scholarly journals Phosphate transporter PHT1;1 as a key determinant of phosphorus acquisition in Arabidopsis natural accessions

2022 ◽  
Author(s):  
Pei-Shan Chien ◽  
Ya-Ting Chao ◽  
Chia-Hui Chou ◽  
Yu-Ying Hsu ◽  
Su-Fen Chiang ◽  
...  
Keyword(s):  
Association Studies ◽  
Phosphate Transporter ◽  
Fine Tuning ◽  
F1 Hybrids ◽  
Genome Wide Association Studies ◽  
Protein Abundance ◽  
Soil P ◽  
P Acquisition ◽  
Genes Encoding ◽  
Uptake Activity

To understand the genetic basis in governing phosphorus (P) acquisition, we performed genome-wide association studies (GWAS) on a diversity panel of Arabidopsis thaliana by two primary determinants of P acquisition, phosphate (Pi)-uptake activity and PHOSPHATE TRANSPORTER 1 (PHT1) protein abundance. Association mapping revealed a shared significant peak on chromosome 5 (Chr5) where the PHT1;1/2/3 genes reside, suggesting a strong correlation between the regulation of Pi-uptake activity and PHT1 protein abundance. Genes encoding transcription factors, kinases, and a metalloprotease associated with both traits were also identified. Conditional GWAS followed by statistical analysis of genotype-dependent expression of PHT1;1 and transcription activity assays revealed an epistatic interaction between PHT1;1 and MYB DOMAIN PROTEIN 52 (MYB52) on Chr1. Analyses of F1 hybrids generated by crossing two subgroups of natural accessions carrying specific SNPs associated with PHT1;1 and MYB52 further revealed the strong effects of potential variants on PHT1;1 expression and Pi uptake activity. Notably, the soil P contents in A. thaliana habitats were found to coincide with PHT1;1 haplotype, underscoring how fine-tuning of the activity of P acquisition by natural variants allows plants to adapt to their environments. This study sheds light on the complex regulation of P acquisition and offers a framework to systematically assess the effectiveness of GWAS approaches in the study of quantitative traits.

scholarly journals Fine-tuning Polygenic Risk Scores with GWAS Summary Statistics

2019 ◽  
Author(s):  
Zijie Zhao ◽  
Yanyao Yi ◽  
Yuchang Wu ◽  
Xiaoyuan Zhong ◽  
Yupei Lin ◽  
...  
Keyword(s):  
Association Studies ◽  
Fine Tuning ◽  
Risk Scores ◽  
Training Dataset ◽  
Validation Dataset ◽  
P Value ◽  
Genome Wide Association Studies ◽  
Summary Statistics ◽  
Polygenic Risk ◽  
Model Tuning

AbstractPolygenic risk scores (PRSs) have wide applications in human genetics research. Notably, most PRS models include tuning parameters which improve predictive performance when properly selected. However, existing model-tuning methods require individual-level genetic data as the training dataset or as a validation dataset independent from both training and testing samples. These data rarely exist in practice, creating a significant gap between PRS methodology and applications. Here, we introduce PUMAS (Parameter-tuning Using Marginal Association Statistics), a novel method to fine-tune PRS models using summary statistics from genome-wide association studies (GWASs). Through extensive simulations, external validations, and analysis of 65 traits, we demonstrate that PUMAS can perform a variety of model-tuning procedures (e.g. cross-validation) using GWAS summary statistics and can effectively benchmark and optimize PRS models under diverse genetic architecture. On average, PUMAS improves the predictive R2 by 205.6% and 62.5% compared to PRSs with arbitrary p-value cutoffs of 0.01 and 1, respectively. Applied to 211 neuroimaging traits and Alzheimer’s disease, we show that fine-tuned PRSs will significantly improve statistical power in downstream association analysis. We believe our method resolves a fundamental problem without a current solution and will greatly benefit genetic prediction applications.

scholarly journals Qtlizer: comprehensive QTL annotation of GWAS results

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Matthias Munz ◽  
Inken Wohlers ◽  
Eric Simon ◽  
Tobias Reinberger ◽  
Hauke Busch ◽  
...  
Keyword(s):  
Association Studies ◽  
Housekeeping Genes ◽  
R Package ◽  
Genome Wide Association Studies ◽  
Protein Abundance ◽  
Base Pairs ◽  
Link Type ◽  
Genome Wide ◽  
Wide Range ◽  
Distance Limit

AbstractExploration of genetic variant-to-gene relationships by quantitative trait loci such as expression QTLs is a frequently used tool in genome-wide association studies. However, the wide range of public QTL databases and the lack of batch annotation features complicate a comprehensive annotation of GWAS results. In this work, we introduce the tool “Qtlizer” for annotating lists of variants in human with associated changes in gene expression and protein abundance using an integrated database of published QTLs. Features include incorporation of variants in linkage disequilibrium and reverse search by gene names. Analyzing the database for base pair distances between best significant eQTLs and their affected genes suggests that the commonly used cis-distance limit of 1,000,000 base pairs might be too restrictive, implicating a substantial amount of wrongly and yet undetected eQTLs. We also ranked genes with respect to the maximum number of tissue-specific eQTL studies in which a most significant eQTL signal was consistent. For the top 100 genes we observed the strongest enrichment with housekeeping genes (P = 2 × 10–6) and with the 10% highest expressed genes (P = 0.005) after grouping eQTLs by r2 > 0.95, underlining the relevance of LD information in eQTL analyses. Qtlizer can be accessed via https://genehopper.de/qtlizer or by using the respective Bioconductor R-package (https://doi.org/10.18129/B9.bioc.Qtlizer).

scholarly journals Uncovering complementary sets of variants for the prediction of quantitative phenotypes

2020 ◽  
Author(s):  
Serhan Yilmaz ◽  
Mohamad Fakhouri ◽  
Mehmet Koyuturk ◽  
A. Ercument Cicek ◽  
Oznur Tastan
Keyword(s):  
Association Studies ◽  
Simple Algorithm ◽  
Fine Tuning ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Selection Methods ◽  
Single Nucleotide ◽  
Phenotype Prediction ◽  
Genome Wide ◽  
Complementary Subset

Recent genome-wide association studies (GWAS) show that mutations in single genetic loci, frequently called single nucleotide polymorphisms (SNPs), alone are not sufficient to explain the phenotypic heritability of complex, quantitative phenotypes. Instead, many methods attempt to deal with this issue by considering a set of loci that can characterize the phenotype together. While the state-of-the-art methods are successful in selecting subsets of SNPs that can achieve high phenotype prediction rates, they are either slow in runtime or have hyper-parameters that require further fine tuning through cross-validation or other similar techniques, which makes such methods inconvenient to use. In this work, we propose a fast and simple algorithm named Macarons to select a small, complementary subset of SNPs by avoiding redundant pairs of SNPs that are likely to be in linkage disequilibrium (LD). Our method features two interpretable parameters that control the time/performance trade-off without requiring any hyper-parameter optimization procedures. In our experiments, we benchmark the performance of the SNP selection methods on the 17 flowering time phenotypes of Arabidopsis Thaliana. Our results consistently show that Macarons has similar or better phenotype prediction performance while being faster and having a simpler premise than other SNP selection methods.

scholarly journals Nuclear lamins and diabetes mellitus

STEMedicine ◽  
2020 ◽  
Vol 2 (5) ◽  
pp. e73
Author(s):  
Wei Xie ◽  
Brian Burke
Keyword(s):  
Diabetes Mellitus ◽  
Association Studies ◽  
Nuclear Lamina ◽  
Major Constituent ◽  
Genome Wide Association Studies ◽  
Intermediate Filament Proteins ◽  
Partial Lipodystrophy ◽  
Nuclear Lamins ◽  
Genes Encoding ◽  
Type V

In metazoans, a thin filamentous network referred to as the nuclear lamina plays an essential role in providing mechanical support to the nucleus. The major constituent of the nuclear lamina is type V intermediate filament proteins that are collectively referred to as lamins. A variety of diseases collectively termed laminopathies have been linked to mutations in genes encoding nuclear envelope proteins, in particular lamins, such as X-linked Emery Dreifus muscular dystrophy, dilated cardiomyopathy, Dunnigan type familial partial lipodystrophy and Hutchinson-Gilford progeria syndrome. Apart from laminopathies, genome-wide association studies have also been implicated nuclear lamins in the pathophysiology of type 2 diabetes mellitus, although little information in terms of the function of lamins in its pathogenesis. Our current review attempts to summarize risk factors of diabetes mellitus that could be attributable to lamin mutations and indirectly linked to lamin-associated factors identified in the last two decades.

scholarly journals Genetic Variants Shaping Inter-individual Differences in Response to Dietary Intakes—A Narrative Review of the Case of Vitamins

2020 ◽  
Vol 7 ◽  
Author(s):  
Aikaterini Niforou ◽  
Valentini Konstantinidou ◽  
Androniki Naska
Keyword(s):  
Vitamin D ◽  
Vitamin C ◽  
Genetic Variants ◽  
Current Knowledge ◽  
Association Studies ◽  
Genetic Variations ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Dietary Intakes ◽  
Genes Encoding

Recent advances in the field of nutrigenetics have provided evidence on how genetic variations can impact the individuals' response to dietary intakes. An objective and reliable assessment of dietary exposures should rely on combinations of methodologies including frequency questionnaires, short-term recalls or records, together with biological samples to evaluate markers of intake or status and to identify genetic susceptibilities. In an attempt to present current knowledge on how genetic fingerprints contribute to an individual's nutritional status, we present a review of current literature describing associations between genetic variants and levels of well-established biomarkers of vitamin status in free-living and generally healthy individuals. Based on the outcomes of candidate gene, genome-wide-association studies and meta-analyses thereof, we have identified several single nucleotide polymorphisms (SNPs) involved in the vitamins' metabolic pathways. Polymorphisms in genes encoding proteins involved in vitamin metabolism and transport are reported to have an impact on vitamin D status; while genetic variants of vitamin D receptor were most frequently associated with health outcomes. Genetic variations that can influence vitamin E status include SNPs involved in its uptake and transport, such as in SCAR-B1 gene, and in lipoprotein metabolism. Variants of the genes encoding the sodium-dependent vitamin C transport proteins are greatly associated with the body's status on vitamin C. Regarding the vitamins of the B-complex, special reference is made to the widely studied variant in the MTHFR gene. Methodological attributes of genetic studies that may limit the comparability and interpretability of the findings are also discussed. Our understanding of how genes affect our responses to nutritional triggers will enhance our capacity to evaluate dietary exposure and design personalized nutrition programs to sustain health and prevent disease.

Polymorphisms Affecting Trace Element Bioavailability

2010 ◽  
Vol 80 (45) ◽  
pp. 314-318 ◽  
Author(s):  
John C. Mathers ◽  
Catherine Méplan ◽  
John E. Hesketh
Keyword(s):  
Trace Element ◽  
Individual Variation ◽  
Association Studies ◽  
Copy Number Variants ◽  
Micro Rna ◽  
Future Research ◽  
Genome Wide Association Studies ◽  
Complex Interactions ◽  
Genome Wide ◽  
Genes Encoding

This review outlines the nature of inter-individual variation in trace element bioavailability, focusing on genetic and epigenetic determinants. We note that pathogenic mutations responsible for dangerously high (or low) status for the micronutrient are unlikely to make large contributions to variability in bioavailability among the general population. Prospective genotyping (for variants in genes encoding selenoproteins) of participants in human studies illustrate one approach to understanding the complex interactions between genotype and trace element supply, which determine the functional bioavailability of selenium. Rapid advances in technological and bioinformatics tools; e. g., as used in Genome-Wide Association Studies, are opening new avenues for research on the genetic determinants of inter-individual variation in trace element bioavailability. This may include copy number variants in addition to the more widely studied polymorphisms. Future research on trace element bioavailability should encompass studies of epigenetic variants, including the role of non-coding (micro) RNA.

scholarly journals Monogenic Diabetes in the Young, Pharmacogenetics and Relevance to Multifactorial Forms of Type 2 Diabetes

2008 ◽  
Vol 29 (3) ◽  
pp. 254-264 ◽  
Author(s):  
Martine Vaxillaire ◽  
Philippe Froguel
Keyword(s):  
Type 2 Diabetes ◽  
Glucose Sensor ◽  
Cell Function ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Dominant Form ◽  
Genes Encoding ◽  
Autosomal Dominant Form ◽  
Β Cell Function

Abstract Most valuable breakthroughs in the genetics of type 2 diabetes for the past two decades have arisen from candidate gene studies and familial linkage analysis of maturity-onset diabetes of the young (MODY), an autosomal dominant form of diabetes typically occurring before 25 years of age caused by primary insulin secretion defects. Despite its low prevalence, MODY is not a single entity but presents genetic, metabolic and clinical heterogeneity. MODY can result from mutations in at least six different genes encoding the glucose sensor enzyme glucokinase and transcription factors that participate in a regulatory network essential for adult β-cell function. Additional genes have been described in other discrete phenotypes or syndromic forms of diabetes. Whereas common variants in the MODY genes contribute very modestly to type 2 diabetes susceptibility in adults, major findings emerging from the advent of genome-wide association studies will deliver an increasing number of genes and new pathways for the pathological events of the disease.

scholarly journals Low tolerance for transcriptional variation at cohesin genes is accompanied by functional links to disease-relevant pathways

2020 ◽  
pp. jmedgenet-2020-107095
Author(s):  
William Schierding ◽  
Julia A Horsfield ◽  
Justin M O'Sullivan
Keyword(s):  
Association Studies ◽  
Genome Wide Association Studies ◽  
Cohesin Complex ◽  
Loss Of Function ◽  
Regulatory Variants ◽  
Genome Wide ◽  
Genes Encoding ◽  
Full Complement ◽  
Transcriptional Changes ◽  
Robust Regulation

Background: The cohesin complex plays an essential role in genome organisation and cell division. A full complement of the cohesin complex and its regulators is important for normal development, since heterozygous mutations in genes encoding these components can be sufficient to produce a disease phenotype. The implication that genes encoding the cohesin subunits or cohesin regulators must be tightly controlled and resistant to variability in expression has not yet been formally tested.Methods: Here, we identify spatial-regulatory connections with potential to regulate expression of cohesin loci (Mitotic: SMC1A, SMC3, STAG1, STAG2, RAD21/RAD21-AS; Meiotic: SMC1B, STAG3, REC8, RAD21L1), cohesin-ring support genes (NIPBL, MAU2, WAPL, PDS5A, PDS5B) and CTCF, including linking their expression to that of other genes. We searched the genome-wide association studies (GWAS) catalogue for SNPs mapped or attributed to cohesin genes by GWAS (GWAS-attributed) and the GTEx catalogue for SNPs mapped to cohesin genes by cis-regulatory variants in one or more of 44 tissues across the human body (expression quantitative trail locus-attributed).Results: Connections that centre on the cohesin ring subunits provide evidence of coordinated regulation that has little tolerance for perturbation. We used the CoDeS3D SNP-gene attribution methodology to identify transcriptional changes across a set of genes coregulated with the cohesin loci that include biological pathways such as extracellular matrix production and proteasome-mediated protein degradation. Remarkably, many of the genes that are coregulated with cohesin loci are themselves intolerant to loss-of-function.Conclusions: The results highlight the importance of robust regulation of cohesin genes and implicate novel pathways that may be important in the human cohesinopathy disorders.

scholarly journals Personality traits and polymorphisms of genes coding neurotransmitter receptors or transporters: review of single gene and genome-wide association studies

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Szymon Zmorzyński ◽  
Wojciech Styk ◽  
Waldemar Klinkosz ◽  
Justyna Iskra ◽  
Agata Anna Filip
Keyword(s):  
Personality Traits ◽  
Five Factor Model ◽  
Association Studies ◽  
Genome Wide Association ◽  
Cochrane Library ◽  
Neurotransmitter Receptors ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Genes Encoding ◽  
The Relationship

Abstract Background The most popular tool used for measuring personality traits is the Five-Factor Model (FFM). It includes neuroticism, extraversion, openness, agreeableness and conscientiousness. Many studies indicated the association of genes encoding neurotransmitter receptors/transporters with personality traits. The relationship connecting polymorphic DNA sequences and FFM features has been described in the case of genes encoding receptors of cannabinoid and dopaminergic systems. Moreover, dopaminergic system receives inputs from other neurotransmitters, like GABAergic or serotoninergic systems. Methods We searched PubMed Central (PMC), Science Direct, Scopus, Cochrane Library, Web of Science and EBSCO databases from their inception to November 19, 2020, to identify original studies, as well as peer-reviewed studies examining the FFM and its association with gene polymorphisms affecting the neurotransmitter functions in central nervous system. Results Serotonin neurons modulate dopamine function. In gene encoding serotonin transporter protein, SLC6A4, was found polymorphism, which was correlated with openness to experience (in Sweden population), and high scores of neuroticism and low levels of agreeableness (in Caucasian population). The genome-wide association studies (GWASs) found an association of 5q34-q35, 3p24, 3q13 regions with higher scores of neuroticism, extraversion and agreeableness. However, the results for chromosome 3 regions are inconsistent, which was shown in our review paper. Conclusions GWASs on polymorphisms are being continued in order to determine and further understand the relationship between the changes in DNA and personality traits.

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