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BACKGROUND: Studies have identified individual blood biomarkers associated with chronic obstructive pulmonary disease (COPD) and related phenotypes. However, complex diseases such as COPD typically involve changes in multiple molecules with interconnections that may not be captured when considering single molecular features. METHODS: Leveraging proteomic data from 3,173 COPDGene Non-Hispanic White (NHW) and African American (AA) participants, we applied sparse multiple canonical correlation network analysis (SmCCNet) to 4,776 proteins assayed on the SomaScan v4.0 platform to derive sparse networks of proteins associated with current vs. former smoking status, airflow obstruction, and emphysema quantitated from high-resolution computed tomography scans. We then used NetSHy, a dimension reduction technique leveraging network topology, to produce summary scores of each proteomic network, referred to as NetSHy scores. We next performed a genome-wide association study (GWAS) to identify variants associated with the NetSHy scores, or network quantitative trait loci (nQTLs). Finally, we evaluated the replicability of the networks in an independent cohort, SPIROMICS. RESULTS: We identified networks of 13 to 104 proteins for each phenotype and exposure in NHW and AA, and the derived NetSHy scores significantly associated with the variable of interests. Networks included known (sRAGE, ALPP, MIP1) and novel molecules (CA10, CPB1, HIS3, PXDN) and interactions involved in COPD pathogenesis. We observed 7 nQTL loci associated with NetSHy scores, 4 of which remained after conditional analysis. Networks for smoking status and emphysema, but not airflow obstruction, demonstrated a high degree of replicability across race groups and cohorts. CONCLUSIONS: In this work, we apply state-of-the-art molecular network generation and summarization approaches to proteomic data from COPDGene participants to uncover protein networks associated with COPD phenotypes. We further identify genetic associations with networks. This work discovers protein networks containing known and novel proteins and protein interactions associated with clinically relevant COPD phenotypes across race groups and cohorts.
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Estudio de Asociación del Genoma Completo , Proteómica , Enfermedad Pulmonar Obstructiva Crónica , Fumar , Humanos , Enfermedad Pulmonar Obstructiva Crónica/genética , Fumar/genética , Masculino , Femenino , Persona de Mediana Edad , Anciano , Sitios de Carácter Cuantitativo , Fenotipo , Polimorfismo de Nucleótido Simple , Variación GenéticaRESUMEN
Enhlink is a computational tool for scATAC-seq data analysis, facilitating precise interrogation of enhancer function at the single-cell level. It employs an ensemble approach incorporating technical and biological covariates to infer condition-specific regulatory DNA linkages. Enhlink can integrate multi-omic data for enhanced specificity, when available. Evaluation with simulated and real data, including multi-omic datasets from the mouse striatum and novel promoter capture Hi-C data, demonstrate that Enhlink outperfoms alternative methods. Coupled with eQTL analysis, it identified a putative super-enhancer in striatal neurons. Overall, Enhlink offers accuracy, power, and potential for revealing novel biological insights in gene regulation.
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Elementos de Facilitación Genéticos , Regiones Promotoras Genéticas , Animales , Ratones , Programas Informáticos , Sitios de Carácter Cuantitativo , Cuerpo Estriado/metabolismo , Análisis de la Célula IndividualRESUMEN
Genome wide association studies (GWAS) have associated thousands of loci with quantitative human blood trait variation. Loci and related genes that impact blood trait variation may regulate blood cell-intrinsic biological processes, or alternatively impact blood cell development and function via systemic factors. Clinical observations have linked tobacco or alcohol use with altered blood traits, but these trait relationships have not been systematically explored at the genetic level. Applying a Mendelian randomization (MR) framework to GWAS summary statistics, we explore relationships between smoking and drinking behaviors with 15 quantitative blood traits. We find that the effects of smoking and drinking are confined to red blood cell traits. An instrumental variable (IV) comprised of 113 single nucleotide polymorphisms (SNPs) associated with smoking initiation is associated with decreased hemoglobin (HGB: Effect = -0.07 standard deviation units [95% confidence interval = -0.03 to -0.10 SD units], P = 1x10-4), hematocrit (HCT: Effect = -0.06 [-0.03 - -0.09] SD units, P = 4x10-4), and red blood cell count (RBC: Effect = -0.05 [-0.02 - -0.09] SD units, P = 5x10-3) without impacting platelet count (P = 0.9) or white blood cell count (P = 0.6). Similarly, an IV associated with an increased number of alcoholic drinks consumed per week is associated with decreased HGB (Effect = -0.22 [-0.42 - -0.02] SD units, P = 3x10-2) and RBC (Effect = -0.27 [-0.51 - -0.03] SD units, P = 3x10-2). Using multivariable MR and causal mediation analyses, we find that an increased genetic predisposition to smoking initiation is associated with increased alcohol intake, and that alcohol use mediates the genetic effect of smoking initiation on red blood cell traits. These findings demonstrate a novel role for genetically influenced behaviors on human blood traits, revealing opportunities to dissect related pathways and mechanisms that influence hematopoiesis and blood cell biology.
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Consumo de Bebidas Alcohólicas , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Humanos , Consumo de Bebidas Alcohólicas/genética , Análisis de la Aleatorización Mendeliana , Hemoglobinas/metabolismo , Hemoglobinas/genética , Fumar/genética , Eritrocitos/metabolismo , Sitios de Carácter Cuantitativo , Recuento de Eritrocitos , HematócritoRESUMEN
Drought is one of the major environmental issues that reduce crop yield. Seed germination is a crucial stage of plant development in all crop plants, including soybean. In soybean breeding, information about genetic mechanism of drought tolerance has great importance. However, at germination stage, there is relatively little knowledge on the genetic basis of soybean drought resistance. The objective of this work was to find the quantitative trait nucleotides (QTNs) linked to drought tolerance related three traits using a genome-wide association study (GWAS), viz., germination rate (GR), root length (RL), and whole seedling length (WSL), using germplasm population of 240 soybean PIs with 34,817 SNPs genotype data having MAF > 0.05. It was observed that heritability (H2) for GR, WSL, and RL across both environments (2020, and 2019) were high in the range of 0.76-0.99, showing that genetic factors play a vital role in drought tolerance as compared to environmental factors. A number of 23 and 27 QTNs were found to be linked to three traits using MLM and mrMLM, respectively. Three significant QTNs, qGR8-1, qWSL13-1, and qRL-8, were identified using both MLM and mrMLM methods among these QTNs. QTN8, located on chromosome 8 was consistently linked to two traits (GR and RL). The area (± 100 Kb) associated with this QTN was screened for drought tolerance based on gene annotation. Fifteen candidate genes were found by this screening. Based on the expression data, four candidate genes i.e. Glyma08g156800, Glyma08g160000, Glyma08g162700, and Glyma13g249600 were found to be linked to drought tolerance regulation in soybean. Hence, the current study provides evidence to understand the genetic constitution of drought tolerance during the germination stage and identified QTNs or genes could be utilized in molecular breeding to enhance the yield under drought stress.
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Sequías , Estudio de Asociación del Genoma Completo , Germinación , Glycine max , Sitios de Carácter Cuantitativo , Semillas , Glycine max/genética , Glycine max/crecimiento & desarrollo , Glycine max/fisiología , Germinación/genética , Semillas/genética , Semillas/crecimiento & desarrollo , Polimorfismo de Nucleótido Simple , Estrés Fisiológico/genética , Genotipo , Fenotipo , Resistencia a la SequíaRESUMEN
The fermentative model yeast Saccharomyces cerevisiae has been extensively used to study the genetic basis of stress response and homeostasis. In this study, we performed quantitative trait loci (QTL) analysis of the high-temperature fermentation trait of the progeny from the mating of the S. cerevisiae natural isolate BCC39850 (haploid#17) and the laboratory strain CEN.PK2-1C. A single QTL on chromosome X was identified, encompassing six candidate genes (GEA1, PTK2, NTA1, NPA3, IRT1, and IML1). The functions of these candidates were tested by reverse genetic experiments. Deletion mutants of PTK2, NTA1, and IML1 showed growth defects at 42 °C. The PTK2 knock-out mutant also showed significantly reduced ethanol production and plasma membrane H+ ATPase activity and increased sensitivity to acetic acid, ethanol, amphotericin B (AMB), and ß-1,3-glucanase treatment. The CRISPR-Cas9 system was used to construct knock-in mutants by replacement of PTK2, NTA1, IML1, and NPA3 genes with BCC39850 alleles. The PTK2 and NTA1 knock-in mutants showed increased growth and ethanol production titers at 42 °C. These findings suggest an important role for the PTK2 serine/threonine protein kinase in regulating plasma membrane H+ ATPase activity and the NTA1 N-terminal amidase in protein degradation via the ubiquitin-proteasome system machinery, which affects tolerance to heat stress in S. cerevisiae.
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Etanol , Fermentación , Calor , Sitios de Carácter Cuantitativo , Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/crecimiento & desarrollo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Etanol/metabolismoRESUMEN
Clinical biomarkers such as fasting glucose, HbA1c, and fasting insulin, which gauge glycemic status in the body, are highly influenced by diet. Indians are genetically predisposed to type 2 diabetes and their carbohydrate-centric diet further elevates the disease risk. Despite the combined influence of genetic and environmental risk factors, Indians have been inadequately explored in the studies of glycemic traits. Addressing this gap, we investigate the genetic architecture of glycemic traits at genome-wide level in 4927 Indians (without diabetes). Our analysis revealed numerous variants of sub-genome-wide significance, and their credibility was thoroughly assessed by integrating data from various levels. This identified key effector genes, ZNF470, DPP6, GXYLT2, PITPNM3, BEND7, and LORICRIN-PGLYRP3. While these genes were weakly linked with carbohydrate intake or glycemia earlier in other populations, our findings demonstrated a much stronger association in the Indian population. Associated genetic variants within these genes served as expression quantitative trait loci (eQTLs) in various gut tissues essential for digestion. Additionally, majority of these gut eQTLs functioned as methylation quantitative trait loci (meth-QTLs) observed in peripheral blood samples from 223 Indians, elucidating the underlying mechanism of their regulation of target gene expression. Specific co-localized eQTLs-meth-QTLs altered the binding affinity of transcription factors targeting crucial genes involved in glucose metabolism. Our study identifies previously unreported genetic variants that strongly influence the diet-glycemia relationship. These findings set the stage for future research into personalized lifestyle interventions integrating genetic insights with tailored dietary strategies to mitigate disease risk based on individual genetic profiles.
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Glucemia , Metabolismo de los Hidratos de Carbono , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo , Humanos , India/epidemiología , Glucemia/metabolismo , Masculino , Metabolismo de los Hidratos de Carbono/genética , Femenino , Diabetes Mellitus Tipo 2/genética , Adulto , Predisposición Genética a la Enfermedad , Persona de Mediana Edad , Metilación de ADN/genética , MultiómicaRESUMEN
Shortening of telomere length (TL) is correlated with many age-related disorders and is a hallmark of biological aging. This study used proteome-wide Mendelian randomization to identify the protein biomarkers associated with telomere length. Protein quantitative trait loci (pQTL) were derived from two studies, the deCODE Health study (4907 plasma proteins) and the UK Biobank Pharma Proteomics Project (2923 plasma proteins). Summary data from genome-wide association studies (GWAS) for TL were obtained from the UK Biobank (472,174 cases) and GWAS Catalog (418,401 cases). The association between proteins and TL was further assessed using colocalization and summary data-based Mendelian randomization (SMR) analyses. The protein-protein network, druggability assessment, and phenome-wide MR were used to further evaluate the potential biological effects, druggability, and safety of the target proteins. Proteome-wide MR analysis identified 22 plasma proteins that were causally associated with telomere length. Five of these proteins (APOE, SPRED2, MAX, RALY, and PSMB1) had the highest evidence of association with TL and should be prioritized. This study revealed telomere length-related protein biomarkers, providing new insights into the development of new treatment targets for chronic diseases and anti-aging intervention strategies.
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Biomarcadores , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Proteómica , Sitios de Carácter Cuantitativo , Humanos , Biomarcadores/sangre , Proteómica/métodos , Homeostasis del Telómero , Telómero/metabolismo , Telómero/genética , Proteoma/metabolismo , Proteínas Sanguíneas/genética , Proteínas Sanguíneas/metabolismo , Acortamiento del TelómeroRESUMEN
Chronic Kidney Disease (CKD) stands as a substantial challenge within the global health landscape. The elevated metabolic demands essential for sustaining normal kidney function have propelled an increasing interest in unraveling the intricate relationship between mitochondrial dysfunction and CKD. However, the authentic causal relationship between these two factors remains to be conclusively elucidated. This study endeavors to address this knowledge gap through the Mendelian Randomization (MR) method. We utilized large-scale QTL datasets (including 31,684 eQTLs samples, 1980 mQTLs samples, and 35,559 pQTLs samples) to precisely identify key genes related to mitochondrial function as exposure factors. Subsequently, we employed GWAS datasets (comprising 480,698 CKD samples and 1,004,040 eGFRcrea samples) as outcome factors. Through a comprehensive multi-level analysis (encompassing expression, methylation, and protein quantification loci), we evaluated the causal impact of these genes on CKD and estimated glomerular filtration rate (eGFR). The integration and validation of diverse genetic data, complemented by the application of co-localization analysis, bi-directional MR analysis, and various MR methods, notably including inverse variance weighted, have collectively strengthened our confidence in the robustness of these findings. Lastly, we validate the outcomes through examination in human RNA sequencing datasets encompassing various subtypes of CKD. This study unveils significant associations between the glycine amidinotransferase (GATM) and CKD, as well as eGFR. Notably, an augmentation in GATM gene and protein expression corresponds to a diminished risk of CKD, whereas distinct methylation patterns imply an increased risk. Furthermore, a discernible reduction in GATM expression is observed across diverse pathological subtypes of CKD, exhibiting a noteworthy positive correlation with GFR. These findings establish a causal relationship between GATM and CKD, thereby highlighting its potential as a therapeutic target. This insight lays the foundation for the development of potential therapeutic interventions for CKD, presenting substantial clinical promise.
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Progresión de la Enfermedad , Estudio de Asociación del Genoma Completo , Tasa de Filtración Glomerular , Análisis de la Aleatorización Mendeliana , Mitocondrias , Sitios de Carácter Cuantitativo , Insuficiencia Renal Crónica , Humanos , Insuficiencia Renal Crónica/genética , Tasa de Filtración Glomerular/genética , Mitocondrias/genética , Polimorfismo de Nucleótido Simple , Predisposición Genética a la EnfermedadRESUMEN
While previous research has shown the potential links between taste perception pathways and brain-related conditions, the area involving Alzheimer's disease remains incompletely understood. Taste perception involves neurotransmitter signaling, including serotonin, glutamate, and dopamine. Disruptions in these pathways are implicated in neurodegenerative diseases. The integration of olfactory and taste signals in flavor perception may impact brain health, evident in olfactory dysfunction as an early symptom in neurodegenerative conditions. Shared immune response and inflammatory pathways may contribute to the association between altered taste perception and conditions like neurodegeneration, present in Alzheimer's disease. This study consists of an exploration of expression-quantitative trait loci (eQTL), utilizing whole-blood transcriptome profiles, of 28 taste perception genes, from a combined cohort of 475 African American subjects. This comprehensive dataset was subsequently intersected with single-nucleotide polymorphisms (SNPs) identified in Genome-Wide Association Studies (GWAS) of Alzheimer's Disease (AD). Finally, the investigation delved into assessing the association between eQTLs reported in GWAS of AD and the profiles of 741 proteins from the Olink Neurological Panel. The eQTL analysis unveiled 3,547 statistically significant SNP-Gene associations, involving 412 distinct SNPs that spanned all 28 taste genes. In 17 GWAS studies encompassing various traits, a total of 14 SNPs associated with 12 genes were identified, with three SNPs consistently linked to Alzheimer's disease across four GWAS studies. All three SNPs demonstrated significant associations with the down-regulation of TAS2R41, and two of them were additionally associated with the down-regulation of TAS2R60. In the subsequent pQTL analysis, two of the SNPs linked to TAS2R41 and TAS2R60 genes (rs117771145 and rs10228407) were correlated with the upregulation of two proteins, namely EPHB6 and ADGRB3. Our investigation introduces a new perspective to the understanding of Alzheimer's disease, emphasizing the significance of bitter taste receptor genes in its pathogenesis. These discoveries set the stage for subsequent research to delve into these receptors as promising avenues for both intervention and diagnosis. Nevertheless, the translation of these genetic insights into clinical practice requires a more profound understanding of the implicated pathways and their pertinence to the disease's progression across diverse populations.
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Enfermedad de Alzheimer , Negro o Afroamericano , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo , Percepción del Gusto , Humanos , Enfermedad de Alzheimer/genética , Negro o Afroamericano/genética , Percepción del Gusto/genética , Femenino , Masculino , Anciano , Predisposición Genética a la Enfermedad , Persona de Mediana Edad , TranscriptomaRESUMEN
The relationship between psoriasis and site-specific cancers remains unclear. Here, we aim to investigate whether psoriasis is causally associated with site-specific cancers. We use observational and genetic data from the UK Biobank, obtaining GWAS summary data, eQTL analysis data, TCGA data, and GTEx data from public datasets. We perform PheWAS, polygenic risk score analysis, and one-sample and two-sample Mendelian randomization analyses to investigate the potential causal associations between psoriasis and cancers. In the unselected PheWAS analysis, psoriasis is associated with higher risks of 16 types of cancer. Using one-sample Mendelian randomization analyses, it is found that genetically predicted psoriasis is associated with higher risks of anal canal cancer, breast cancer, follicular non-Hodgkin's lymphoma and nonmelanoma skin cancer in women; and lung cancer and kidney cancer in men. Our two-sample Mendelian randomization analysis indicates that psoriasis is causally associated with breast cancer and lung cancer. Gene annotation shows that psoriasis-related genes, such as ERAP1, are significantly different in lung and breast cancer tissues. Taken together, clinical attention to lung cancer and breast cancer may be warranted among patients with psoriasis.
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Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Psoriasis , Humanos , Psoriasis/genética , Psoriasis/epidemiología , Femenino , Masculino , Neoplasias/genética , Neoplasias/epidemiología , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Neoplasias de la Mama/genética , Neoplasias de la Mama/epidemiología , Reino Unido/epidemiología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/epidemiología , Persona de Mediana Edad , Sitios de Carácter Cuantitativo , Herencia Multifactorial/genéticaRESUMEN
BACKGROUND: Low levels of the essential amino acid lysine in maize endosperm is considered to be a major problem regarding the nutritional quality of food and feed. Increasing the lysine content of maize is important to improve the quality of food and feed nutrition. Although the genetic basis of quality protein maize (QPM) has been studied, the further exploration of the quantitative trait loci (QTL) underlying lysine content variation still needs more attention. RESULTS: Eight maize inbred lines with increased lysine content were used to construct four double haploid (DH) populations for identification of QTLs related to lysine content. The lysine content in the four DH populations exhibited continuous and normal distribution. A total of 12 QTLs were identified in a range of 4.42-12.66% in term of individual phenotypic variation explained (PVE) which suggested the quantitative control of lysine content in maize. Five main genes involved in maize lysine biosynthesis pathways in the QTL regions were identified in this study. CONCLUSIONS: The information presented will allow the exploration of candidate genes regulating lysine biosynthesis pathways and be useful for marker-assisted selection and gene pyramiding in high-lysine maize breeding programs.
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Lisina , Sitios de Carácter Cuantitativo , Zea mays , Zea mays/genética , Zea mays/metabolismo , Lisina/metabolismo , Fenotipo , Haploidia , Mapeo CromosómicoRESUMEN
BACKGROUND: Osteoarthritis (OA) is a degenerative osteoarticular disease, involving genetic predisposition. How the risk variants confer the risk of OA through their effects on proteins remains largely unknown. Therefore, we aimed to discover new and effective drug targets for OA and its subtypes. METHODS: A proteome-wide association study (PWAS) was performed based on OA and its subtypes genome-wide association studies (GWAS) summary datasets and the protein quantitative trait loci (pQTL) data. Subsequently, Mendelian randomization (MR) and colocalization analysis was conducted to estimate the associations between protein and OA risk. The replication analysis was performed in an independent dataset of human plasma pQTL data. RESULTS: The abundance of seven proteins was causally related to OA, two proteins to knee OA and six proteins to hip OA, respectively. We replicated 2 of these proteins using an independent pQTL dataset. With the further support of colocalization, and higher ECM1 level was causally associated with a higher risk of OA and hip OA. Higher PCSK1 level was causally associated with a lower risk of OA. And higher levels of ITIH1, EFEMP1, and ERLEC1 were associated with decreased risk of hip OA. CONCLUSION: Our study provides new insights into the genetic component of protein abundance in OA and a promising therapeutic target for future drug development.
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Estudio de Asociación del Genoma Completo , Proteoma , Sitios de Carácter Cuantitativo , Humanos , Osteoartritis/genética , Osteoartritis/sangre , Osteoartritis de la Rodilla/genética , Osteoartritis de la Rodilla/sangre , Predisposición Genética a la Enfermedad/genética , Osteoartritis de la Cadera/genética , Osteoartritis de la Cadera/sangre , Análisis de la Aleatorización Mendeliana , Masculino , Femenino , Terapia Molecular Dirigida/métodosRESUMEN
Insulin resistance causes multiple epidemic metabolic diseases, including type 2 diabetes, cardiovascular disease, and fatty liver, but is not routinely measured in epidemiological studies. To discover novel insulin resistance genes in the general population, we conducted genome-wide association studies in 382,129 individuals for triglyceride to HDL-cholesterol ratio (TG/HDL), a surrogate marker of insulin resistance calculable from commonly measured serum lipid profiles. We identified 251 independent loci, of which 62 were more strongly associated with TG/HDL compared to TG or HDL alone, suggesting them as insulin resistance loci. Candidate causal genes at these loci were prioritized by fine mapping with directions-of-effect and tissue specificity annotated through analysis of protein coding and expression quantitative trait variation. Directions-of-effect were corroborated in an independent cohort of individuals with directly measured insulin resistance. We highlight two phospholipase encoding genes, PLA2G12A and PLA2G6, which liberate arachidonic acid and improve insulin sensitivity, and VGLL3, a transcriptional co-factor that increases insulin resistance partially through enhanced adiposity. Finally, we implicate the anti-apoptotic gene TNFAIP8 as a sex-dimorphic insulin resistance factor, which acts by increasing visceral adiposity, specifically in females. In summary, our study identifies several candidate modulators of insulin resistance that have the potential to serve as biomarkers and pharmacological targets.
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HDL-Colesterol , Estudio de Asociación del Genoma Completo , Resistencia a la Insulina , Triglicéridos , Humanos , Resistencia a la Insulina/genética , Triglicéridos/sangre , Femenino , HDL-Colesterol/sangre , HDL-Colesterol/genética , Masculino , Sitios de Carácter Cuantitativo , Persona de Mediana Edad , Adulto , Polimorfismo de Nucleótido Simple , Genómica/métodosRESUMEN
Background: Mitochondrial dysfunction plays a crucial role in Type 2 Diabetes Mellitus (T2DM) and its complications. However, the genetic pathophysiology remains under investigation. Through multi-omics Mendelian Randomization (MR) and colocalization analyses, we identified mitochondrial-related genes causally linked with T2DM and its complications. Methods: Summary-level quantitative trait loci data at methylation, RNA, and protein levels were retrieved from European cohort studies. GWAS summary statistics for T2DM and its complications were collected from the DIAGRAM and FinnGen consortiums, respectively. Summary-data-based MR was utilized to estimate the causal effects. The heterogeneity in dependent instrument test assessed horizontal pleiotropy, while colocalization analysis determined whether genes and diseases share the same causal variant. Enrichment analysis, drug target analysis, and phenome-wide MR were conducted to further explore the biological functions, potential drugs, and causal associations with other diseases. Results: Integrating evidence from multi-omics, we identified 18 causal mitochondrial-related genes. Enrichment analysis revealed they were not only related to nutrient metabolisms but also to the processes like mitophagy, autophagy, and apoptosis. Among these genes, Tu translation elongation factor mitochondrial (TUFM), 3-hydroxyisobutyryl-CoA hydrolase (HIBCH), and iron-sulfur cluster assembly 2 (ISCA2) were identified as Tier 1 genes, showing causal links with T2DM and strong colocalization evidence. TUFM and ISCA2 were causally associated with an increased risk of T2DM, while HIBCH showed an inverse causal relationship. The causal associations and colocalization effects for TUFM and HIBCH were validated in specific tissues. TUFM was also found to be a risk factor for microvascular complications in T2DM patients including retinopathy, nephropathy, and neuropathy. Furthermore, drug target analysis and phenome-wide MR underscored their significance as potential therapeutic targets. Conclusions: This study identified 18 mitochondrial-related genes causally associated with T2DM at multi-omics levels, enhancing the understanding of mitochondrial dysfunction in T2DM and its complications. TUFM, HIBCH, and ISCA2 emerge as potential therapeutic targets for T2DM and its complications.
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Diabetes Mellitus Tipo 2 , Análisis de la Aleatorización Mendeliana , Mitocondrias , Humanos , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/complicaciones , Mitocondrias/metabolismo , Mitocondrias/genética , Estudio de Asociación del Genoma Completo , Sitios de Carácter Cuantitativo , Predisposición Genética a la Enfermedad , Complicaciones de la Diabetes/genética , MultiómicaRESUMEN
BACKGROUND: Our previous genomewide association studies (GWAS) have suggested rs912304 in 14q12 as a suggestive risk variant for type 1 diabetes (T1D). However, the association between this risk region and T1D subgroups and related clinical risk features, the underlying causal functional variant(s), putative candidate gene(s), and related mechanisms are yet to be elucidated. METHODS: We assessed the association between variant rs912304 and T1D, as well as islet autoimmunity and islet function, stratified by the diagnosed age of 12. We used epigenome bioinformatics analyses, dual luciferase reporter assays, and expression quantitative trait loci (eQTL) analyses to prioritize the most likely functional variant and potential causal gene. We also performed functional experiments to evaluate the role of the causal gene on islet function and its related mechanisms. RESULTS: We identified rs912304 as a risk variant for T1D subgroups with diagnosed age ≥ 12 but not < 12. This variant is associated with residual islet function but not islet-specific autoantibody positivity in T1D individuals. Bioinformatics analysis indicated that rs912304 is a functional variant exhibiting spatial overlaps with enhancer active histone marks (H3K27ac and H3K4me1) and open chromatin status (ATAC-seq) in the human pancreas and islet tissues. Luciferase reporter gene assays and eQTL analyses demonstrated that the biallelic sites of rs912304 had differential allele-specific enhancer activity in beta cell lines and regulated STXBP6 expression, which was defined as the most putative causal gene based on Open Targets Genetics, GTEx v8 and Tiger database. Moreover, Stxbp6 was upregulated by T1D-related proinflammatory cytokines but not high glucose/fat. Notably, Stxbp6 over-expressed INS-1E cells exhibited decreasing insulin secretion and increasing cell apoptosis through Glut1 and Gadd45ß, respectively. CONCLUSIONS: This study expanded the genomic landscape regarding late-onset T1D risk and supported islet function mechanistically connected to T1D pathogenesis.
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Diabetes Mellitus Tipo 1 , Islotes Pancreáticos , Humanos , Diabetes Mellitus Tipo 1/genética , Islotes Pancreáticos/metabolismo , Femenino , Masculino , Polimorfismo de Nucleótido Simple/genética , Predisposición Genética a la Enfermedad , Citocinas/genética , Citocinas/metabolismo , Niño , Adolescente , Sitios de Carácter Cuantitativo , Animales , Edad de Inicio , Regulación de la Expresión Génica , Estudio de Asociación del Genoma CompletoRESUMEN
High-density genomic data analyzed by accurate statistical methods are of potential to enlighten past breeding practices such as selection by unraveling fixed regions. In this study, four native Turkish sheep breeds (80 samples) were genotyped via 296.097 single nucleotide polymorphisms (SNPs) detected by double-digest restriction site-associated DNA (ddRADseq) library preparation combined with the Illumina HiSeq X Ten instrument in order to identify genes under selection pressure. A total of 32, 136, 133, and 119 protein-coding genes were detected under selection pressure by runs of homozygosity (ROH), integrated haplotype score (iHS), the ratio of extended haplotype homozygosity (Rsb), and fixation index (FST) approaches, respectively. Of these, a total of 129 genes were identified by at least two statistical models which overlapped with a total of 52 quantitative trait loci (QTL)-associated SNPs, known to be related to fiber diameter, milk content, body weight, carcass traits, some blood parameters, and entropion. A total of six genes under selection pressure were validated by three statistical approaches five of which are of potential to be integrated into animal breeding since they were associated with wool fiber diameter (ZNF208B), behaviors related to neurocognitive development (CBX1 and NFE2L1), adaptation to high-altitude (SDK1), and anxiety causing internal stress (GSG1L). The sixth gene (COPZ1) turned out to play an important role in coping with different types of cancer in mammals. In particular, ROH analysis uncovered significant findings that the Güney Karaman (GKR) had experienced different selection practices than the Akkaraman (AKR) breed. Moreover, some genes specifically under selection in the GKR breed turned out to be associated with olfaction (OR6K6, OR6N1, OR6N2, and OR4C16), survival during the gestation period (PRR15L), and heat stress (CDK5RAP9). The results of this study imply that GKR may become genetically different from the AKR breed at the genome level due to most probably experiencing different adaptation processes occurring in raised climatic conditions. These differences should be conserved to face future challenges, while other native Turkish sheep breeds could be monitored via genome-wide high-density SNP data to obtain deeper knowledge about the effects of natural selection.
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Polimorfismo de Nucleótido Simple , Selección Genética , Animales , Ovinos/genética , Sitios de Carácter Cuantitativo , Cruzamiento , Turquía , Estudio de Asociación del Genoma Completo/métodos , Haplotipos , Homocigoto , GenotipoRESUMEN
KEY MESSAGE: We identified novel physiological and genetic responses to phosphorus starvation in sorghum diversity lines that augment current knowledge of breeding for climate-smart crops in Europe. Phosphorus (P) deficiency and finite P reserves for fertilizer production pose a threat to future global crop production. Understanding root system architecture (RSA) plasticity is central to breeding for P-efficient crops. Sorghum is regarded as a P-efficient and climate-smart crop with strong adaptability to different climatic regions of the world. Here we investigated early genetic responses of sorghum RSA to P deficiency in order to identified genotypes with interesting root phenotypes and responses under low P. A diverse set of sorghum lines (n = 285) was genotyped using DarTSeq generating 12,472 quality genome wide single-nucleotide polymorphisms. Root phenotyping was conducted in a paper-based hydroponic rhizotron system under controlled greenhouse conditions with low and optimal P nutrition, using 16 RSA traits to describe genetic and phenotypic variability at two time points. Genotypic and phenotypic P-response variations were observed for multiple root traits at 21 and 42 days after germination with high broad sense heritability (0.38-0.76). The classification of traits revealed four distinct sorghum RSA types, with genotypes clustering separately under both low and optimal P conditions, suggesting genetic control of root responses to P availability. Association studies identified quantitative trait loci in chromosomes Sb02, Sb03, Sb04, Sb06 and Sb09 linked with genes potentially involved in P transport and stress responses. The genetic dissection of key factors underlying RSA responses to P deficiency could enable early identification of P-efficient sorghum genotypes. Genotypes with interesting RSA traits for low P environments will be incorporated into current sorghum breeding programs for later growth stages and field-based evaluations.
Asunto(s)
Genotipo , Fenotipo , Fósforo , Raíces de Plantas , Polimorfismo de Nucleótido Simple , Sorghum , Sorghum/genética , Sorghum/crecimiento & desarrollo , Sorghum/fisiología , Fósforo/metabolismo , Fósforo/deficiencia , Raíces de Plantas/crecimiento & desarrollo , Raíces de Plantas/genética , Fitomejoramiento , Sitios de Carácter CuantitativoRESUMEN
Soil-borne cereal mosaic virus (SBCMV), the causative agent of wheat mosaic, is a Furovirus challenging wheat production all over Europe. Differently from bread wheat, durum wheat shows greater susceptibility and stronger yield penalties, so identification and genetic characterization of resistance sources are major targets for durum genetics and breeding. The Sbm1 locus providing high level of resistance to SBCMV was mapped in bread wheat to the 5DL chromosome arm (Bass in Genome 49:1140-1148, 2006). This excluded the direct use of Sbm1 for durum wheat improvement. Only one major QTL has been mapped in durum wheat, namely QSbm.ubo-2B, on the 2BS chromosome region coincident with Sbm2, already known in bread wheat as reported (Bayles in HGCA Project Report, 2007). Therefore, QSbm.ubo-2B = Sbm2 is considered a pillar for growing durum in SBCMV-affected areas. Herein, we report the fine mapping of Sbm2 based on bi-parental mapping and GWAS, using the Infinium 90 K SNP array and high-throughput KASP®. Fine mapping pointed out a critical haploblock of 3.2 Mb defined by concatenated SNPs successfully converted to high-throughput KASP® markers coded as KUBO. The combination of KUBO-27, wPt-2106-ASO/HRM, KUBO-29, and KUBO-1 allows unequivocal tracing of the Sbm2-resistant haplotype. The interval harbors 52 high- and 41 low-confidence genes, encoding 17 cytochrome p450, three receptor kinases, two defensins, and three NBS-LRR genes. These results pave the way for Sbm2 positional cloning. Importantly, the development of Sbm2 haplotype tagging KASP® provides a valuable case study for improving efficacy of the European variety testing system and, ultimately, the decision-making process related to varietal characterization and choice.
Asunto(s)
Mapeo Cromosómico , Resistencia a la Enfermedad , Enfermedades de las Plantas , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo , Triticum , Triticum/genética , Triticum/virología , Enfermedades de las Plantas/virología , Enfermedades de las Plantas/genética , Resistencia a la Enfermedad/genética , Fenotipo , Cromosomas de las Plantas/genética , Virus del Mosaico/patogenicidad , Genes de Plantas , Marcadores GenéticosRESUMEN
Alternative splicing (AS) in human genes is widely viewed as a mechanism for enhancing proteomic diversity. AS can also impact gene expression levels without increasing protein diversity by producing 'unproductive' transcripts that are targeted for rapid degradation by nonsense-mediated decay (NMD). However, the relative importance of this regulatory mechanism remains underexplored. To better understand the impact of AS-NMD relative to other regulatory mechanisms, we analyzed population-scale genomic data across eight molecular assays, covering various stages from transcription to cytoplasmic decay. We report threefold more unproductive splicing compared with prior estimates using steady-state RNA. This unproductive splicing compounds across multi-intronic genes, resulting in 15% of transcript molecules from protein-coding genes being unproductive. Leveraging genetic variation across cell lines, we find that GWAS trait-associated loci explained by AS are as often associated with NMD-induced expression level differences as with differences in protein isoform usage. Our findings suggest that much of the impact of AS is mediated by NMD-induced changes in gene expression rather than diversification of the proteome.
Asunto(s)
Empalme Alternativo , Degradación de ARNm Mediada por Codón sin Sentido , Humanos , Empalme Alternativo/genética , Regulación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Sitios de Carácter Cuantitativo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Intrones/genéticaRESUMEN
KEY MESSAGES: Sixty-nine quantitative trait nucleotides conferring maize resistance to Gibberella ear rot were detected, including eighteen novel loci. Four candidate genes were predicted, and four kompetitive allele-specific PCR markers were developed. Maize Gibberella ear rot (GER), caused by Fusarium graminearum, is one of the most devastating diseases in maize-growing regions worldwide. Enhancing maize cultivar resistance to this disease requires a comprehensive understanding of the genetic basis of resistance to GER. In this study, 334 maize inbred lines were phenotyped for GER resistance in five environments and genotyped using the Affymetrix CGMB56K SNP Array, and a genome-wide association study of resistance to GER was performed using a 3V multi-locus random-SNP-effect mixed linear model. A total of 69 quantitative trait nucleotides (QTNs) conferring resistance to GER were detected, and all of them explained individually less than 10% of the phenotypic variation, suggesting that resistance to GER is controlled by multiple minor-effect genetic loci. A total of 348 genes located around the 200-kb genomic region of these 69 QTNs were identified, and four of them (Zm00001d029648, Zm00001d031449, Zm00001d006397, and Zm00001d053145) were considered candidate genes conferring susceptibility to GER based on gene expression patterns. Moreover, four kompetitive allele-specific PCR markers were developed based on the non-synonymous variation of these four candidate genes and validated in two genetic populations. This study provides useful genetic resources for improving resistance to GER in maize.