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PubMed1979

Androgenic regulation of messenger RNA sequence complexity in accessory sexual tissues of the male rat studied with fractionated complementary DNA.

Effects of androgens on mRNA sequence complexity in the rat seminal vesicle have been investigated using complementary DNA fractionated on the basis of sequence abundance. Total cDNA complementary to poly(A)-rich RNA from normal rats was hybridised with an excess of the same RNA to controlled rot values and then the free cDNA was separated from cDNA . RNA hybrids by hydroxyapatite chromatography. Three cDNA fractions were obtained with very different hybridisation characteristics. Abundant cDNA hybridised to an excess of its parental RNA with an rot 1/2 of 2.46 x 10(-3) mol 1(-1) s and is complementary to about six or seven average-sized sequences. Use of hybrid-arrested translation in a cell-free protein-synthesising system has shown that this class of mRNA includes mRNAs coding for major androgen-dependent secretory proteins. Moderate and scarce cDNA fractions each showed more complex hybridization kinetics; computer analysis suggested each is complementary to two groups of average-sized sequences. Each cDNA fraction was hybridised to excess poly(A)-rich RNA from normal or castrated rats and the kinetics compared. Castration had no effect on the total number of sequences present in any class and did not alter the relative concentration of the scarce sequences. A small (threefold) decrease was seen in the concentration of abundant sequences with a larger (tenfold) decrease in the moderate class. Both de-reases were reversed by testosterone in vivo. The results are consistent with earlier studies where the effects of testosterone on seminal vesicle mRNA were followed using a translation assay and confirm that no gross differential effects are exerted on abundant mRNA coding for major secretory proteins. The cDNA fractions were also used to investigate the overlap in genetic expression between seminal vesicle and ventral prostate. Both tissues share all the scarce sequences in the same relative abundance. Less than 0.0015% and 0.004% of prostatic mRNA is complementary to seminal vesicle abundant and moderate sequences respectively. Similarly prostatic abundant sequences account for less than 0.004% of seminal vesicle mRNA.

Animals↗
PubMed2026

Common genetic mechanisms between obesity and COVID-19 severity: unravelling pleiotropic loci and biological pathways.

COVID-19 and obesity are complex conditions marked by immune and metabolic dysfunction, with the former still ranking among the leading causes of death from infectious diseases worldwide and the latter reaching pandemic proportions. Clinical evidence consistently shows that obesity increases the risk of severe COVID-19, yet the biological mechanisms underlying this association remain unclear. Given their physiological and clinical overlap, they may share genetic pathways. We investigated genetic variants jointly associated with body mass index (BMI) and COVID-19 using publicly available genome-wide data. A conjunctional false discovery rate (conjFDR) approach identified shared variants between BMI and three COVID-19 phenotypes: infection, hospitalization and very severe respiratory illness. Functional annotation and pathway enrichment analyses were performed to explore the biological context of these variants, followed by a phenome-wide association study (PheWAS) to characterize pleiotropy. Shared variants were enriched in immune, metabolic and hormonal signaling pathways, including metal ion transport and glycosylation. The overlap with BMI was strongest for hospitalized and severe cases, suggesting common mechanisms underlying disease progression rather than infection. These findings suggest a biologically meaningful genetic overlap between obesity and COVID-19 severity, highlighting pleiotropy as a key feature in complex disease interactions and potential shared therapeutic targets.

BMI↗
PubMed2026

Shared genetic architecture between major depression and intrinsic brain functional connectome organization.

BACKGROUND: Major depression (MD) is increasingly understood as a disorder characterized by widespread abnormalities in intrinsic brain functional network organization. Although both MD and brain functional connectome architecture are highly heritable, the genetic architecture underlying their relationship remains poorly characterized. METHODS: We integrated genome-wide association studies of MD with 191 ICA-based resting-state functional connectome traits to investigate their shared genetic architecture. These traits captured intrinsic connectome organization across amplitude, functional connectivity, and global connectivity domains. Cross-trait genetic analyses were used to assess pleiotropic overlap between traits. Locus-level and gene-based analyses integrating multi-omics evidence were performed to characterize the biological relevance of shared genetic signals. RESULTS: We identified significant genetic overlap between MD and 148 of 191 brain functional connectome traits. Cross-trait analyses revealed widespread shared genetic signals organized into 627 genomic loci across amplitude, functional connectivity, and global connectivity measures. Among these, 193 loci showed evidence consistent with shared causal variants based on colocalization analyses. Gene-level integration mapped these loci to 1459 protein-coding genes (390 unique genes). Multi-layer prioritization identified 17 high-confidence genes supported by convergent genomic, transcriptomic, and proteomic evidence, with enrichment in neurodevelopmental and lipid-related metabolism pathways. CONCLUSIONS: This study provides a multi-scale characterization of the shared genetic architecture between MD and intrinsic brain functional connectome organization, revealing that shared genetic signals between MD and brain functional systems are distributed across multiple functional levels and converge at the molecular level.

Connectome↗
PubMed2025

Dissecting the shared genetic architecture of schizophrenia with ventricular subregion volumes.

Schizophrenia is characterized by cerebral ventricular enlargement as an early and consistent structural anomaly. While genetic factors significantly influence both schizophrenia and cerebral ventricular enlargement, the shared genetic etiology between them requires further investigation. Using summary statistics from recent large genome-wide association studies on schizophrenia and 9 ventricular subregion volumes phenotypes. Gaussian causal mixture modeling was applied to characterize the genetic architecture and overlap between schizophrenia and ventricular subregion volumes phenotypes. Local genetic correlation was investigated with Local Analysis of Variant Association. The conjunctional false discovery rate framework was used to identify the specific shared genetic loci, annotated with FUMA. Gaussian causal mixture modeling estimated schizophrenia to be more polygenic more polygenic (9574 trait-influencing variants) than ventricular subregion volumes phenotypes (157-1267 trait-influencing variants). Conjunctional false discovery rate analysis identified 42 shared genetic loci, 17 loci were identified as novel for both schizophrenia and the ventricular subregion volumes phenotypes. Local Analysis of Variant Association revealed that 11 distinct loci demonstrated significant differences, among which 4 loci were situated in the Major Histocompatibility Complex region. Annotated genes in shared loci were enriched in molecular signaling pathways involved in inflammation and the brain structure. The shared loci between them were annotated and enriched in Major Histocompatibility Complex and inflammation-related pathways, highlighting new opportunities for future investigation.

Schizophrenia↗
PubMed2026

Schizophrenia and bipolar disorder: a comparative analysis of genetic and brain network connectivity.

BACKGROUND: Schizophrenia (SCZ) and bipolar disorder (BD) are severe psychiatric conditions with overlapping clinical presentations, genetic risk factors, and brain network dysfunction. Whether alterations in large-scale intrinsic brain networks reflect shared or disorder-specific genetic influences remains poorly understood. Clarifying this distinction is essential for refining etiological models and improving diagnostic precision. METHODS: Genome-wide inferred statistics (GWIS) were applied to decompose the genetic architecture of SCZ and BD into shared and unique components. Using resting-state network (RSN) data from the UK Biobank, functional connectivity (FC) and structural connectivity (SC) were extracted as neuroimaging phenotypes. Causal inference approaches were subsequently employed to infer potential directional relationships between brain network connectivity and each disorder. RESULTS: Analyses revealed both common and distinct patterns of brain network connectivity associated with SCZ and BD. Notably, SC within the default mode network (DMN) exhibited opposing effects across the two disorders, suggesting divergent structural underpinnings despite clinical overlap. Additionally, SC within the limbic network (LN) and frontotemporal control network demonstrated potential causal relationships with both conditions, implicating these circuits astransdiagnostic neural substrates. CONCLUSION: These findings illuminate the shared and disorder-specific genetic and neural architecture underlying SCZ and BD. Integrating genome-wide genetic methods with large-scale neuroimaging data offers a powerful framework for disentangling psychiatric comorbidity and may inform more targeted diagnostic criteria and individualized treatment strategies.

Humans↗
PubMed2026

Baseline Computed Tomography Coronary Angiography and Polygenic Risk Profiles in Adults With Type 2 Diabetes: A Cross-Sectional Analysis From the VOLTAIRE Study.

AIMS: To characterise baseline clinical, anatomical, and genetic cardiovascular risk profiles in participants enrolled in the VOLTAIRE (Evaluation of Polygenic Scores and CT Imaging in Risk Factor Modification in Patients with Type 2 Diabetes) study and examine concordance across these domains. METHODS: This analysis included adults with T2D who completed baseline computed tomography coronary angiography (CTCA) and polygenic risk score (PRS) assessment prior to randomisation in the VOLTAIRE study. Coronary atherosclerosis was evaluated using coronary artery calcium (CAC) score and CTCA-derived stenosis severity. Clinical risk was assessed using the New Zealand Society for the Study of Diabetes 5-year cardiovascular risk calculator. Polygenic risk for coronary artery disease was assessed using a genome-wide PRS and categorised into tertiles. RESULTS: Among 126 participants with T2D (mean age 57.5 ± 8.7 years; 62.7% male), coronary atherosclerotic burden was highly heterogeneous: 34.9% had CAC = 0, whereas 19.8% had CAC ≥ 400. Moderate-to-severe coronary stenosis (≥ 50%) was present in 40.5% of participants overall, including 20.4% of those classified as low clinical risk. PRS distribution was variable (low 37.3%, intermediate 35.7%, high 27.0%). Overlap between anatomical, genetic, and clinical domains was limited, with only 8.7% of participants classified as high risk across all three. CONCLUSIONS: Substantial heterogeneity and limited overlap exist between anatomical, genetic, and clinical cardiovascular risk measures in T2D. These findings support a multimodal approach to risk assessment integrating imaging and genetic profiling. TRIAL REGISTRATION: https://www. CLINICALTRIALS: gov; ID: NCT07091162.

Aged↗
PubMed1976

Convergence of genetic compositions assuming infinite population-size and overlapping generations.

The assumptions for the model treated in this paper are based on a population of hypothetically infinite size, which has reached its optimum density within a limited habitat. The aim has been to derive sufficient conditions for the genetic composition of a population to converge to a limit if generations overlap and time is measured in discrete intervals. Trivially the genetic composition does not change if at the starting point of time the compositions within all age-classes are the same; otherwise global convergence of the age-class distributions implies uniform convergence of the genetic compositions within the single age-classes if mating takes place between at least two age-classes, or within the first age-class only. Excluding age-class 1 mating within one age-class only results in periodical change of genetic compositions.

Age Factors↗
PubMed2018

Chronotype and cellular circadian rhythms predict the clinical response to lithium maintenance treatment in patients with bipolar disorder.

Bipolar disorder (BD) is a serious mood disorder associated with circadian rhythm abnormalities. Risk for BD is genetically encoded and overlaps with systems that maintain circadian rhythms. Lithium is an effective mood stabilizer treatment for BD, but only a minority of patients fully respond to monotherapy. Presently, we hypothesized that lithium-responsive BD patients (Li-R) would show characteristic differences in chronotype and cellular circadian rhythms compared to lithium non-responders (Li-NR). Selecting patients from a prospective, multi-center, clinical trial of lithium monotherapy, we examined morning vs. evening preference (chronotype) as a dimension of circadian rhythm function in 193 Li-R and Li-NR BD patients. From a subset of 59 patient donors, we measured circadian rhythms in skin fibroblasts longitudinally over 5 days using a bioluminescent reporter (Per2-luc). We then estimated circadian rhythm parameters (amplitude, period, phase) and the pharmacological effects of lithium on rhythms in cells from Li-R and Li-NR donors. Compared to Li-NRs, Li-Rs showed a difference in chronotype, with higher levels of morningness. Evening chronotype was associated with increased mood symptoms at baseline, including depression, mania, and insomnia. Cells from Li-Rs were more likely to exhibit a short circadian period, a linear relationship between period and phase, and period shortening effects of lithium. Common genetic variation in the IP3 signaling pathway may account for some of the individual differences in the effects of lithium on cellular rhythms. We conclude that circadian rhythms may influence response to lithium in maintenance treatment of BD.

Adult↗
PubMed2025

Co-morbid monogenic disorders at chromosome region 1q2: LMNA- and FLG-related disorders in a patient referred for assessment of joint hypermobility.

The phenotypic similarities and genetic heterogeneity occurring in diverse forms of Ehlers Danlos Syndrome (EDS) subtypes and many heritable connective tissue disorders can pose a diagnostic challenge. In the wake of the growing applications of next-generation sequencing technologies including exome and genome sequencing, opportunities for achieving definitive genetic diagnosis are increasingly arising. We present a 46-year-old man with joint laxity, recurrent joint subluxations, pelvic floor dysfunction, and postural orthostatic tachycardia syndrome (POTS), who was referred for EDS assessment. His medical history included morbid obesity requiring gastric bypass surgery, hearing loss, asthma, retinopathy, myopia, atrial septal defect, narcolepsy with cataplexy, polyneuropathy, folliculitis, lichen simplex chronicus, atopic dermatitis, and hypogonadism. His family history was significant for multiple first- and second-degree relatives who died from cardiac diseases including cases of childhood deaths. Physical examination showed joint laxity with Beighton score of 3/9, bilateral pes planus, hearing loss and macrocephaly. Exome sequencing revealed heterozygous variants LMNA c.1262 T > C p.L421P [classified as likely pathogenic], FLG c.2282_2285del p. S761Cfs*36 [classified as pathogenic], and FLG c.1501 C > T p. R501* [classified as pathogenic]. Mitochondria sequencing revealed a variant of uncertain significance (VUS), MT-ND2 m.5047 T > C p.V193A that is present at 9% heteroplasmy in blood. These findings show co-occurrence of pathogenic sequence variants in neighboring genes located in chromosome 1q2 region [LMNA and FLG] in a patient with features of hereditary connective tissue disorders. Our study highlights the capability of exome sequencing in achieving some actionable diagnosis in cases of co-morbid genetic disorders with overlapping and non-specific symptoms.

Humans↗
PubMed2026

Shared genetic architecture and neurobiological pathways of problematic alcohol use and anxiety disorders.

Problematic alcohol use (PAU) and anxiety disorders (ANX) frequently co-occur, implying shared genetic and neurobiological foundations. However, the directionality of potential causal relationships and the specific mechanisms underlying the overlap remain unclear. Thus, we investigated the shared genetic architecture and neurobiological pathways between PAU and ANX using a multimethod genomic approach. We analyzed summary statistics from genome-wide association studies (GWAS) of PAU and ANX using Mendelian Randomization to assess causal associations between ANX and PAU. We used MiXeR to assess the overall shared genomic architecture, Local Analysis of (co)Variant Association to estimate regional genetic correlations, and conjunctional false discovery rate (conjFDR) to identify individual overlapping loci. We used FUMA to map single-nucleotide polymorphisms (SNPs) to independent loci, conduct differential gene expression analyses across 30 general and 54 specific tissue types, and perform cell-type specificity analyses using a human brain cell atlas. Druggability of identified targets was also evaluated. Mendelian Randomization analyses indicated bidirectional causal associations between ANX and PAU. MiXeR identified moderate polygenic overlap (52.5%) and genetic correlation (rg = 0.44) between the traits, with high effect direction concordance among shared estimated causal variants (86.4%). ConjFDR identified 97 shared lead SNPs, of which 89 had concordant and 8 discordant effects on PAU and ANX. These loci mapped to 97 genes, including DRD2 and PDE4B, genes linked to dopaminergic and cAMP signaling pathways, respectively. Concordant gene expression was enriched in brain, nerve, adrenal gland, esophagus, stomach, and colon, with enriched expression specifically in the prefrontal cortex, anterior cingulate cortex, hippocampus, hypothalamus, substantia nigra and amygdala. FUMA cell-type enrichment analysis identified associations predominantly in neurons from the cerebral cortex, hippocampus, and thalamus. We found substantial genetic and neurobiological overlap between PAU and ANX, highlighting reciprocal, causal relationships between the traits, with differentially expressed genes enriched in addiction- and anxiety-relevant brain regions. These findings support shared genetic and neurobiological mechanisms linking PAU and ANX, while acknowledging that some signals may reflect broader internalizing or psychiatric liability.

Journal Article↗
PubMed2025

Phenotypic and Genetic Associations Between Cardiovascular Disease Subtypes and Alzheimer's Disease.

BACKGROUND: Cardiovascular disease (CVD) and Alzheimer's disease (AD) are major public health concerns that share overlapping risk factors and potential mechanistic pathways. While vascular contributions to cognitive decline are well-documented, the specific relationships between AD and different CVD subtypes remain poorly understood. METHODS: We examined associations between AD and 11 CVD subtypes using logistic regression models in two large biobanks: the UK Biobank (n = 502,133) and the All of Us Research Program (n = 287,011). Models were adjusted for demographic, lifestyle, and clinical covariates. We also explored genetic overlap between AD and CVD traits through colocalization of significant single nucleotide polymorphisms (SNPs) (p < 5&#xd7;10-8) using genome-wide association study (GWAS) data. RESULTS: Most CVD subtypes were significantly associated with AD in both cohorts. Hypotension had the strongest and most consistent association, followed by hypertension and cerebral infarction. Acute myocardial infarction was the only subtype not significantly linked to AD. Genetic analyses revealed shared loci between AD and CVD-related traits, particularly in regions near APOE, MAPT, and genes influencing myocardial structure and vascular function. CONCLUSIONS: This study identifies subtype-specific CVD associations with AD across two diverse cohorts and highlights shared genetic architecture underlying heart-brain interactions. These findings underscore the importance of vascular health in AD risk and suggest that certain CVD subtypes, especially hypotension, may play underrecognized roles in cognitive decline.

Alzheimer&#x2019;s disease↗
PubMed2025

A Comprehensive Review of GWASs of Human Hair Traits.

Hair traits are nonpathogenic features that vary among individuals. Unlike hair follicle (HF) diseases, which are rare in the population, hair traits can be measured in everyone. This facilitates the construction of large cohorts that are well-powered for gene discovery. GWASs identify genetic variants that are widely shared among people globally, providing knowledge with broad population relevance. We compile findings from hair trait GWASs to deepen our understanding of HF biology. In reviewing genetic factors that influence hair traits, we demonstrate overlap with disease genes, underscoring that genetic studies of traits improve our knowledge about health and disease.

Humans↗
PubMed2026

Shared genetic architecture and therapeutic targets across paediatric immune-mediated diseases.

OBJECTIVES: Paediatric-onset immune-mediated inflammatory diseases (IMIDs), including juvenile idiopathic arthritis and related rheumatic diseases, remain genetically undercharacterised. We aimed to define shared and category-specific genetic architecture across paediatric IMIDs, compare signals with adult IMIDs, and identify therapeutic opportunities. METHODS: We analysed 24 paediatric IMIDs classified as autoimmune, polygenic-autoinflammatory, mixed-pattern, or allergic. Genome-wide association analyses included 18,086 cases and 131,019 controls of European ancestry. We estimated single nucleotide polymorphism (SNP)-based heritability, genetic correlations, and polygenic overlap; performed subset-based meta-analysis; and conducted functional annotation, gene prioritisation, pathway and protein network analyses, adult-IMID comparison, and drug-target prioritisation. RESULTS: SNP-based heritability ranged from 28.9% for allergic IMIDs to 61.9% for autoimmune IMIDs. Genetic correlation and polygenic modelling supported partial sharing across categories with category-specific components. Meta-analysis identified 39 genome-wide significant loci outside the Major Histocompatibility Complex (MHC) region, including 15 previously unreported loci; 19 loci were shared between categories. Gene-prioritisation and protein interaction analyses identified a core MHC-centred antigen-presentation network, with category-enriched modules involving complement, innate/barrier pathways, epithelial biology, and type 2 immunity. Enriched pathways included nuclear factor &#x3ba;B signalling, T helper 17 related pathways, Janus kinase-signal transducer and activator of transcription signalling, programmed cell death protein 1/programmed death&#x2011;ligand 1, cytotoxic T&#x2011;lymphocyte associated protein 4 regulation, and osteoclast differentiation, several of which are relevant to rheumatic diseases. Paediatric IMIDs shared broad polygenic architecture with adult IMIDs, whereas top-ranked genes converged strongly with adult rheumatic diseases. Priority Index analysis identified 178 high-scoring genes, including 43 approved or investigational IMID drug targets. CONCLUSIONS: Paediatric-onset IMIDs share core pathways with adult forms but exhibit distinct genetic architecture shaped by age-specific immune and neurodevelopmental biology. These findings provide a genomic framework for paediatric precision medicine, guiding classification, risk prediction, and therapeutic development.

Humans↗
PubMed1978

A single base-pair change creates a Chi recombinational hotspot in bacteriophage lambda.

X4+ mutations, responsible for the Chi phenotype in phage lambda, locally increase the rate of recombination promoted by the Escherichia coli recombination system (Rec). X+ mutations in the cII gene, one of a few sites in lambda at which such mutations arise, were located genetically and physically with overlapping deletions. DNA sequence analysis of the deletion segment containing the X+ C mutations showed that two independent X+ C mutations arose by the same A-T to T-A transversion. Presumably, this change creates a nucleotide sequence recognized by a protein involved in a rate-limiting step of recombination.

Base Sequence↗
PubMed2026

Host Genetic Regulation of NLRP3 Inflammasome Cytokines Reveals Immune and Vascular Pathways in HIV.

People with HIV exhibit elevated inflammation and cardiovascular risk despite antiretroviral therapy. To define the genetic architecture of inflammasome-associated inflammation, we performed whole-genome sequencing and quantified plasma IL-6, IL-1&#x3b2;, and IL-18 in 1,000 ART-suppressed PWH from the U.S. Military HIV Natural History Study. Genome-wide analyses identified 14 loci implicating antiviral defense (DDX17, DDX41, EEA1, BCL11A), lipid metabolism (ABCA1, ABCA12, ABCC1, AGMO), and vascular remodeling (KLHL29, RNF213, ETV1). Transcriptome-wide analyses across cardiovascular and immune tissues identified regulatory programs linking interferon signaling, immune activation, and vascular biology to circulating cytokine levels. Mendelian randomization analyses supported causal relationships between inflammasome-associated cytokines and vascular events. Functional integration with genome-wide CRISPR perturbation datasets in primary CD4+ T cells linked cytokine-associated loci to HIV antiviral pathways and cytokine regulatory networks. External validation in cohorts without HIV demonstrated pathway-level convergence despite limited variant-level overlap. These findings define genetic mechanisms linking inflammasome signaling, antiviral defense, and cardiovascular risk.

HIV↗
PubMed2026

Testicular aggressive B-cell lymphoma with plasmablastic morphology harboring concurrent IGH::MYC and IGH::BCL2 rearrangements.

BACKGROUND: Aggressive B-cell lymphomas with plasmablastic morphology are uncommon neoplasms that may exhibit overlapping morphologic, immunophenotypic, and genetic features of plasmablastic lymphoma (PBL) and double-hit lymphoma (DHL). Concurrent IGH::MYC and IGH::BCL2 rearrangements are rarely encountered in this setting, particularly in the testis. Here, we describe an unusual case presenting significant diagnostic challenges at the interface between PBL and DHL. CASE PRESENTATION: We report a 66-year-old, immunocompetent man presenting with a 5&#xa0;cm left testicular mass. Histologic examination revealed diffuse proliferation of large atypical lymphoid cells with plasmablastic morphology. Immunohistochemically, the tumor expressed CD138, CD38, and MUM1, with focal BCL2, c-MYC protein, and CD79a positivity, while CD20, CD19, PAX5, CD10, BCL6, and ALK were negative. EBV-encoded RNA in situ hybridization was negative. Fluorescence in situ hybridization identified IGH::MYC [t(8;14)] rearrangement in 45% and IGH::BCL2 [t(14;18)] rearrangement in 21% of analyzed nuclei. Next-generation sequencing additionally revealed BRAF V600E mutation, CDKN2A deletion, and human leukocyte antigen class I genomic alterations. CONCLUSION: This case highlights a rare testicular aggressive B-cell lymphoma with plasmablastic morphology and concurrent IGH::MYC and IGH::BCL2 rearrangements, representing a diagnostically challenging neoplasm at the interface between PBL and DHL. Our findings underscore the value of integrated morphologic, immunophenotypic, cytogenetic, and molecular analyses in evaluating aggressive B-cell lymphomas with plasmablastic features arising in immune-privileged sites.

Humans↗
PubMed2025

Potential therapeutic targets for ovarian hyperstimulation syndrome revealed by proteome-wide mendelian randomization and colocalization analysis.

Ovarian hyperstimulation syndrome (OHSS) is a severe complication associated with assisted reproductive technologies, characterized by metabolic, immune and vascular disorders. Understanding the molecular mechanisms underlying OHSS could reveal potential therapeutic targets and improve patient outcomes. In this study, We aimed to utilize proteome-wide Mendelian randomization (MR) and colocalization analysis to identify plasma proteins associated with OHSS and evaluate their potential as therapeutic targets through druggability assessment. We employed proteome-wide MR analysis summary data-based Mendelian randomization (SMR) analysis and phenome-wide association study (PheWAS) analysis to establish causal relationships between plasma proteins and OHSS. Colocalization analysis confirmed overlaps between proteins and genetic signals associated with OHSS. Pathway and network analyses were conducted to explore biological functions and protein interactions, while drug-target databases were queried for potential therapeutic interventions. Our results showed that 4 key proteins, including Suprabasin (SBSN), SLAMF4 (CD244), Enolase 3 (ENO3) and Thioredoxin domain-containing protein 12 (TXNDC12) were identified as significant contributors to OHSS. Pathway enrichment and interaction analyses further supported their involvement in metabolic, immune and structural pathways related to OHSS. Drug availability for colocalized proteins reveled potential drug targets for ENO3 (2-deoxy-D-glucose), CD244 (lenalidomide) and TXNDC12 (Auranofin), while no potential drug targets were identified for SBSN. Over all, our study identified15 plasma proteins, including SBSN, CD244, ENO3, and TXNDC12, as key contributors to the risk of OHSS through MR and colocalization analysis. These proteins were involved in metabolic regulation, immune response and antioxidant pathways, highlighting potential therapeutic targets and suggesting new directions for treatment strategies.

Humans↗