Jul 2026· Journal of Obstetrics and Gynaecology Research· Vol 46 1, pp.
2706674
· 0 citations· 80 references
Medicine
TL;DR
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.
Abstract
Background
Observational studies have established a strong epidemiological connection between obesity and an increased risk of pre-eclampsia (PE). However, the genetic mechanisms underlying this comorbidity remain largely unexplored. In this study, we conducted a comprehensive cross-trait analysis to elucidate the shared genetic architecture between various adiposity-related traits and PE.
Methods
Using the genome-wide association study (GWAS) statistics, we first evaluated the overall genetic overlap between adiposity-related traits and PE through multiple approaches, including linkage disequilibrium score regression (LDSC), high-definition likelihood inference (HDL), genetic covariance analysis, and pleiotropy and annotation methods. Causal relationships were then evaluated through bi-directional Generalised Summary-data-based Mendelian Randomisation (GSMR). Candidate pleiotropic loci were identified using a robust suite of analytical tools, including cross-phenotype association analysis, Multi-Trait Analysis of GWAS (MTAG), pleiotropic analysis under a composite null hypothesis, a pleiotropy-informed conditional false discovery rate (pleioFDR) framework, and Functional Mapping and Annotation (FUMA). Bayesian colocalisation (COLOC) was subsequently applied to these loci to pinpoint independent, significant causal single nucleotide polymorphisms (SNPs). To identify and validate shared genes, we performed tissue enrichment analysis, using Multi-marker Analysis of Genomic Annotation, and integrated SPrediXcan with COLOC. Finally, gene functional enrichment was characterised via Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) enrichment analyses.
Results
We identified significant positive genetic correlations and robust causal associations between adiposity-related traits and PE-related diseases. Our analyses revealed 35 independent significant causal SNPs, 32 enriched tissues, and 7 shared high-confidence genes supported by COLOC analysis.
Conclusions
Collectively, our study indicates a genetic correlation and common risk genes, linking adiposity-related traits to PE-related diseases. These findings offer novel insights into the biological mechanisms underlying this comorbidity, highlighting promising targets for future mechanistic studies and stratified preventative strategies.
Background: Chronic obstructive pulmonary disease (COPD) is accompanied by systemic vascular dysfunction and microcirculatory impairment. Retinal vascular traits provide a non-invasive window into microvascular characteristics, although their shared genetic architecture with COPD remains unclear. Methods: We integrated genome-wide association study summary statistics for COPD and 17 retinal vascular traits in individuals of European ancestry. Genome-wide genetic correlations were evaluated using linkage disequilibrium score regression and high-definition likelihood. Shared pleiotropic variants were identified using pleiotropic analysis under a composite null hypothesis, followed by functional mapping and annotation, Bayesian colocalization, multi-marker analysis of genomic annotation, and functional enrichment analyses. Smoking-adjusted analyses were further conducted using genome-wide association study-by-subtraction based on genomic structural equation modeling. Results: Genetic correlation analyses identified significant associations between COPD and 10 retinal vascular traits after false discovery rate correction, with consistent directions across both methods; high-definition likelihood identified one additional trait. Positive correlations were observed for vascular bifurcation and density traits, whereas venous caliber traits showed negative correlations. Pleiotropic analysis identified 3,846 significant single-nucleotide polymorphisms across 10 trait pairs, corresponding to 2,246 unique variants and 56 unique loci. Recurrent signals were observed at 8p23.1, 15q25.1, 20q13.33, 4q31.21, and 6q24.1. Bayesian colocalization provided strong evidence for shared local genetic signals at six loci, particularly 8p23.1 and 20q13.33. Smoking-adjusted analyses showed that several genome-wide and locus-level associations remained detectable, whereas nicotinic receptor-related signals, especially at 15q25.1, were attenuated. Conclusion: COPD and retinal vascular traits show evidence of shared genetic architecture involving vascular branching, density, and venous caliber. These findings support retinal vascular traits as candidate research phenotypes for investigating systemic microvascular involvement in COPD. Further validation across diverse populations and functional studies is required.
Yu-Li Chen, Yi-Bin Li, Yijiao Tang et al.· International Journal of COP...· 0 citations
Background Osteoarthritis (OA) and cardiovascular diseases (CVDs) are leading global causes of disability. While evidence indicates a significant association in their prevalence, the underlying biological mechanisms driving this comorbidity remain unclear. Objectives This study seeks to elucidate the epidemiological association between OA and common CVDs, and investigate whether shared genetic architecture underlies their comorbidity. Design cross-sectional study and genome-wide pleiotropic analysis. Methods Among 21,019 participants, multivariable logistic regression was used to examine the associations between OA and five CVDs (angina pectoris, coronary artery disease, myocardial infarction, heart failure, and stroke). Genetic correlations were then estimated using large-scale GWAS summary data of European ancestry, with the OA GWAS specifically focusing on knee and hip. Subsequent pleiotropy and multi-trait colocalization analyses were performed to identify shared loci, genes, and biological mechanisms. Results A positive association was observed between the prevalence of CVDs and OA, potentially explained by shared genetic factors. The genetic correlations (rg) and P values were: AP-OA (rg = 0.2229, p < 0.001), CAD-OA (rg = 0.1530, p < 0.001), MI-OA (rg = 0.1685, p < 0.001), HF-OA (rg = 0.3094, p < 0.001), and stroke-OA (rg = 0.1605, p < 0.001), indicating a robust and consistent shared genetic architecture between OA and these cardiovascular conditions. A total of 80 pleiotropic loci were identified, with 20 showing significant colocalization. Gene-level analysis revealed 84 distinct pleiotropic genes, including APOE, SMG6, UQCC1, and FES. Tissue enrichment analysis highlighted the role of pleiotropic mechanisms in central and peripheral blood vessels. Pathway assessment and multi-trait colocalization suggested that abnormal lipid metabolism may be a common cause of CVDs and OA. Conclusion Our study revealed a positive association and a shared genetic connection between CVDs and OA, and illuminated the potential mechanisms that could be involved.
Yuheng Lu, Dexi Hu, Fei Tian et al.· Therapeutic Advances in Musc...· 0 citations
Early pregnancy bleeding is a common pregnancy complication, yet its genetic basis and potential links with psychiatric traits remain poorly understood. This study aimed to characterize the shared genetic architecture between early pregnancy bleeding and reproductive, psychiatric, and cardiometabolic traits.
We integrated linkage disequilibrium score regression (LDSC), local genetic correlation analysis (LAVA), and multi-trait genome-wide association analysis (MTAG). LDSC was used to estimate genome-wide genetic correlations, including sex-stratified analyses. LAVA was applied to identify genomic regions contributing to local genetic sharing. Guided by these correlation patterns, MTAG was performed to improve locus discovery, followed by cis-eQTL analysis using GTEx v8 to explore potential regulatory mechanisms.
LDSC revealed significant positive genetic correlations between early pregnancy bleeding and reproductive traits, including endometriosis, miscarriage, and uterine fibroids. Strong positive correlations were also observed with several psychiatric disorders, including major depressive disorder, post-traumatic stress disorder, and attention deficit hyperactivity disorder. Sex-stratified analyses suggested stronger genetic correlations with emotional reactivity-related traits in females, whereas social and behavioral traits were more prominent in males. LAVA localized these shared signals to specific genomic regions and identified pleiotropic hotspots at 8q21 near
RUNX1T1
and 9p21 near
CDKN2A/B
. MTAG identified two novel loci, 15q15.1 marked by rs45457497 and 11q13.1 marked by rs2452681. Cis-eQTL analysis showed that the lead variant at 15q15.1 regulates
RMDN3
expression across multiple brain regions, while the 11q13.1 locus regulates
PACS1, GAL3ST3
, and
SF3B2
expression in brain tissues and the pituitary.
These findings position early pregnancy bleeding as a multifactorial trait shaped by shared reproductive, psychiatric, neuroendocrine, and stress-related biology. The implication of
RMDN3
, which encodes a mitochondrial outer membrane protein involved in ER-mitochondria tethering and calcium homeostasis, suggests a potential molecular link between neuroendocrine stress pathways, psychiatric susceptibility, and reproductive vulnerability.
De-Yu Ji, Xianjin Wang, Meng Zhao et al.· Frontiers in Psychiatry· 0 citations
Background Endometriosis (EMS) and inflammatory bowel disease (IBD) are both chronic inflammatory disorders with overlapping clinical features, suggesting a potentially shared etiology. Although epidemiological studies have reported an association between the two conditions, the genetic basis of this relationship remains poorly understood. This study is aimed at characterizing the shared genetic architecture of EMS and IBD, identify pleiotropic loci implicated in both conditions, and explore the potential causal relationships and underlying biological mechanisms. Methods We analyzed large‐scale GWAS summary statistics to investigate the genetic relationship between EMS and IBD. Linkage‐disequilibrium score regression (LDSC) was used to estimate genetic correlation. The PLACO method was applied to identify pleiotropic loci, which were further evaluated by Bayesian colocalization. Functional implications were assessed using MAGMA gene‐set analysis, tissue enrichment analysis, and functional annotation. Bidirectional two‐sample Mendelian randomization (MR) was performed to examine causal inference, accompanied by leave‐one‐out sensitivity analyses and statistical power calculations. Results A statistically significant but modest positive genetic correlation was observed between EMS and IBD (rg = 0.0957, p = 0.0042). Twenty‐four genomic loci showed evidence of pleiotropic effects, and six of these carried strong evidence of a shared causal variant (posterior probability: PP.H4 > 0.7), including loci at 2p23.3 (ADCY3/DNAJC27), 4q12, 5q23.3, 7p15.2, 11q13.1 (CCDC88B), and 1q22. Functional analyses consistently implicated eight pleiotropic genes across multiple platforms: ADCY3, CCDC88B, GREB1, NOD2, RSPO3, SYNE1, THADA, and TRAIP. Pathway enrichment highlighted “positive regulation of gene expression” as a key shared mechanism (p < 0.05). Tissue‐specific analyses revealed strong signals in whole blood, spleen, and colon, consistent with the immunoinflammatory etiology of both diseases. Bidirectional MR did not support a causal relationship in either direction (IBD on EMS: OR = 1.007, 95% CI: 0.986–1.028, p = 0.543; EMS on IBD: OR = 1.054, 95% CI: 0.991–1.122, p = 0.092). Leave‐one‐out analyses confirmed that no single variant drove these estimates, and power analysis indicated adequate power to detect moderate causal effects. Conclusions The findings provide evidence for a shared, albeit modest, and genetic basis between EMS and IBD that is likely mediated through immune regulation, hormonal signaling, and tissue repair. The absence of significant causal effects in MR suggests that the observed comorbidity reflects common genetic susceptibility rather than a direct causal link. These results offer new insight into the mechanisms underlying the co‐occurrence of the two conditions and may inform future investigation of shared therapeutic targets.
Xinyue Cui, Jian-Hong Wang, Jingjing Chen et al.· BioMed Research Internationa...· 0 citations
Aortic aneurysm (AA) is a life-threatening cardiovascular condition with a strong genetic component, however, its molecular mechanisms remain poorly understood. Although genome-wide association studies (GWAS) have identified numerous risk loci, most prior studies have investigated genetic and metabolic factors separately, leaving the causal pathways from genetic variants to disease largely unexplored.
We established an integrative framework combining cross-tissue transcriptome-wide association studies (TWAS) with metabolomic mediation analysis. First, we integrated GWAS data from FinnGen R12 with multi-tissue expression quantitative trait loci (eQTL) data from Genotype-Tissue Expression Project (GTEx) V8, then performed cross-tissue TWAS using the Unified Test for MOlecular SignaTures (UTMOST) and single-tissue validation with the Functional Summary-based Imputation (FUSION) to prioritize susceptibility genes. Second, we applied Mendelian randomization (MR), colocalization, and Fine-mapping Of CaUsal gene Sets (FOCUS) to assess causality and identify high-confidence genes. Third, we performed metabolite mediation analysis to uncover metabolic pathways linking genetic variants to disease risk. Finally, we validated key findings in mouse models of thoracic aortic aneurysm (TAA) and abdominal aortic aneurysm (AAA) using Quantitative Real-Time Reverse Transcription Polymerase Chain Reaction (RT-qPCR) and Western blotting.
We identified multiple novel susceptibility genes for AA and its subtypes. Key genes included ADH family members (
ADH1A, ADH1B, ADH4, ADH6
) and
ZNF827
, which showed cross-subtype associations with strong colocalization evidence in vascular tissues. Metabolite mediation analysis revealed significant pathways involving N-acetylphenylalanine and methionine sulfoxide. Functional enrichment revealed distinct biological mechanisms: AA and AAA were primarily associated with metabolic pathways, whereas TAA-related genes were enriched in developmental and contractile processes. PheWAS indicated no significant off-target associations. Critically, experimental validation in mouse models confirmed significant upregulation of
ZNF827
in TAA and
ADH6
in AAA at both mRNA and protein levels, corroborating the genetic predictions.
This integrated cross-omics analysis identifies novel genetic loci and, crucially, uncovers specific nutrient-related metabolic pathways that mediate genetic risk. These findings provide a mechanistic basis for future nutritional and metabolic intervention studies in AA and its subtypes.
Hanxi Wang, Junjie Cheng, Jiali Yao et al.· Frontiers in Nutrition· 0 citations