Cross-Trait Genome-Wide Association Study Identifies Shared Genetic Architecture Between COPD and Retinal Vascular Phenotypes

Genetic architecture shared between body shape phenotypes and preeclampsia-related diseases: a genome-wide cross-trait analysis.

This study indicates a genetic correlation and common risk genes, linking adiposity-related traits to PE-related diseases, and offers novel insights into the biological mechanisms underlying this comorbidity.

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.

Shared genetic basis and spatial cellular atlas of psoriasis and metabolic syndrome

Background Psoriasis (PS) and metabolic syndrome (MetS) frequently co-occur. Characterizing their shared genetic architecture and spatially enriched cellular populations may clarify the context of their co-occurrence and generate hypotheses for functional validation. Methods We integrated genome-wide association study (GWAS) summary statistics for PS, MetS, and five related components with spatially resolved single-cell transcriptomic data. Global and local genetic correlations were assessed using linkage disequilibrium score regression, genetic covariance analysis, high-definition likelihood, and local analysis of variant association. A bivariate causal mixture model quantified polygenic overlap. Conditional/conjunctional false discovery rate and composite-null pleiotropy analyses identified shared susceptibility loci. Finally, gsMap evaluated trait-associated enrichment across annotated embryonic tissues at single-cell resolution. Results Genetic approaches identified significant genome-wide correlations and polygenic sharing between PS, MetS, and its components. Local and cross-trait analyses identified region-specific signals and cross-validated shared loci. gsMap revealed trait-specific tissue enrichment. PS showed the strongest enrichment in the epidermis (pCauchy = 1.0573 × 10  − ⁴), adipose tissue (pCauchy = 1.5366 × 10 − ⁴), and liver (pCauchy = 1.0167 × 10 − ³). Across MetS, FBG, HDL-C, hypertension, and TG, enriched regions mainly involved the liver, adipose tissue, and epidermis. WC enrichment was predominantly observed in adipose tissue (pCauchy = 1.7823 × 10 − ⁴), with no significant liver or epidermal enrichment. Conclusion Integrating GWAS with single-cell transcriptomic and spatial information characterized shared genetic architecture between PS and MetS-related phenotypes and their spatial enrichment patterns. These findings provide a framework for generating testable hypotheses about comorbidity biology and guiding future functional and clinical validation.

Positive association and shared genetic structure between cardiovascular diseases and osteoarthritis: Insights from cross-sectional study and genome-wide pleiotropic analysis

A positive association was observed between the prevalence of CVDs and OA, potentially explained by shared genetic factors, and Pathway assessment and multi-trait colocalization suggested that abnormal lipid metabolism may be a common cause of CVDs and OA.

Integrative Multivariate Genomics Identifies Shared Epithelial–Immune and Cytokine-Regulatory Mechanisms Across Major Chronic Lung Diseases

Chronic lung diseases, including asthma, chronic obstructive pulmonary disease, bronchiectasis, and idiopathic pulmonary fibrosis, are clinically distinct but share epithelial injury, host-defense, inflammatory, and remodeling processes. We integrated European-ancestry genome-wide association study (GWAS) summary statistics for these four diseases using genomic structural equation modeling to construct a multivariate chronic lung disease (mvCLD) factor. Variant-level association testing was combined with genomic control assessment, locus annotation, GWAS-by-subtraction, fine-mapping, transcriptomic prioritization, pathway enrichment, single-cell spatial mapping, and heritability partitioning. For discovery, across 6,255,777 autosomal variants, mvCLD identified 2067 genome-wide significant variants, 30 loci, and 53 lead variants. Five lead variants were genome-wide significant for mvCLD but not for any component disease and showed high-confidence fine-mapping support. For gene prioritization, transcriptomic and gene-level analyses prioritized 21 candidate genes, including ORMDL3, GSDMB, IL18RAP, IL18R1, IL1R1, SMAD3, and CLEC16A. In exploratory functional analyses, enrichment analyses converged on interleukin, cytokine-receptor, JAK-STAT, interleukin-4/interleukin-13, thymic stromal lymphopoietin, asthma, and lung fibrosis pathways. Exploratory single-cell spatial mapping, based on a mouse embryonic atlas, showed the strongest overall enrichment in the lung annotation, although cross-dataset cell-type and tissue analyses did not reach significance after false discovery rate correction; heritability partitioning implicated conserved and active regulatory elements. These findings support a shared epithelial–immune and cytokine-regulatory genetic architecture across major chronic lung diseases and nominate biologically coherent candidate genes and pathways for future functional and translational studies.

Shared genetic architecture and cellular convergence between female reproductive disorders and pulmonary function: a genome-wide cross-trait analysis