scholarly journals Analysis of coding variants in the human FTO gene from the ExAC (gnomAD) Database

2021 ◽  
Author(s):  
Mauro Lúcio Ferreira Souza ◽  
Jaime Viana de Sousa ◽  
João Farias Guerreiro
Keyword(s):  
Genome Wide Association Study ◽  
Rare Variants ◽  
Human Populations ◽  
Nucleotide Polymorphisms ◽  
Fto Gene ◽  
Low Frequencies ◽  
Functional Variants ◽  
Pathogenicity Prediction ◽  
A Genome ◽  
Coding Variants

AbstractSingle nucleotide polymorphisms (SNPs) in the first intron of the FTO gene (alpha-ketoglutarate-dependent dioxygenase) identified by a genome-wide association study (GWAS) in 2007 continue to be the known variants with the greatest effect on adiposity in different human populations. Currently available data reveal a total of 61 different intronic SNPs associated with adiposity. Coding variants in the FTO gene, on the other hand, have been little explored, but data from complete sequencing of the exomes of various populations are available in public databases and provide an excellent opportunity to investigate potential functional variants in FTO. This study aimed to track nonsynonymous variants in the exons of the FTO gene in different population groups using the ExAC database (gnomAD) (http://exac.broadinstitute.org/) and to analyze the potential functional impact of these variants on the FTO protein. Variants were analyzed using five publicly available pathogenicity prediction programs. Of the 158 mutations identified (152 missense and 6 stop-gain), 64 (40.5%) were classified as pathogenic, 67 (42.4%) were classified as benign, and 27 (17%) were classified as inconclusive. Thirty variants were classified as pathogenic by all five predictors used in this study, and 16 mutations were classified as pathogenic by only one predictor. The largest number of mutations was found in Europeans (non-Finnish) (85/158), all with very low frequencies, and half (32/64) of the variants classified as pathogenic by the five predictors used were also found in this population. The data obtained in this analysis show that a large number of rare coding variants classified as pathogenic or potentially pathogenic by different in silico pathogenicity prediction programs are not detected by GWAS due to the low linkage disequilibrium as well as the limitations of GWAS in capturing rare variants present in less than 1.0% of the population.

scholarly journals Analysis of coding variants in the human FTO gene from the gnomAD database

PLoS ONE ◽  
2022 ◽  
Vol 17 (1) ◽  
pp. e0248610
Author(s):  
Mauro Lúcio Ferreira Souza Junior ◽  
Jaime Viana de Sousa ◽  
João Farias Guerreiro
Keyword(s):  
Human Populations ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Functional Studies ◽  
Rare Mutations ◽  
Functional Variants ◽  
Pathogenicity Prediction ◽  
Complete Sequencing ◽  
Coding Variants

Single nucleotide polymorphisms (SNPs) in the first intron of the FTO gene reported in 2007 continue to be the known variants with the greatest effect on adiposity in different human populations. Coding variants in the FTO gene, on the other hand, have been little explored, although data from complete sequencing of the exomes of various populations are available in public databases and provide an excellent opportunity to investigate potential functional variants in FTO. In this context, this study aimed to track nonsynonymous variants in the exons of the FTO gene in different population groups employing the gnomAD database and analyze the potential functional impact of these variants on the FTO protein using five publicly available pathogenicity prediction programs. The findings revealed 345 rare mutations, of which 321 are missense (93%), 19 are stop gained (5.6%) and five mutations are located in the splice region (1.4%). Of these, 134 (38.8%) were classified as pathogenic, 144 (41.7%) as benign and 67 (19.5%) as unknown. The available data, however, suggest that these variants are probably not associated with BMI and obesity, but instead, with other diseases. Functional studies are, therefore, required to identify the role of these variants in disease genesis.

scholarly journals Rare non-coding variants are associated with plasma lipid traits in a founder population

2017 ◽  
Author(s):  
Catherine Igartua ◽  
Sahar V Mozaffari ◽  
Dan L Nicolae ◽  
Carole Ober
Keyword(s):  
Genome Wide Association Study ◽  
Rare Variants ◽  
Plasma Lipid ◽  
Hdl Cholesterol ◽  
Clinical Effects ◽  
Nucleotide Polymorphisms ◽  
Founder Population ◽  
Isolated Populations ◽  
General Populations ◽  
Coding Variants

AbstractFounder populations are ideally suited for studies on the clinical effects of alleles that are rare in general populations but occur at higher frequencies in these isolated populations. Whole genome sequencing in 98 South Dakota Hutterites, a founder population of European descent, and subsequent imputation to the Hutterite pedigree revealed 660,238 single nucleotide polymorphisms (SNPs; 98.9% non-coding) that are rare (<1%) or absent in European populations, but occur at frequencies greater than 1% in the Hutterites. We examined the effects of these rare in European variants on plasma levels of LDL cholesterol (LDL-C), HDL cholesterol (HDL-C), total cholesterol and triglycerides (TG) in 828 Hutterites and applied a Bayesian hierarchical framework to prioritize potentially causal variants based on functional annotations. We identified two novel non-coding rare variants associated with LDL-C (rs17242388 in LDLR) and HDL-C (rs189679427 between GOT2 and APOOP5), and replicated previous associations of a splice variant in APOC3 (rs138326449) with TG and HDL-C. All three variants are at well-replicated loci in genome wide association study (GWAS) but are independent from and have larger effect sizes than the known common variation in these regions. We also identified variants at two novel loci (rs191020975 in EPHA6 and chr1:224811120 in CNIH3) at suggestive levels of significance with LDL-C. Candidate expression quantitative loci (eQTL) analyses in lymphoblastoid cell lines (LCLs) in the Hutterites suggest that these rare non-coding variants are likely to mediate their effects on lipid traits by regulating gene expression. Overall, we provide insights into the mechanisms regulating lipid traits and potentially new therapeutic targets.

scholarly journals Genomic Association vs. Serological Determination of ABO Blood Types in a Chinese Cohort, with Application in Mendelian Randomization

Genes ◽  
2021 ◽  
Vol 12 (7) ◽  
pp. 959
Author(s):  
Mengqiao Wang ◽  
Jiaqi Gao ◽  
Jin Liu ◽  
Xing Zhao ◽  
Yi Lei
Keyword(s):  
Genetic Variants ◽  
Genome Wide Association Study ◽  
Linear Models ◽  
Mendelian Randomization ◽  
Human Populations ◽  
Nucleotide Polymorphisms ◽  
A Genome ◽  
Genomic Association ◽  
Multi Class Classification ◽  
Log Linear

ABO blood system is an inborn trait determined by the ABO gene. The genetic-phenotypic mechanism underneath the four mutually exclusive and collectively exhaustive types of O, A, B and AB could theoretically be elucidated. However, genetic polymorphisms in the human populations render the link elusive, and importantly, past studies using genetically determined rather than biochemically determined ABO types were not and could not be evaluated for the inference errors. Upon both blood-typing and genotyping a cohort of 1008 people of the Han Chinese population, we conducted a genome-wide association study in parallel with both binomial and multinomial log-linear models. Significant genetic variants are all mapped to the ABO gene, and are quantitatively evaluated for binary and multi-class classification performances. Three single nucleotide polymorphisms of rs8176719, rs635634 and rs7030248 would together be sufficient to establish a multinomial predictive model that achieves high accuracy (0.98) and F1 scores (micro 0.99 and macro 0.97). Using the set of identified ABO-associated genetic variants as instrumental variables, we demonstrate the application in causal analysis by Mendelian randomization (MR) studies on blood pressures (one-sample MR) and severe COVID-19 with respiratory failure (two-sample MR).

scholarly journals Non-Coding Variants in Cancer: Mechanistic Insights and Clinical Potential for Personalized Medicine

2021 ◽  
Vol 7 (3) ◽  
pp. 47
Author(s):  
Marios Lange ◽  
Rodiola Begolli ◽  
Antonis Giakountis
Keyword(s):  
Disease Onset ◽  
Cancer Genome ◽  
Driver Mutations ◽  
Nucleotide Polymorphisms ◽  
Structural Variations ◽  
Coding Regions ◽  
Functional Variants ◽  
Coding Variants ◽  
Clinical Potential

The cancer genome is characterized by extensive variability, in the form of Single Nucleotide Polymorphisms (SNPs) or structural variations such as Copy Number Alterations (CNAs) across wider genomic areas. At the molecular level, most SNPs and/or CNAs reside in non-coding sequences, ultimately affecting the regulation of oncogenes and/or tumor-suppressors in a cancer-specific manner. Notably, inherited non-coding variants can predispose for cancer decades prior to disease onset. Furthermore, accumulation of additional non-coding driver mutations during progression of the disease, gives rise to genomic instability, acting as the driving force of neoplastic development and malignant evolution. Therefore, detection and characterization of such mutations can improve risk assessment for healthy carriers and expand the diagnostic and therapeutic toolbox for the patient. This review focuses on functional variants that reside in transcribed or not transcribed non-coding regions of the cancer genome and presents a collection of appropriate state-of-the-art methodologies to study them.

EXPRESS: Effect of genetic liability to visceral adiposity on stroke and its subtypes: a Mendelian randomization study

2021 ◽  
pp. 174749302110062
Author(s):  
Bin Yan ◽  
Jian Yang ◽  
Li Qian ◽  
Fengjie Gao ◽  
Ling Bai ◽  
...  
Keyword(s):  
Sensitivity Analysis ◽  
Ischemic Stroke ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Visceral Adiposity ◽  
Large Artery ◽  
Nucleotide Polymorphisms ◽  
Genetic Liability ◽  
A Genome ◽  
Increased Risk

Background: Observational studies have found an association between visceral adiposity and stroke. Aims: The purpose of this study was to investigate the role and genetic effect of visceral adipose tissue (VAT) accumulation on stroke and its subtypes. Methods: In this two-sample Mendelian randomization (MR) study, genetic variants (221 single nucleotide polymorphisms; P<5×10-8) using as instrumental variables for MR analysis was obtained from a genome-wide association study (GWAS) of VAT. The outcome datasets for stroke and its subtypes were obtained from the MEGASTROKE consortium (up to 67,162 cases and 453,702 controls). MR standard analysis (inverse variance weighted method) was conducted to investigate the effect of genetic liability to visceral adiposity on stroke and its subtypes. Sensitivity analysis (MR-Egger, weighted median, MR-PRESSO) were also utilized to assess horizontal pleiotropy and remove outliers. Multi-variable MR analysis was employed to adjust potential confounders. Results: In the standard MR analysis, genetically determined visceral adiposity (per 1 SD) was significantly associated with a higher risk of stroke (odds ratio [OR] 1.30; 95% confidence interval [CI] 1.21-1.41, P=1.48×10-11), ischemic stroke (OR 1.30; 95% CI 1.20-1.41, P=4.01×10-10), and large artery stroke (OR 1.49; 95% CI 1.22-1.83, P=1.16×10-4). The significant association was also found in sensitivity analysis and multi-variable MR analysis. Conclusions: Genetic liability to visceral adiposity was significantly associated with an increased risk of stroke, ischemic stroke, and large artery stroke. The effect of genetic susceptibility to visceral adiposity on the stroke warrants further investigation.

scholarly journals An artificial neural network approach integrating plasma proteomics and genetic data identifies PLXNA4 as a new susceptibility locus for pulmonary embolism

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Misbah Razzaq ◽  
Maria Jesus Iglesias ◽  
Manal Ibrahim-Kosta ◽  
Louisa Goumidi ◽  
Omar Soukarieh ◽  
...  
Keyword(s):  
Pulmonary Embolism ◽  
Genome Wide Association Study ◽  
Susceptibility Gene ◽  
Biological Traits ◽  
Nucleotide Polymorphisms ◽  
Ann Model ◽  
Neural Network Approach ◽  
A Genome ◽  
Increased Risk ◽  
Artificial Neural

AbstractVenous thromboembolism is the third common cardiovascular disease and is composed of two entities, deep vein thrombosis (DVT) and its potential fatal form, pulmonary embolism (PE). While PE is observed in ~ 40% of patients with documented DVT, there is limited biomarkers that can help identifying patients at high PE risk. To fill this need, we implemented a two hidden-layers artificial neural networks (ANN) on 376 antibodies and 19 biological traits measured in the plasma of 1388 DVT patients, with or without PE, of the MARTHA study. We used the LIME algorithm to obtain a linear approximate of the resulting ANN prediction model. As MARTHA patients were typed for genotyping DNA arrays, a genome wide association study (GWAS) was conducted on the LIME estimate. Detected single nucleotide polymorphisms (SNPs) were tested for association with PE risk in MARTHA. Main findings were replicated in the EOVT study composed of 143 PE patients and 196 DVT only patients. The derived ANN model for PE achieved an accuracy of 0.89 and 0.79 in our training and testing sets, respectively. A GWAS on the LIME approximate identified a strong statistical association peak (rs1424597: p = 5.3 × 10–7) at the PLXNA4 locus. Homozygote carriers for the rs1424597-A allele were then more frequently observed in PE than in DVT patients from the MARTHA (2% vs. 0.4%, p = 0.005) and the EOVT (3% vs. 0%, p = 0.013) studies. In a sample of 112 COVID-19 patients known to have endotheliopathy leading to acute lung injury and an increased risk of PE, decreased PLXNA4 levels were associated (p = 0.025) with worsened respiratory function. Using an original integrated proteomics and genetics strategy, we identified PLXNA4 as a new susceptibility gene for PE whose exact role now needs to be further elucidated.

scholarly journals Genome-Wide Association Study (GWAS) for Examining the Genomics Controlling Prickle Production in Red Raspberry (Rubus idaeus L.)

Agronomy ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 27
Author(s):  
Archana Khadgi ◽  
Courtney A. Weber
Keyword(s):  
Association Study ◽  
Genome Wide Association Study ◽  
Genomic Region ◽  
Rubus Idaeus ◽  
Genome Wide Association ◽  
Nucleotide Polymorphisms ◽  
Red Raspberry ◽  
Genome Wide ◽  
A Genome ◽  
Genotype By Sequencing

Red raspberry (Rubus idaeus L.) is an expanding high-value berry crop worldwide. The presence of prickles, outgrowths of epidermal tissues lacking vasculature, on the canes, petioles, and undersides of leaves complicates both field management and harvest. The utilization of cultivars with fewer prickles or prickle-free canes simplifies production. A previously generated population segregating for prickles utilizing the s locus between the prickle-free cultivar Joan J (ss) and the prickled cultivar Caroline (Ss) was analyzed to identify the genomic region associated with prickle development in red raspberry. Genotype by sequencing (GBS) was combined with a genome-wide association study (GWAS) using fixed and random model circulating probability unification (FarmCPU) to analyze 8474 single nucleotide polymorphisms (SNPs) and identify significant markers associated with the prickle-free trait. A total of four SNPs were identified on chromosome 4 that were associated with the phenotype and were located near or in annotated genes. This study demonstrates how association genetics can be used to decipher the genetic control of important horticultural traits in Rubus, and provides valuable information about the genomic region and potential genes underlying the prickle-free trait.

scholarly journals Genome-Wide Association Analysis of Growth Curve Parameters in Chinese Simmental Beef Cattle

Animals ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 192
Author(s):  
Xinghai Duan ◽  
Bingxing An ◽  
Lili Du ◽  
Tianpeng Chang ◽  
Mang Liang ◽  
...  
Keyword(s):  
Beef Cattle ◽  
Candidate Genes ◽  
Growth Curve ◽  
Growth And Development ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Coefficient Of Determination ◽  
Nucleotide Polymorphisms ◽  
Genome Wide ◽  
A Genome

The objective of the present study was to perform a genome-wide association study (GWAS) for growth curve parameters using nonlinear models that fit original weight–age records. In this study, data from 808 Chinese Simmental beef cattle that were weighed at 0, 6, 12, and 18 months of age were used to fit the growth curve. The Gompertz model showed the highest coefficient of determination (R2 = 0.954). The parameters’ mature body weight (A), time-scale parameter (b), and maturity rate (K) were treated as phenotypes for single-trait GWAS and multi-trait GWAS. In total, 9, 49, and 7 significant SNPs associated with A, b, and K were identified by single-trait GWAS; 22 significant single nucleotide polymorphisms (SNPs) were identified by multi-trait GWAS. Among them, we observed several candidate genes, including PLIN3, KCNS3, TMCO1, PRKAG3, ANGPTL2, IGF-1, SHISA9, and STK3, which were previously reported to associate with growth and development. Further research for these candidate genes may be useful for exploring the full genetic architecture underlying growth and development traits in livestock.

scholarly journals Examining the effect of mitochondrial DNA variants on blood pressure in two Finnish cohorts

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jaakko Laaksonen ◽  
Pashupati P. Mishra ◽  
Ilkka Seppälä ◽  
Leo-Pekka Lyytikäinen ◽  
Emma Raitoharju ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Mitochondrial Dna ◽  
Genome Wide Association Study ◽  
Rare Variants ◽  
Meta Analysis ◽  
Noncommunicable Diseases ◽  
Nucleotide Polymorphisms ◽  
Genetic Determinants ◽  
Genome Wide ◽  
Mitochondrial Dna Variants

AbstractHigh blood pressure (BP) is a major risk factor for many noncommunicable diseases. The effect of mitochondrial DNA single-nucleotide polymorphisms (mtSNPs) on BP is less known than that of nuclear SNPs. We investigated the mitochondrial genetic determinants of systolic, diastolic, and mean arterial BP. MtSNPs were determined from peripheral blood by sequencing or with genome-wide association study SNP arrays in two independent Finnish cohorts, the Young Finns Study and the Finnish Cardiovascular Study, respectively. In total, over 4200 individuals were included. The effects of individual common mtSNPs, with an additional focus on sex-specificity, and aggregates of rare mtSNPs grouped by mitochondrial genes were evaluated by meta-analysis of linear regression and a sequence kernel association test, respectively. We accounted for the predicted pathogenicity of the rare variants within protein-encoding and the tRNA regions. In the meta-analysis of 87 common mtSNPs, we did not observe significant associations with any of the BP traits. Sex-specific and rare-variant analyses did not pinpoint any significant associations either. Our results are in agreement with several previous studies suggesting that mtDNA variation does not have a significant role in the regulation of BP. Future studies might need to reconsider the mechanisms thought to link mtDNA with hypertension.

scholarly journals Haplotype- and SNP-Based GWAS for Growth and Wood Quality Traits in Eucalyptus cladocalyx Trees under Arid Conditions

Plants ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 148
Author(s):  
Camilo E. Valenzuela ◽  
Paulina Ballesta ◽  
Sunny Ahmar ◽  
Sajid Fiaz ◽  
Parviz Heidari ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Wood Quality ◽  
Tree Height ◽  
Mediterranean Ecosystems ◽  
Primary Metabolism ◽  
Arid Environments ◽  
Nucleotide Polymorphisms ◽  
Haplotype Blocks ◽  
A Genome ◽  
Stem Straightness

The agricultural and forestry productivity of Mediterranean ecosystems is strongly threatened by the adverse effects of climate change, including an increase in severe droughts and changes in rainfall distribution. In the present study, we performed a genome-wide association study (GWAS) to identify single-nucleotide polymorphisms (SNPs) and haplotype blocks associated with the growth and wood quality of Eucalyptus cladocalyx, a tree species suitable for low-rainfall sites. The study was conducted in a progeny-provenance trial established in an arid site with Mediterranean patterns located in the southern Atacama Desert, Chile. A total of 87 SNPs and 3 haplotype blocks were significantly associated with the 6 traits under study (tree height, diameter at breast height, slenderness coefficient, first bifurcation height, stem straightness, and pilodyn penetration). In addition, 11 loci were identified as pleiotropic through Bayesian multivariate regression and were mainly associated with wood hardness, height, and diameter. In general, the GWAS revealed associations with genes related to primary metabolism and biosynthesis of cell wall components. Additionally, associations coinciding with stress response genes, such as GEM-related 5 and prohibitin-3, were detected. The findings of this study provide valuable information regarding genetic control of morphological traits related to adaptation to arid environments.

Sign in / Sign up

Export Citation Format

Share Document