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Results for “quantitative trait locus”

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PubMed2026

Integrative genomic and transcriptomic analysis of hypertension in a Taiwanese population.

OBJECTIVES: Hypertension is highly prevalent in Asian populations and represents a major cardiovascular risk factor. However, most genome-wide association studies (GWASs) and transcriptome-wide association studies (TWASs) have focused primarily on Caucasian cohorts. This study aimed to identify genetic loci and gene expression signatures associated with hypertension in an Asian population. METHODS: We analyzed 10 739 hypertensive patients and 49 668 controls from the Taiwan Biobank, testing 4 512 191 genome-wide single nucleotide polymorphisms (SNPs). Integrated GWAS, TWAS, and expression quantitative trait locus (eQTL) analyses were conducted to characterize genetic risk. Additionally, a polygenic risk score (PRS) was constructed using a split-sample design to evaluate genetic risk stratification. RESULTS: We identified 14 loci significantly associated with hypertension, including a novel locus at 5p13.1. eQTL analysis linked this locus to DAB2 expression in whole blood. TWAS detected 55 hypertension-associated genes, with 20 (36%) overlapping GWAS loci. Several novel genes outside GWAS loci, including FBXL15, KCNIP2, and CRIP3, were highly significant and implicated in vascular biology and hypertension mechanisms. PRS analysis effectively differentiated hypertension risk, with individuals in the top 10% showing a > 3.5-fold increased risk compared to the bottom 10%. CONCLUSIONS: Our findings provide new insights into the genetic and transcriptomic landscape of hypertension in Asians. The identification of novel loci and genes advances understanding of disease biology and may guide precision medicine approaches for risk prediction and therapeutic development.

Female↗

PubMed2026

First genomic insights into the introgression of almond PPV-Marcus resistance into peach.

AIM: Sharka, caused by Plum pox virus (PPV), is one of the most damaging viral diseases of stone fruit crops, with peach among the most susceptible cultivated Prunus species. Almond is a promising source of resistance, but its genetic architecture and expression in a peach genetic background remain largely unknown. This study aimed to construct parental genetic linkage maps and identify genomic regions associated with PPV response in almond × peach interspecific populations. METHODS: Progenies derived from the almond cultivars 'Del Cid', 'Garrigues', and 'Mono' were evaluated by RT-PCR after graft inoculation with the PPV-Marcus (PPV-M) strain over consecutive infection cycles. Phenotypic data were summarized for each genotype using best linear unbiased estimates (BLUEs). High-density SNP almond and peach arrays were used to construct parental maps for 'Garrigues' and 'Mono' and perform quantitative trait locus (QTL) analysis. RESULTS: Phenotypic variation was observed among and within families. 'Del Cid'-derived progenies showed the greatest resistance, 'Garrigues'-derived progenies displayed intermediate responses, and 'Mono'-derived progenies showed greater susceptibility and variability. The parental maps covered 546.69 cM in 'Mono' and 521.72 cM in 'Garrigues', with average intervals of 0.61 and 1.26 cM per unique marker position, respectively, and showed strong collinearity with the reference genome. QTL associated with PPV-M response were detected on linkage groups (LG) 1 and 6 in 'Garrigues' and LG2 in 'Mono'. The main QTL in 'Garrigues' peaked near 22.39 Mb on LG1, whereas the 'Mono' QTL was located at 22.27-22.62 Mb on LG2; a weaker QTL was detected near 25.38 Mb on LG6 in 'Garrigues'. The results support a quantitative and genetic-background-dependent architecture of PPV resistance. CONCLUSION: This study provides the first evidence of genomic regions associated with PPV-Marcus response in almond × peach populations. The detected QTLs provide an initial basis to support the introgression of almond-derived resistance into peach breeding material.

Prunus↗

PubMed2026

Holistic approaches for improvement of maize resistance against lodging stress: current status and future perspective.

Lodging is a major constraint in maize production, causing significant yield losses, reduced grain quality, and harvesting inefficiencies, thereby posing a serious challenge to global food security and climate-resilient agriculture. This review synthesizes current knowledge on the genetic, physiological, and agronomic determinants of maize lodging resistance and evaluates holistic strategies for improving tolerance to lodging stress. Recent advances in quantitative trait locus (QTL) mapping, genome-wide association studies (GWAS), functional gene characterization, genome editing, high-throughput phenotyping, and precision agronomy have provided powerful tools to enhance stalk biomechanics, root anchorage, and adaptive plant architecture. Integrating genomic discovery with advanced phenomics and optimized agronomic management offers a scalable framework for accelerating the development of high-yielding, lodging-resilient maize cultivars. However, critical gaps remain in understanding the genetic coordination between stalk strength and root system architecture, integrating multi-omics approaches to unravel regulatory networks, validating genome-editing interventions across diverse agro-ecologies, and developing environment-responsive predictive breeding models and cost-effective phenotyping tools, particularly for stress-prone regions. Addressing these challenges through coordinated multi-environment trials and integrative molecular-agronomic strategies will facilitate the translation of genomic discoveries into climate-resilient, high-performing maize cultivars. By consolidating molecular insights with applied breeding and management practices, this review provides a comprehensive framework that guides researchers in designing genome-informed and field-validated approaches to improve maize resistance to lodging stress and support sustainable crop production systems.

Zea mays↗

PubMed2026

Integrative TWAS and multi-omics analyses prioritize HSPE1 as a candidate risk gene for bipolar disorder with immune cell-specific regulatory evidence.

BACKGROUND: Bipolar disorder (BD) is a severe psychiatric disorder associated with substantial disability. Although genome-wide association studies have identified multiple BD-associated loci, the underlying genes and mechanisms remain incompletely understood. METHODS: We integrated a European-ancestry BD genome-wide association dataset with cross-tissue and tissue-specific transcriptome-wide association studies (TWAS) and complementary gene-based analysis. Candidate genes were further evaluated using differential expression analysis, consensus clustering, immune infiltration analysis, machine learning, summary-data-based Mendelian randomization, Mendelian randomization using single-cell expression quantitative trait locus data, single-nucleus transcriptomics, phenome-wide association analysis, and virtual screening. RESULTS: The integrative analyses prioritized 37 candidate genes. Peripheral-blood differential-expression analysis identified 14 genes that remained significant after FDR correction, and their expression profiles separated BD samples into two expression-defined clusters. Machine-learning analysis selected UNC50, LMAN2L, LYG2, HSPE1, and KANSL3 for an exploratory classification nomogram. SMR associated genetically predicted higher HSPE1 expression with increased BD risk in two blood eQTL datasets. Cell-type-specific analyses indicated HSPE1-related associations in T-cell and natural killer cell subsets, while single-nucleus analysis descriptively showed higher HSPE1 expression in medial thalamic T cells from BD samples. PheWAS identified no genome-wide significant associations for HSPE1, whereas virtual screening identified candidate compounds with favorable predicted docking scores against the HSPE1 structure. CONCLUSION: This integrative multi-omics study identified HSPE1 as a candidate BD risk gene with immune-cell-related regulatory evidence, providing insight into BD pathogenesis and supporting functional validation.

Humans↗

PubMed2026

Selection of GhTT2-A07 promoter enhances fiber quality in improved cotton varieties.

Modern cultivated cotton fibers are predominantly white with enhanced quality compared to their wild ancestors. However, the molecular mechanisms and evolutionary drivers linking fiber color to quality remain least focused. In this study, we identified FQC1 (Fiber Quality and Color 1), a major quantitative trait locus (QTL) on chromosome A07 that concurrently regulates both fiber quality and pigmentation. Through map-based cloning, we revealed that Gossypium hirsutum TRANSPARENT TESTA2-A07 (GhTT2-A07), an R2R3-MYB transcription factor, resides within this locus. GhTT2-A07 modulates fiber development by directly activating genes in the general phenylpropanoid pathway, thereby promoting the metabolic flux toward downstream secondary metabolites. Variations in the GhTT2-A07 promoter led to its reduced expression in modern white cotton cultivars. This down-regulation suppresses the accumulation of S/G/H-type lignin monomers and proanthocyanidins, resulting in altered secondary cell wall composition and ultimately enhancing the quality of mature white fibers. Population genetic analyses further indicate that the white-fiber allele GhTT2-A07W has been fixed in modern breeding genotypes, underscoring the impact of artificial selection during cotton domestication. Overall, our study elucidates the biochemical and molecular mechanisms underlying fiber quality and pigmentation in cotton, clarifies the selection criteria for high-quality white fibers in modern cultivars, and provides a theoretical basis for future targeted genetic improvement of cotton fibers.

Alleles↗

PubMed2026

Genetic diversity of Collaborative Cross mice implicates FFAR3 as a target for ILC2 anti-inflammatory reprogramming.

Pulmonary group 2 innate lymphoid cells (ILC2s) are key drivers of Type 2 inflammation in diseases like asthma, yet the molecular mechanisms regulating their function are incompletely understood. Using the genetically diverse Collaborative Cross (CC) mouse panel, we mapped a quantitative trait locus (QTL) that governs ILC2 prevalence in the lung after aeroallergen exposure. This QTL induces a large population of ILC2s in the lung that are resistant to activation and have diminished Type 2 effector function. We identified free-fatty acid receptor 3 (Ffar3) as a gene responsible for this effect and demonstrated that FFAR3 signaling reprograms ILC2s to an anti-inflammatory state by promoting their survival, reducing Type 2 cytokine production, and enhancing IL-10 expression. This anti-inflammatory state is dependent on IL-2 signaling, is characterized by decreased ST2 expression, and is distinct from previously described IL-10-producing ILC2 phenotypes. FFAR3-dependent reprogramming is mediated by epidermal growth factor receptor (EGFR) upregulation, and FFAR3's anti-inflammatory effect is partially conserved in human ILC2s.

Animals↗

PubMed2025

Role of HLA-DRA-CREB3L4 regulatory axis in the pathogenesis of ovarian endometriosis: Inhibition of CREB3L4 expression by HLA-DRA increases the risk of disease.

BACKGROUND: Ovarian endometriosis is a common gynecological condition characterized by the abnormal growth of endometrial-like tissue in locations outside the uterus, and its development remains poorly understood. This study aims to investigate potential protein regulatory networks and assess their impact on disease risk using both protein quantitative trait locus (pQTL) analysis and Mendelian randomization (MR) techniques. METHODS: This study systematically integrates two major genome-wide pQTL databases, UKB-PPP and deCODE, to identify pQTL signals associated with ovarian endometriosis. Additionally, we utilized the GEO database to validate differences in protein expression. We conducted a Mendelian randomization analysis to further explore the regulatory relationships between proteins and their roles in disease development. RESULTS: After the Bonferroni correction, we identified 33 pQTL signals from UKB-PPP and 19 pQTL signals from deCODE. Among these, 8 signals from UKB-PPP and 3 signals from deCODE were validated based on expression differences. The mediation analysis results indicate that HLA-DRA significantly increases the risk of developing ovarian endometriosis by inhibiting the expression of CREB3L4 (with a mediation proportion of 13.99 %), and the direction of the mediation effect is consistent with the total effect. CONCLUSION: This study provides new insights that HLA-DRA downregulates the expression of CREB3L4, which may affect the risk of developing endometriosis. The results provide new evidence for understanding the genetic and molecular basis of ovarian endometriosis and establish a theoretical foundation for the development of future diagnostic markers and targeted treatment strategies.

Humans↗

PubMed2025

SUG2 controls grain size and weight by influencing GS2 transcription level in rice.

Grain size is a critical yield determinant and a complex quantitative trait in rice. The major quantitative trait locus GS2, which encodes the transcriptional regulator OsGRF4, has been characterized as a key controller of grain size and grain weight in rice. Building upon existing germplasm resources, exploring the upstream and downstream genes of known grain size regulators is an effective approach to gradually refine and expand the molecular regulatory network underlying grain size. Here, we report that a suppressor of the gain-of-function allele GS2AA, SUG2, which encodes an importin β nuclear transport protein. Phenotypic characterization reveals that the sug2 GS2AA mutant exhibits small grains by inhibiting cell expansion in the spikelet hull. Protein interaction analyses demonstrate that SUG2 physically interacts with GS2 both in vivo and in vitro, and the SUG2A mutation reduces SUG2 expression levels and inhibits GS2 transcriptional activation activity, resulting in decreased GS2 expression levels and GS2 protein abundance in sug2 GS2AA. Genetic analyses indicate that SUG2 and GS2 may be partially involved in a common pathway regulating grain size and weight in rice. These findings elucidate the grain size regulatory relationship between SUG2 and GS2 and provide novel insights into the precision breeding of yield optimization in rice.

Oryza↗

PubMed2026

The impact for causal associations between common diseases and inflammatory bowel disease: a disease-wide bidirectional Mendelian randomization study.

OBJECTIVES: Observational studies on associations between various diseases and inflammatory bowel disease (IBD) are often limited by confounding and reverse causation. We aimed to assess potential causal relationships between a wide range of diseases and IBD, including Crohn's disease (CD) and ulcerative colitis (UC). METHODS: We performed a comprehensive bidirectional Mendelian randomization (MR) analysis of 104 common diseases and IBD traits using the generalized summary-data-based MR (GSMR) approach. Genome-wide association study (GWAS) summary statistics for diseases were obtained from the MRC Integrative Epidemiology Unit, and IBD data from the International IBD Genetics Consortium. Summary-data-based MR (SMR) integrating GWAS and expression quantitative trait locus data was applied to identify pleiotropic genes associated with IBD. RESULTS: MR analyses identified 38, 34, and 52 exposures significantly associated with IBD, UC, and CD, respectively. Childhood- and adult-onset asthma showed distinct causal effects on UC and CD. Reverse MR indicated associations between IBD traits and 15 diseases, including multiple sclerosis. SMR identified RGS14 and CARD9 as pleiotropic genes linked to IBD, suggesting shared genetic mechanisms with asthma and multiple sclerosis. CONCLUSIONS: These findings provide evidence for causal links and shared immune-related genetic mechanisms underlying IBD, highlighting potential targets for future research.

Humans↗

PubMed2016

Androgen-sensitive hypertension associated with soluble guanylate cyclase-α1 deficiency is mediated by 20-HETE.

Dysregulated nitric oxide (NO) signaling contributes to the pathogenesis of hypertension, a prevalent and often sex-specific risk factor for cardiovascular disease. We previously reported that mice deficient in the α1-subunit of the NO receptor soluble guanylate cyclase (sGCα1 (-/-) mice) display sex- and strain-specific hypertension: male but not female sGCα1 (-/-) mice are hypertensive on an 129S6 (S6) but not a C57BL6/J (B6) background. We aimed to uncover the genetic and molecular basis of the observed sex- and strain-specific blood pressure phenotype. Via linkage analysis, we identified a suggestive quantitative trait locus associated with elevated blood pressure in male sGCα1 (-/-)S6 mice. This locus encompasses Cyp4a12a, encoding the predominant murine synthase of the vasoconstrictor 20-hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE). Renal expression of Cyp4a12a in mice was associated with genetic background, sex, and testosterone levels. In addition, 20-HETE levels were higher in renal preglomerular microvessels of male sGCα1 (-/-)S6 than of male sGCα1 (-/-)B6 mice. Furthermore, treating male sGCα1 (-/-)S6 mice with the 20-HETE antagonist 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid (20-HEDE) lowered blood pressure. Finally, 20-HEDE rescued the genetic background- and testosterone-dependent impairment of acetylcholine-induced relaxation in renal interlobar arteries associated with sGCα1 deficiency. Elevated Cyp4a12a expression and 20-HETE levels render mice susceptible to hypertension and vascular dysfunction in a setting of sGCα1 deficiency. Our data identify Cyp4a12a as a candidate sex-specific blood pressure-modifying gene in the context of deficient NO-sGC signaling.

Androgens↗

PubMed2025

Complex and Dynamic Gene-by-Age and Gene-by-Environment Interactions Underlie Functional Morphological Variation in Adaptive Divergence in Arctic Charr (Salvelinus alpinus).

The evolution of adaptive phenotypic divergence requires heritable genetic variation. However, it is underappreciated that trait heritability is molded by developmental processes interacting with the environment. We hypothesized that the genetic architecture of divergent functional traits was dependent on age and foraging environment. Thus, we induced plasticity in full-sib families of Arctic charr (Salvelinus alpinus) morphs from two Icelandic lakes by mimicking prey variation in the wild. We characterized variation in body shape and size at two ages and investigated their genetic architecture with quantitative trait locus (QTL) analysis. Age had a greater effect on body shape than diet in most families, suggesting that development strongly influences phenotypic variation available for selection. Consistent with our hypothesis, multiple QTL were detected for all traits and their location depended on age and diet. Many of the genome-wide QTL were located within a subset of duplicated chromosomal regions suggesting that ancestral whole genome duplication events have played a role in the genetic control of functional morphological variation in the species. Moreover, the detection of two body shape QTL after controlling for the effects of age provides additional evidence for genetic variation in the plastic response of morphological traits to environmental variation. Thus, functional morphological traits involved in phenotypic divergence are molded by complex genetic interactions with development and environment.

Animals↗

PubMed2026

Co-regulation of HIV control and cytomegalovirus pp65-specific IL-1β and TNF-α responses by genetic variants in the MHC region.

The spontaneous control of HIV infection in the absence of antiretroviral therapy, termed HIV control, is associated with genetic variation in the Major Histocompatibility Complex (MHC) locus. These variants are known to influence the immune response to HIV itself. However, people living with HIV are often co-infected with other pathogens that can also elicit immune responses, which might also be regulated by these variants. Here, we assessed whether genetic variants associated with HIV control influence cytokine responses to various co-pathogens. HIV-control-associated single nucleotide polymorphisms (SNPs) were enriched among variants regulating TNF-α and IL-1β production upon CMV pp65 peptide pool stimulation. The top enriched SNPs, rs1128175-A and rs2853971-A, were linked to lower odds of HIV control and increased cytokine responses to CMV. These SNPs were in linkage disequilibrium (LD) with classical HLA alleles HLA-B*07:02 and HLA-C*07:02. Intracellular cytokine staining showed CMV serostatus-dependent production of TNF-α by monocytes and CD8 T cells. The rs1128175-A/rs2853971-A/HLA-B*07:02/HLA-C*07:02 haplotype was associated with increased IFN-γ production by CD8 T cells upon CMV pp65 peptide pool stimulation, indicating an effect on memory responses. Quantitative trait locus (QTL) mapping showed that rs1128175 and rs2853971 influence HLA-B and HLA-C expression, DNA methylation levels and cell-type-specific cis-effects on chromatin accessibility, as well as CD8 T cell subset abundance. These QTL associations suggest that variants associated with poor HIV control are linked to heightened pro-inflammatory responses to CMV pp65 through effects on antigen presentation, epigenetic modifications, gene expression and immune cell repertoire, potentially negatively affecting HIV control status.

Humans↗

PubMed2025

Genetic Architecture of Idiopathic Inflammatory Myopathies From Meta-Analyses.

OBJECTIVE: Idiopathic inflammatory myopathies (IIMs, myositis) are rare systemic autoimmune disorders that lead to muscle inflammation, weakness, and extramuscular manifestations, with a strong genetic component influencing disease development and progression. Previous genome-wide association studies identified loci associated with IIMs. In this study, we imputed data from two prior genome-wide myositis studies and analyzed the largest myositis data set to date to identify novel risk loci and susceptibility genes associated with IIMs and its clinical subtypes. METHODS: We performed association analyses on 14,903 individuals (3,206 patients and 11,697 controls) with genotypes and imputed data from the Trans-Omics for Precision Medicine reference panel. Fine-mapping and expression quantitative trait locus colocalization analyses in myositis-relevant tissues indicated potential causal variants. Functional annotation and network analyses using the random walk with restart (RWR) algorithm explored underlying genetic networks and drug repurposing opportunities. RESULTS: Our analyses identified novel risk loci and susceptibility genes, such as FCRLA, NFKB1, IRF4, DCAKD, and ATXN2 in overall IIMs; NEMP2 in polymyositis; ACBC11 in dermatomyositis; and PSD3 in myositis with anti-histidyl-transfer RNA synthetase autoantibodies (anti-Jo-1). We also characterized effects of HLA region variants and the role of C4. Colocalization analyses suggested putative causal variants in DCAKD in skin and muscle, HCP5 in lung, and IRF4 in Epstein-Barr virus (EBV)-transformed lymphocytes, lung, and whole blood. RWR further prioritized additional candidate genes, including APP, CD74, CIITA, NR1H4, and TXNIP, for future investigation. CONCLUSION: Our study uncovers novel genetic regions contributing to IIMs, advancing our understanding of myositis pathogenesis and offering new insights for future research.

Humans↗

PubMed2025

Possible linking and treatment between Parkinson's disease and inflammatory bowel disease: a study of Mendelian randomization based on gut-brain axis.

BACKGROUND: Mounting evidence suggests that Parkinson's disease (PD) and inflammatory bowel disease (IBD) are closely associated and becoming global health burdens. However, the causal relationships and common pathogeneses between them are uncertain. Furthermore, they are uncurable. Thus, we aimed to identify the causal relationships and novel therapeutic targets shared between them based on their common pathophysiological mechanisms in gut-brain-axis (GBA). METHODS: A meta-analysis on bidirectional Mendelian randomization (MR) utilizing various datasets was performed to estimate their causal relationship. Then, pleiotropic analysis under the composite null hypothesis (PLACO) with functional mapping combined with annotation of genetic associations (FUMA) analysis were conducted to identify pleiotropic genes. Next, blood, brain and intestine expression quantitative trait locus (eQTL) were taken to perform drug-target MR finding common causal genes in two diseases. Colocalization analysis ensured the eQTLs of corresponding gene colocalized with disease. Enrichment analysis and protein‒protein interaction (PPI) network were done to explore common pathogenesis pathways. Genes passed all analysis were regarded as drug targets. RESULTS: Our MR meta-analysis revealed the bidirectional causal relationship between diseases, with combined ORs for PD on IBD, CD, UC (1.050 [95% CI 1.014-1.086], 1.044 [95% CI 0.995-1.095], 1.063 [95% CI 1.016-1.120]); for IBD, CD, UC on PD (1.003 [95% CI 0.973-1.034], 1.035 [95% CI 1.004-1.067], 1.008 [95% CI 0.977-1.040]). Overall, 277, 216 and 201 genes were identified as pleiotropic genes between PD and IBD, CD, UC. Total of 733 genes were classified as tier 3 (found in only one tissue) druggable targets, 57 as tier 2 (found in two tissues, 51 protein-coding genes) and 9 as tier 3 (found in three tissues). Among 60 protein-coding druggable targets over tier 2, 18 overlapped with pleiotropic genes and enriched in mitochondria, antigen presentation, processing and immune cell regulation pathways. Three druggable genes (LRRK2, RAB29 and HLA-DQA2) passed colocalization analysis. LRRK2 and RAB29 were reported to be pleiotropic genes, and RAB29 and HLA-DQA2 were reported for the first time as potential drug targets. CONCLUSIONS: This study established a reliable causal relationship, possible shared drug targets and common pathogenesis pathways of two diseases, which had important implications for intervention and treatment of two diseases simultaneously.

Humans↗

PubMed2026

The role of ferroptosis in juvenile idiopathic arthritis: Causal inference and mediation by immune phenotypes.

This study employed a bidirectional 2-step, two-sample Mendelian randomization approach to investigate the causal relationships between ferroptosis-related genes and juvenile idiopathic arthritis (JIA) and to explore the mediating role of immune cells. Ferroptosis genes were identified from the deCODE database and matched with protein quantitative trait locus data as exposures to evaluate their causal effects on JIA, while immune cell traits were similarly assessed. For genes showing positive Mendelian randomization results, further analyses were conducted to determine whether immune cells mediated the effects on JIA, with mediation analysis performed only in the presence of causal associations. Data were sourced from the GWAS, FerrDb, and other public repositories. Nine ferroptosis-related genes were found to have causal links with JIA: HSPB1, DECR1, LIFR, and CTSB increased JIA risk, whereas PIEZO1, DPP4, BID, and others were protective. Forty immune cell traits were also causally associated with JIA. Mediation analysis revealed that several immune cells, including CD127- CD8+ T cells, partially mediated the genetic effects, with mediation proportions reaching up to 18.6%. Collectively, these results point to a ferroptosis-immune-JIA axis, suggesting that ferroptosis-related genes contribute to JIA pathogenesis through immune cell mediation and offering new mechanistic insights and potential therapeutic targets.

Arthritis, Juvenile↗

PubMed2025

Identification of novel type 1 and type 2 diabetes genes by co-localization of human islet eQTL and GWAS variants with colocRedRibbon.

Over 1,000 genetic variants have been associated with diabetes by genome-wide association studies (GWASs), but for most, their functional impact is unknown; only 7% alter gene expression in pancreatic islets in expression quantitative trait locus (eQTL) studies. To fill this gap, we developed a co-localization pipeline, colocRedRibbon, that prefilters eQTLs by the direction of effect on gene expression and shortlists overlapping eQTL and GWAS variants prior to co-localization. Applying colocRedRibbon to recent diabetes and glycemic trait GWASs, we identified 292 co-localizing gene regions, including 24 co-localizations for type 1 diabetes and 268 for type 2 diabetes and glycemic traits, representing a 4-fold increase. A low-frequency type 2 diabetes protective variant increases islet MYO5C expression, and a type 1 diabetes protective variant increases FUT2 expression. These novel co-localizations advance the understanding of diabetes genetics and its impact on human islet biology. colocRedRibbon has broad applicability to co-localize GWASs and various QTLs.

Humans↗

PubMed2026

Robust human genetic evidence supporting causal effects of FGF21 on reducing alcohol consuming behaviours.

BACKGROUND: Alcohol use disorder (AUD) represents a tremendous societal burden, yet few efficacious therapies are available and widely used. Pre-clinical and human observational data support fibroblast growth factor 21 (FGF21) as a promising therapeutic target for the treatment of AUD. The objective of this study is to identify a robust genetic instrument for FGF21 agonism and leverage it to explore the effects of FGF21 agonism on AUD and related traits, as well as metabolic outcomes more widely. METHODS: We first compared associations with the positive control outcomes of liver fat and liver cirrhosis risk for the FGF21 cis-protein quantitative trait locus (cis-pQTL) (rs838131) to those for the common allele FGF21 L174P missense variant (rs739320). Having identified the L174P missense variant as a plausible genetic instrument, we subsequently performed association analyses investigating effects on AUD, related traits, and metabolic outcomes more widely. Finally, we performed colocalisation analyses to test whether observed association results reflect a causal mechanism that overlaps with the clinical effects of FGF21 on liver fat and liver cirrhosis. RESULTS: Consistent association and colocalisation evidence support a protective association between genetically predicted FGF21 agonism and alcohol consumption (association p = 1 × 10-18, colocalisation posterior probability = 0.90), problematic alcohol use (association p = 0.02, posterior probability = 0.64), and AUD (association p = 9 × 10-8, posterior probability = 0.97). Similar evidence was also observed for favourable effects of FGF21 on improving kidney function, lowering triglyceride levels, lowering proportional energy intake from carbohydrates, increasing proportional energy intake from protein and fat, increasing body weight and lowering waist-to-hip ratio. CONCLUSIONS: This study identifies a genetic instrument for FGF21 effects to provide causal human evidence supporting favourable effects of FGF21 analogues for the treatment of AUD and related traits, as well as on metabolic outcomes more broadly. Further clinical study is duly warranted.

Humans↗

PubMed2025

From genetic causality to druggable targets: A multiomics framework identifies ZSCAN16 in gout pathogenesis.

ObjectiveGout is a prevalent form of inflammatory arthritis in which many patients respond suboptimally to current therapies. Drug development is hampered by a lack of genetically validated targets, leading to high clinical trial attrition. This study aimed to systematically identify and prioritize novel, druggable targets for gout via a multilayered genetic and functional genomics approach.MethodsWe performed two-sample Mendelian randomization (MR) using cis-expression quantitative trait locus (cis-eQTL) data and dual independent gout genome-wide association study (GWAS) cohorts (openGWAS and FinnGen). The candidate genes were subjected to a rigorous validation pipeline including Bayesian colocalization, phenome-wide association studies (PheWASs) to assess pleiotropy and on-target safety, and single-cell RNA sequencing (scRNA-seq) to delineate the cellular context. Molecular docking was used to evaluate the structural druggability of prioritized targets.ResultsMR analysis revealed 15 genes causally associated with gout. Colocalization analysis (PPH4 > 0.8) prioritized two targets: ZSCAN16 (risk-increasing, OR = 1.04, 95% CI [1.02-1.06]) and TRIM10 (protective, OR = 0.96, 95% CI [0.94-0.98]). Crucially, PheWAS revealed that ZSCAN16 is highly specific to gout, whereas TRIM10 exhibited extensive pleiotropy with hematological and cardiometabolic traits, indicating significant safety risks. Single-cell analysis provided orthogonal validation, demonstrating flare-specific upregulation of ZSCAN16 in cytotoxic T/NK cells. Molecular docking confirmed ZSCAN16 as a structurally druggable target, showing high-affinity binding with known compounds (e.g. digoxin, binding energy = -9.6 kcal/mol).ConclusionsOur study identifies ZSCAN16 as a high-potential, druggable therapeutic target for gout, highlighting its genetic influence on specific immune cell activities during acute flares. Conversely, TRIM10 was deprioritized owing to substantial pleiotropic liabilities and poor chemical tractability. These findings suggest that ZSCAN16 could play a crucial role in the pathogenesis of gout and may provide a valuable lead for future drug discovery efforts.

Humans↗