fusion framework that integrates the local nucleotide context with read-level quality-control (QC) covariates derived from matched tumor-normal sequencing data. This integration generates QC-aware prioritization scores for the downstream review of candidate variants. Unlike conventional variant callers, SeqQC-Former is designed not to infer biological truth but to support post-calling review and prioritization under heterogeneous sequencing conditions. The framework was trained and evaluated on a SEQC2-derived dataset comprising 89,447 candidate loci, including 1378 positive and 88,069 negative loci. In chromosome-held-out validation, which aims to reduce potential genomic-position leakage, SeqQC-Former demonstrated strong discrimination (AUROC = 0.9479; AUPRC = 0.9448), indicating good generalization to previously unseen chromosomes. Given that the SEQC2-derived labels contain QC-associated information; these results should be interpreted as an evaluation of QC-aware prioritization capability rather than an independent validation of biological variant correctness. Ablation analyses revealed that structured QC covariates provided the dominant predictive signal under the current SEQC2-derived labeling regime. SeqQC-Former achieved a significantly higher AUROC than classical machine-learning baselines, as determined by DeLong's test (p < 0.01). Application to 53,164 glioblastoma variants demonstrated that external predictions were sensitive to QC scaling and threshold selection, underscoring that model outputs should be interpreted as QC-dependent prioritization scores rather than calibrated probabilities or definitive biological classifications. Overall, SeqQC-Former offers a reproducible post-calling QC-aware prioritization framework for large-scale somatic SNV review and underscores the importance of explicitly modeling sequencing-quality information when interpreting structured cancer genomics datasets.

Humans↗

PubMed2026

Shared genetic architecture of smoking dependence and Crohn's disease: A cross-trait analysis of GWAS summary statistics.

INTRODUCTION: Smoking dependence (SD) and Crohn's disease (CD) are epidemiologically associated, but whether this relationship reflects shared genetic susceptibility remains unclear. METHODS: We conducted a cross-trait genetic analysis of SD and CD using publicly available genome-wide association study (GWAS) summary statistics from European-ancestry populations. Genome-wide genetic correlation was estimated using linkage disequilibrium score regression (LDSC) and high-definition likelihood (HDL). Pleiotropic variants were identified using PLACO and mapped to genomic loci using FUMA. Regional signal sharing was assessed by Bayesian colocalization. Functional analyses included stratified LDSC, Multi-marker Analysis of GenoMic Annotation (MAGMA), GTEx tissue analysis, and Metascape. Expression-linked candidate genes were prioritized using expression quantitative trait locus (eQTL)-based summary-data-based Mendelian randomization (SMR) with heterogeneity in dependent instruments (HEIDI) testing. Genetically informed spatial mapping of cells for complex traits (gsMap) was used for spatial mapping. RESULTS: SD and CD showed positive genetic correlation by LDSC (rg=0.2090, p=0.0008) and HDL (rg=0.3817, p=0.00106). PLACO identified 81 genome-wide significant pleiotropic SNPs, which were mapped by FUMA to three loci at 1p31.3, 5p13.1, and 12q12, represented by rs11209031, rs1395152, and rs17467116, respectively. MAGMA identified 22 FDR-significant genes, four of which remained Bonferroni significant: LRRK2, TNFRSF6B, ZGPAT, and RP4-583P15.15. Cross-trait tissue analysis showed significant enrichment of the shared genetic signal in whole blood and small intestine, while gene-set analysis highlighted inflammatory response (pbon=1.86×10-5) and T-helper 17 cell differentiation (pbon=7.37×10-4). SMR/HEIDI analysis further prioritized RPS6KB1 as a shared expression-linked candidate. Spatial mapping revealed a prominent signal in the embryonic gastrointestinal tract and gene-specific regional patterns involving LRRK2 and SLC2A13 in the adult mouse brain. CONCLUSIONS: SD and CD showed measurable shared genetic susceptibility, with convergent evidence from pleiotropic loci, immune-inflammatory pathway enrichment, tissue-level associations, and spatial transcriptomic mapping.

Crohn's disease↗