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PubMed2026

Microglial PICALM: A novel genetic driver and therapeutic target in vascular dementia.

BACKGROUND: Vascular dementia (VaD) lacks well-defined genetic mechanisms. Cell-type-specific effects of GWAS loci remain unexplored. METHODS: We integrated single‑cell eQTL data (183 donors, eight cell types) with VaD GWAS (3624 cases, 475,484 controls) using Mendelian randomization and Bayesian colocalization, replicated in an independent cohort (2074 cases, 456,366 controls). Subtype, snRNA‑seq, cell‑cell communication, PheWAS, expression profiling, and drug prediction with BBB permeability assessment were performed. RESULTS: Microglial PICALM was the only robustly replicated signal (OR = 0.8334, p = 5.3 × 10⁻⁴; colocalization PP.H4 > 0.75). The effect was strongest in multiple infarctions dementia (OR = 0.7746). Exploratory snRNA-seq analysis (4 VaD vs. 4 controls; GSE282111) provided supporting evidence for microglial PICALM enrichment and downregulation (p < 0.001). PICALM‑high microglia showed enhanced neurovascular‑ and phagocytosis‑related communication (e.g., SPP1, GAS6, GRN). PheWAS revealed no pleiotropy. In silico drug repurposing prioritised three FDA-approved BBB-penetrant compounds (disopyramide, benzocaine, amantadine) as candidates warranting further mechanistic validation. CONCLUSIONS: Microglial PICALM is identified as a likely genetic determinant of VaD, especially in the multiple infarctions subtype. Upregulating PICALM may be associated with a neuroprotective microglial phenotype, highlighting PICALM as a candidate therapeutic target warranting further experimental validation.

Humans↗

PubMed2025

Integrative omics of the genetic basis for wheat WUE and drought resilience reveal the function of TaMYB7-A1.

Improving wheat drought resilience and water use efficiency (WUE) is critical for sustaining productivity under increasing water scarcity. Here, we integrate genome-wide association study (GWAS), expression quantitative trait locus (eQTL) mapping, population-transcriptome analysis, and summary-data-based mendelian randomization (SMR), followed by functional validation using indexed EMS mutants and transgenic lines, to systematically identify key WUE regulators. GWAS across water conditions in 228 accessions identifies 73 quantitative trait loci (QTLs) for WUE-traits. Transcriptome profiling of 110 diverse accessions reveals 28 drought-responsive modules. eQTL mapping uncovers 146,966 regulatory variants, including condition-specific hotspots associated with key drought-related pathways. Integrative analysis underscores 85 high-confidence candidate genes, notably TaMYB7-A1. Overexpression of TaMYB7-A1 enhances photosynthesis, WUE, root development, and grain yield under drought condition by activating TaPIP2;2-B1 (water transport), TaRD20-D1 (stomatal regulation), and TaABCB4-B1 (root growth), reflecting reduced water loss and improved physiological resilience. Our study presents a comprehensive regulatory map and robust targets for wheat drought adaptation and resilient cultivar breeding.

Triticum↗

PubMed2026

Genomic and integrative based progression biomarker discovery in adult sepsis: toward clinical stratification and precision medicine.

Sepsis is a life-threatening syndrome characterized by a heterogeneous host response to infection that remains a major cause of mortality worldwide. Current clinical scoring systems capture organ dysfunction but fail to reflect the underlying biological diversity, limiting their utility for patient stratification and targeted therapy. This review provides a comprehensive overview of molecular biomarker approaches used to predict sepsis course and prognosis in adult patients, covering genetic, transcriptomic, proteomic, and integrative strategies up to May 2026. Here, we summarize findings from genetic association studies, along with analyses based on polygenic risk scores to aggregate genetic effects, Mendelian randomization, and rare-variant sequencing approaches. We also review transcriptomic and proteomic strategies for endotyping, and diagnostic and prognostic discrimination. Lastly, we discuss how multi-omics integration is emerging as a promising framework to assist in distinguishing causal therapeutic targets from non-causal biomarkers. We also address the challenges that still constrain clinical translation towards precision medicine.

Biomarker↗

PubMed1999

Molecular characterization of MRJP3, highly polymorphic protein of honeybee (Apis mellifera) royal jelly.

Major proteins of honey bee (Apis mellifera) royal jelly are members of the MRJP protein family. One MRJP protein termed MRJP3 exhibits a size polymorphism as detected by SDS-PAGE. In this report we show that polymorphism of the MRJP3 protein is a consequence of the polymorphism of a region with a variable number of tandem repeats (VNTR) located at the C-terminal part of the MRJP3 coding region. We present the characterization of five polymorphic alleles of MRJP3 by DNA sequencing. By PCR analyses, at least 10 alleles of distinct sizes were found in randomly sampled bees. Studies with nurse bees from a single honeybee colony revealed both Mendelian inheritance and very high variability of the MRJP3 genomic locus. The high variability and simple detection of the MRJP3 polymorphism may be useful for genotyping of individuals in studies of the honeybee.

Alleles↗

PubMed2005

Transmission ratio distortion in the spinal muscular atrophy locus: data from 314 prenatal tests.

BACKGROUND: Spinal muscular atrophy (SMA) is a recessive neurodegenerative disorder characterized by the loss of alpha-motor neurons in the spinal cord and subsequent death of motor neuron cells. SMA occurs with a frequency of 1 in 6,000 live births, with a carrier frequency of 1 in 40, and is a leading genetic cause of infant mortality. SMA is caused by loss or mutation of the telomeric survival motor neuron gene (SMN1), which is deleted in almost 94% of SMA patients OBJECTIVE: To analyze the transmission ratio at the SMA locus, examining the segregation of the SMN1-deleted alleles in 314 fetuses from carrier parents who requested prenatal testing for the disease. METHODS: Prenatal diagnosis of SMA in families at 25% risk of the disease has been performed on chorionic villous sampling specimens, through direct detection of the SMN1 gene mutation and linkage analysis using microsatellite markers from the 5q13 region. Analysis of the genotypic/allelic frequencies of the SMN1 gene was performed using the chi2 test, assuming a recessive mendelian inheritance. RESULTS: Of 314 fetuses analyzed, 95 were homozygous for the wild-type allele (30.3%), 154 were carriers (49.0%), and the remaining 65 were homozygous for the mutated allele (20.7%). Statistical analysis demonstrated that proportion of fetuses predicted with SMA is lower than 25% expected for a recessive disorder, resulting in a transmission rate of the SMN1-deleted allele deviant from the 50% expected in a random the segregation of a mendelian tract (p = 0.016) CONCLUSIONS: This is the first study to evaluate the genotypic frequencies at the spinal muscular atrophy (SMA) locus based on data derived from prenatal analysis, which are not subject to ascertainment bias. The analysis showed a transmission ratio distortion at the SMA locus in favor of the SMN1 wild-type alleles.

Chorionic Villi Sampling↗

PubMed2026

Causal Effects Between Neurodegenerative Diseases, Metabolites, and Brain Volume.

INTRODUCTION/OBJECTIVE: Neurodegenerative diseases such as Alzheimer's disease (AD), Lewy dody dementia (LBD), and Parkinson's disease (PD) are linked to changes in brain volume. However, causal evidence on how these diseases affect brain volume and whether metabolites mediate these causal effects remains limited. METHODS: We applied mediation Mendelian randomization analysis using GWAS summary statistics. The inverse variance-weighted method was used to assess causal effects and identify potential metabolite mediators. RESULTS: The MR analyses indicated that bilateral thalamus and putamen volumes (FDR < 0.05) had causal effects on PD. AD and LBD showed causal effects on bilateral thalamus and hippocampus (FDR < 0.01), with LBD specifically showing a causal effect on bilateral putamen (FDR < 0.05). Mediation analyses revealed that AD had a genetically predicted association with Nervonoy- L-carnitine and 1-linoleoyl-2-arachidonoyl-GPC (p-value = 0.04 and 0.01, respectively). Moreover, Nervonoy-L-carnitine was suggestively negatively associated with hippocampus volume (p-value = 0.03 and 0.02, respectively). 1-linoleoyl-2-arachidonoyl-GPC exhibited a negative genetically predicted association with hippocampus volume (p-value < 0.05). Additionally, LBD showed a negative genetically predicted association on the ratio of retinol to linoleoyl-arachidonoyl- glycerol (p-value = 0.02), and a positive genetically predicted association on Nervonoy-L-- carnitine (p-value < 0.05) and 1-linoleoyl-2-arachidonoyl-GPC (p-value = 0.03). DISCUSSION: These results suggest that AD and LBD affect brain regions through causal pathways. The involvement of specific metabolites highlights potential mechanisms linking neurodegeneration to brain volume. CONCLUSION: Nervonoylcarnitine and 1-linoleoyl-2-arachidonoyl-GPC may mediate the predicted effects of AD and LBD on hippocampal volumes, while the ratio of retinol to linoleoyl-arachidonoyl- glycerol mediates only LBD.

Humans↗

PubMed2026

Associations of genetically predicted interleukin-6 and tumor necrosis factor signaling pathways with mortality among persons with colorectal cancer: a two-sample Mendelian randomization.

BACKGROUND: Despite significant progress in identifying risk factors for colorectal cancer (CRC), factors influencing survival in people with CRC remain less understood. Pro-inflammatory cytokines like interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) have been implicated in cancer progression and may influence CRC outcomes. We investigated associations between genetically predicted levels of IL-6 and TNF-α signaling pathways and mortality in people with CRC. METHODS: We conducted a two-sample Mendelian randomization (MR) analysis using cis-acting single nucleotide polymorphisms (SNPs) associated with soluble IL-6 receptor alpha (sIL6-RA) and IL-6 signal transducer gp130 (IL6ST), representing IL-6 signaling, and with TNF-α, and its soluble receptors (sTNF-R1, sTNF-R2). SNPs were obtained separately from two large genome-wide association studies (GWAS): deCODE and UK Biobank (UKB). The outcome was CRC-specific mortality among 16,964 CRC cases (4010 deaths) in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Analyses were stratified by tumor site and stage. The inverse variance weighted (IVW) method, incorporating a correlation matrix for dependent SNPs, was used for primary analyses. Because literature links TNF-α to CRC incidence, we additionally performed a simulation study to evaluate the potential impact of collider bias resulting from restricting analyses to CRC cases. RESULTS: Genetically predicted sIL6-RA was weakly positively associated with CRC-specific mortality (deCODE-SNPs (n = 13) HR per 1 SD increase: 1.06; 95% CI: 1.00-1.12; UKB-SNPs (n = 11) HR: 1.09; 95% CI: 1.02-1.17). Genetically proxied IL6ST levels showed no association with CRC-specific mortality in the overall sample (deCODE-SNPs (n = 19) HR: 1.04; 95% CI: 0.90-1.21; UKB-SNPs (n = 9) HR: 1.11; 95% CI: 0.87-2.42), while higher IL6ST levels were associated with increased mortality among patients with stage 2/3 disease (deCODE-SNPs (n = 19) HR: 1.45; 95% CI: 1.10-1.91; UKB-SNPs (n = 9) HR: 1.87; 95% CI: 1.22-2.89). No associations were observed for TNF-α, sTNF-R1, or sTNF-R2. Findings for all exposures were consistent across both GWAS datasets. Simulation analyses for TNF-α indicated collider bias was present but limited in magnitude. CONCLUSIONS: Our findings suggest that IL-6 signaling may play a role in CRC progression although of limited magnitude, whereas TNF-related pathways appear less relevant for prognosis.

Humans↗

PubMed2026

Mitochondrial dysfunction in the pathogenesis of intervertebral disc herniation: a mitochondrial related genome-wide Mendelian randomization analysis.

BACKGROUND: As a degenerative disease, the pathophysiology of intervertebral disc herniation (IDH) closely related to mitochondrial dysfunction. However, the specific molecular mechanisms involved have yet to be precisely established. METHODS: Here, we employed a two-sample, two-step Mendelian Randomization (MR) approach, along with summary-Data-Based MR, genetic colocalization, full phenomenon association analysis, and GO and KEGG enrichment analysis to investigate the genetical effects of mitochondrial dysfunction on IDH. RESULTS: From the intercross between mitochondrial-related genes and eQTLGen genes, we obtained seven genes (DMPK, EHHADH, SLC25A16, ME3, METTL17, TUFM, NDUFA13) with strong causal association with disc herniation. By SMR and genetic colocalization analysis, we further identify five key genes (EHHADH, METTL17, TUFM, NDUFA13, DMPK) as the direct causal tartgeted genes with no heterogeneity and pleiotropy in the SNPs of the genes. Full phenomenon Mendelian randomization was performed to determine possible side effects of the 5 targeting genes. Finally, we validated the expressions of key genes in the degenerative intervertebral discs tissues by qRT-PCR and double-immunofluorescence examinations, and the results were consistent with the MR analysis. CONCLUSIONS: Our study provided genetic support for the relationship between mitochondrial related genes and IDH, implicating potential therapeutic targets for future development. However, more basic experiments need to be finished to validate the role of key genes in the development of IDH.

Intervertebral Disc Displacement↗

PubMed2026

A regulatory network underlying idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease in which genetic susceptibility interacts with epithelial, immune, and mesenchymal remodeling. Although the chromosome 11p15.5 locus contains established IPF susceptibility signals near MUC5B and TOLLIP, the broader regulatory architecture of this region remains incompletely resolved. METHODS: We integrated IPF genome-wide association study summary statistics with methylation, expression, and protein quantitative trait loci using summary-data-based Mendelian randomization (SMR). SMR-prioritized candidates were evaluated in independent transcriptomic and methylation cohorts and further contextualized using microRNA, transcription-factor, protein-interaction, machine-learning, single-cell, and spatial transcriptomic analyses. Fibrosis-associated expression patterns were assessed in a bleomycin-induced pulmonary fibrosis rat model. RESULTS: The analyses recovered the established MUC5B and TOLLIP signals and prioritized BRSK2 as a comparatively underexplored candidate supported by eQTL-based SMR and independent molecular evidence. The BRSK2 pQTL association did not pass the HEIDI test and was therefore not interpreted as convergent protein-level genetic evidence. Network analyses linked BRSK2 to cell-cycle, metabolic-stress, and senescence-related programs, while cross-cohort machine learning prioritized FOXA2, CDC25B, and NFE2 as informative network features. Single-cell and spatial analyses localized BRSK2 preferentially to fibroblast and myofibroblast compartments and to regions with greater histological fibrosis severity. In fibrotic rat lungs, BRSK2 expression increased, whereas FOXA2 and CDC25B decreased at the transcript and protein levels. CONCLUSIONS: These findings refine the molecular landscape of the chromosome 11p15.5 IPF susceptibility locus and prioritize BRSK2 as a candidate component of an IPF-associated profibrotic fibroblast state. Its causal contribution, direct regulatory relationships, and therapeutic tractability require targeted mechanistic validation.

Idiopathic Pulmonary Fibrosis↗

PubMed2026

DNA Methylation-Mediated Regulation of TAGLN2 Expression Promotes Pulmonary Arterial Hypertension.

BACKGROUND: Succinylation, a key post-translational modification, is implicated in the metabolic reprogramming and vascular remodeling of pulmonary arterial hypertension (PAH). While epigenetic regulation, particularly DNA methylation, potentially governs succinylation-related gene expression, its causal links to PAH remain unclear. METHODS: We performed an integrative causal analysis using two-sample Mendelian randomization (MR) and summary-data-based MR (SMR) to identify succinylation-related genes that influence PAH risk. We leveraged PAH GWAS data (FinnGen) and gene expression quantitative trait loci (eQTLGen). Subsequently, methylation-mediated effect decomposition was applied using DNA methylation data (GoDMC) to explore epigenetic regulation. Experimental validation was conducted in lung tissues from a monocrotaline (MCT)-induced PAH rat model via quantitative reverse transcription polymerase chain reaction (qRT-PCR). RESULTS: Genetic analyses identified a significant causal effect of elevated Transgelin 2 (TAGLN2) expression on increased PAH risk. This effect was mediated by two specific DNA methylation sites, cg13892570 and cg16107628, which influenced PAH pathogenesis by regulating TAGLN2 transcription, with mediation proportions of 86.46 and 97.65%, respectively. Sensitivity analyses supported the robustness of these findings. Consistent with the genetic evidence, TAGLN2 mRNA was significantly upregulated in the lungs of MCT-induced PAH rats. CONCLUSIONS: This study establishes a clear epigenetic causal pathway in which DNA methylation regulates TAGLN2 expression to promote PAH. TAGLN2 is validated as a key disease driver and presents a promising target for diagnostic and therapeutic strategies in PAH.

Animals↗

PubMed2021

High-impact rare genetic variants in severe schizophrenia.

Extreme phenotype sequencing has led to the identification of high-impact rare genetic variants for many complex disorders but has not been applied to studies of severe schizophrenia. We sequenced 112 individuals with severe, extremely treatment-resistant schizophrenia, 218 individuals with typical schizophrenia, and 4,929 controls. We compared the burden of rare, damaging missense and loss-of-function variants between severe, extremely treatment-resistant schizophrenia, typical schizophrenia, and controls across mutation intolerant genes. Individuals with severe, extremely treatment-resistant schizophrenia had a high burden of rare loss-of-function (odds ratio, 1.91; 95% CI, 1.39 to 2.63; P = 7.8 × 10-5) and damaging missense variants in intolerant genes (odds ratio, 2.90; 95% CI, 2.02 to 4.15; P = 3.2 × 10-9). A total of 48.2% of individuals with severe, extremely treatment-resistant schizophrenia carried at least one rare, damaging missense or loss-of-function variant in intolerant genes compared to 29.8% of typical schizophrenia individuals (odds ratio, 2.18; 95% CI, 1.33 to 3.60; P = 1.6 × 10-3) and 25.4% of controls (odds ratio, 2.74; 95% CI, 1.85 to 4.06; P = 2.9 × 10-7). Restricting to genes previously associated with schizophrenia risk strengthened the enrichment with 8.9% of individuals with severe, extremely treatment-resistant schizophrenia carrying a damaging missense or loss-of-function variant compared to 2.3% of typical schizophrenia (odds ratio, 5.48; 95% CI, 1.52 to 19.74; P = 0.02) and 1.6% of controls (odds ratio, 5.82; 95% CI, 3.00 to 11.28; P = 2.6 × 10-8). These results demonstrate the power of extreme phenotype case selection in psychiatric genetics and an approach to augment schizophrenia gene discovery efforts.

Aged↗

PubMed2025

Evidence supporting the role of hypertension in the onset of migraine.

BACKGROUND: The association between hypertension and migraine remains unclear. OBJECTIVE: The aim of this study employ multi-layered evidence chain that revealed the association between hypertension and migraine. METHODS: We first strictly included data from the NHANES 1999-2004 population and applied logistic regression, subgroup analysis and RCS to assess the correlation between hypertension, SBP, DBP and migraine. Meanwhile, LDSC and Mendelian randomization were conducted based on the GWAS to determine the causal relationship between hypertension and migraine. Inverse-variance weighted (IVW) was used as the primary method. Sensitivity analysis and Colocalization analysis were performed to confirm the robustness of the results. LDSC validated the genetic correlation between traits. Enrichment analysis revealed their underlying biological mechanisms. RESULTS: After strict inclusion in NHANES, 10,743 participants were included. The logistic regression showed a significant correlation between hypertension (OR = 1.21 [95% CI, 1.08-1.36], FDR < 0.001)、DBP (OR = 1.01 [95% CI, 1.01-1.02], FDR < 0.001) and migraine. This association did not show significant group differences in subgroup. The MR results further supported the existence of a significant causal relationship between hypertension (OR = 1.77 [95% CI, 1.43-2.30], FDR < 0.001)、DBP (OR = 1.02 [95% CI, 1.01-1.03], FDR < 0.001) and migraine onset. Additionally, the RCS analysis showed a linear relationship (P non-linear = 0.897) between the two. The LDSC result showed a significant genetic correlation between the two (Rg = 0.1092, SE = 0.028, P < 0.001). CONCLUSION: The development of migraine caused by hypertension is mainly realized through high DBP.

Humans↗

PubMed1994

Limits of resolution of genetic linkage studies: implications for the positional cloning of human disease genes.

Positional cloning studies to identify disease genes are being carried out for many human genetic diseases. Such studies often include a genome-scan linkage analysis to identify the rough chromosomal location of a disease gene, fine structure genetic mapping to define and narrow the chromosomal interval in which the disease gene may be located, and physical mapping and gene identification in the genetically defined interval to clone the disease gene. During the planning of a positional cloning study, it is important to know that, if linkage is found, the genetic interval identified is likely to be sufficiently narrow to be dissected efficiently by methods of physical mapping and gene identification. Thus, we wish to know the limits of resolution of a genetic linkage study. In this paper, I determine for Mendelian diseases the distributions and moments of three measures of linkage resolution: (1) in a set of N chromosomes, the distance between the nearest crossovers that flank a disease locus, (2) the distance between the nearest genetic markers that flank the pair of flanking crossovers after a genome scan, and (3) the distance between the nearest flanking markers after additional randomly placed markers are generated and typed in an identified interval. These results provide explicit sample-size guidelines for future positional cloning studies of Mendelian diseases and make possible a more objective evaluation of whether a proposed positional cloning study is likely to be successful. I also briefly discuss the more difficult problem of linkage resolution for complex genetic diseases.

Chromosome Mapping↗

PubMed2025

Evaluating the causal effect of mitochondrial dysfunction on Alzheimer's and Parkinson's disease using Polygenic Risk Scores and Mendelian Randomization.

INTRODUCTION: Mitochondrial DNA copy number (mtDNAcn), a measure of mitochondrial genomes per nucleated cell, has an unclear causal relationship with AD and PD. We integrate genetic correlation, Polygenic Risk Scores (PRS), and Mendelian Randomization (MR) to assess whether mtDNAcn influences the risk of AD and PD, and evaluate how study-specific factors in mtDNAcn genome-wide association studies (GWAS) may distort these causal estimates. METHODS: Using GWAS of four mtDNAcn measures, AD, AD/dementia, and PD, we evaluated genetic correlations, generated ancestry-normalized PRS in the AD Genetics Consortium (N=27,383), and applied MR methods including Latent Heritable Confounder MR (LHC-MR). RESULTS: Across the four mtDNAcn GWAS, only one was consistently associated with AD/dementia and PD, with genetic correlations and PRS analysis showing negative correlations and MR indicating that higher mtDNAcn reduced AD/dementia and PD risk. DISCUSSION: Higher blood-based mtDNAcn was causally associated with reduced risk of AD/dementia and PD, with limited evidence to suggest a bidirectional effect.

Alzheimer’s disease↗

PubMed2026

Genetic Association of the Transcriptome and Immunoglobulin G N-glycome with Cognitive Function.

OBJECTIVE: Immunoglobulin G (IgG) N-glycosylation is associated with mild cognitive impairment through the regulation of inflammatory balance; however, the underlying mechanisms remain unclear. METHODS: Our study utilized a post-genome-wide association studies (GWAS) method that integrated GWAS data for cognitive function with gene expression quantitative trait loci (eQTL), protein QTL (pQTL), and IgG N-glycan-QTL data. RESULTS: Mendelian randomization (MR) analyses suggested bidirectional causalities between glycan peaks (GPs) and cognitive function, with GP7, GP12, and GP19 showing a causal effect on cognitive function, while cognitive function conversely showed a causal effect on GP1 and GP8. Two proteins and 10 genes were implicated in the regulation of IgG N-glycosylation. Furthermore, multivariable MR results suggested complex causalities between genes/proteins and IgG N-glycans, which jointly promote or independently affect cognitive function. CONCLUSION: Our study reveals a novel mechanism by which genes, proteins, and modified IgG N-glycans converge to pathologically affect cognitive function.

Immunoglobulin G↗

PubMed2024

Assessing the causal link between liver function and acute pancreatitis: A Mendelian randomisation study.

A correlation has been reported to exist between exposure factors (e.g. liver function) and acute pancreatitis. However, the specific causal relationship remains unclear. This study aimed to infer the causal relationship between liver function and acute pancreatitis using the Mendelian randomisation method. We employed summary data from a genome-wide association study involving individuals of European ancestry from the UK Biobank and FinnGen. Single-nucleotide polymorphisms (SCNPs), closely associated with liver function, served as instrumental variables. We used five regression models for causality assessment: MR-Egger regression, the random-effect inverse variance weighting method (IVW), the weighted median method (WME), the weighted model, and the simple model. We assessed the heterogeneity of the SNPs using Cochran's Q test. Multi-effect analysis was performed using the intercept term of the MR-Egger method and leave-one-out detection. Odds ratios (ORs) were used to evaluate the causal relationship between liver function and acute pancreatitis risk. A total of 641 SNPs were incorporated as instrumental variables. The MR-IVW method indicated a causal effect of gamma-glutamyltransferase (GGT) on acute pancreatitis (OR = 1.180, 95%CI [confidence interval]: 1.021-1.365, P = 0.025), suggesting that GGT may influence the incidence of acute pancreatitis. Conversely, the results for alkaline phosphatase (ALP) (OR = 0.997, 95%CI: 0.992-1.002, P = 0.197) and aspartate aminotransferase (AST) (OR = 0.939, 95%CI: 0.794-1.111, P = 0.464) did not show a causal effect on acute pancreatitis. Additionally, neither the intercept term nor the zero difference in the MR-Egger regression attained statistical significance (P = 0.257), and there were no observable gene effects. This study suggests that GGT levels are a potential risk factor for acute pancreatitis and may increase the associated risk. In contrast, ALP and AST levels did not affect the risk of acute pancreatitis.

Humans↗

PubMed2026

Shared genetic architecture of obesity and gastroesophageal reflux disease.

Obesity is identified as a risk factor of gastroesophageal reflux disease (GERD). This study aims to elucidate the shared genetic architecture of obesity-related phenotypes and GERD. Based on the publicly available genome-wide association studies' datasets, this genome-wide pleiotropic association study was conducted with various genetic approaches (including linkage disequilibrium score regression, high-definition likelihood inference for genetic correlations, pleiotropic analysis under composite null hypothesis, Functional Mapping and Annotation, Bayesian colocalization, summary-based Mendelian randomization, and multi-marker analysis of genomic annotation analysis) sequentially to unravel the genetic associations from single-nucleotide polymorphism to gene levels, and to reveal the underlying shared genetic architecture between obesity-related phenotypes and GERD. This study discovered shared genetic mechanisms between GERD and several obesity-related phenotypes, including arm fat percentage (left), arm fat percentage (right), leg fat percentage (left), leg fat percentage (right), trunk fat percentage, waist-to-hip ratio, and body mass index. Significant genetic correlations were observed by linkage disequilibrium score regression and high-definition likelihood inference for genetic correlations, with multiple associated pleiotropic loci and their mapped genes identified by pleiotropic analysis under composite null hypothesis, Functional Mapping and Annotation, Bayesian colocalization, summary-based Mendelian randomization, and multi-marker analysis of genomic annotation analysis. Additionally, several brain tissues were identified to be linked to both obesity and GERD by multi-marker analysis of genomic annotation. This research provided strong evidence of genetic correlations and brought novel insights into the underlying genetic connections and shared genetic architectures of obesity and GERD.

Humans↗

PubMed1989

Using genetically-defined rodent strains for the identification of hippocampal traits relevant for two-way avoidance behavior: a non-invasive approach.

Genetically-defined rodent strains permit the identification of hippocampal traits which are of functional relevance for the performance of two-way avoidance behavior. This is exemplified here by analyzing the relationship between infrapyramidal mossy fibers (a tiny projection terminating upon the basal dendrites of hippocampal pyramidal neurons) and two-way avoidance learning in about 800 animals. The necessary steps include 1) identification of structural traits sensitive to selective breeding for extremes in two-way avoidance, 2) testing the robustness of the associations found by studying individual and genetical correlations between hippocampal traits and behavior, 3) establishing causal relationships by Mendelian crossing of strains with extreme structural traits and studying the behavioral consequences of such structural 'randomization', 4) confirming causal relationships by manipulating the structural variable in inbred (isogenic) strains, thereby eliminating the possibility of genetic linkage, and 5) ruling out the possibility of spurious associations by studying the correlations between the hippocampal trait and other behaviors known to depend on hippocampal functioning. In comparison with the classical lesion approach for identifying relationships between brain and behavior, the present procedure appears to be superior in two aspects: it is non-invasive, and it focuses automatically on those brain traits which are used by natural selection to shape behaviorally-defined animal populations, i.e., it reveals the natural regulators of behavior.

Animals↗