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 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 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 Genetic Polymorphisms of Pharmacogenes among the Genetically Isolated Circassian Subpopulation from Jordan

2020 ◽  
Vol 10 (1) ◽  
pp. 2 ◽  
Author(s):  
Laith N. AL-Eitan ◽  
Doaa M. Rababa’h ◽  
Nancy M. Hakooz ◽  
Mansour A. Alghamdi ◽  
Rana B. Dajani
Keyword(s):  
Genetic Variants ◽  
Rare Variants ◽  
Optimal Dose ◽  
Nucleotide Polymorphisms ◽  
Treatment Efficiency ◽  
Isolated Populations ◽  
Single Nucleotide ◽  
Interindividual Variations ◽  
Different Populations ◽  
Pharmacogenomic Studies

Several genetic variants have been identified that cause variation among different populations and even within individuals of a similar descent. This leads to interindividual variations in the optimal dose of the drug that is required to sustain the treatment efficiency. In this study, 56 single nucleotide polymorphisms (SNPs) within several pharmacogenes were analyzed in 128 unrelated subjects from a genetically isolated group of Circassian people living in Jordan. We also compared these variant distributions to other ethnic groups that are available at two databases (Genome 1000 and eXAC). Our results revealed that the distribution of allele frequencies within genes among Circassians in Jordan showed similarities and disparities when compared to other populations. This study provides a powerful base for clinically relevant SNPs to enhance medical research and future pharmacogenomic studies. Rare variants detected in isolated populations can significantly guide to novel loci involved in the development of clinically relevant traits.

scholarly journals The Effect of Haplotypes in the CETP and LIPC Genes on the Triglycerides to HDL-C Ratio and Its Components in the Roma and Hungarian General Populations

Genes ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 56 ◽  
Author(s):  
Peter Piko ◽  
Szilvia Fiatal ◽  
Nardos Abebe Werissa ◽  
Bayu Begashaw Bekele ◽  
Gabor Racz ◽  
...  
Keyword(s):  
Cardiovascular Diseases ◽  
Odds Ratio ◽  
Hepatic Lipase ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Roma Population ◽  
Transfer Protein ◽  
General Populations

Background: The triglycerides (TG) to high-density lipoprotein (HDL)-cholesterol (HDL-C) ratio (TG/HDL-C) is a well-known predictor for cardiovascular diseases (CVDs) with great heritability background. The cholesteryl ester transfer protein (CETP) and hepatic lipase (LIPC) gene affect TG/HDL-C ratio. This study aims to explore the association between haplotypes (H) in CETP (based on 5 single nucleotide polymorphisms (SNPs)) and LIPC (based on 6 SNPs) genes and the TG/HDL-C ratio and its components, among Roma and Hungarian general populations. Methods: The prevalence of haplotypes and their effect on HDL-C, TG and TG/HDL-C ratio were calculated in both populations and compared. Results: Ten haplotypes in CETP and 6 in LIPC gene were identified. Three haplotypes in CETP and 3 in LIPC have significant effect on HDL-C level, whereas two in CETP and 3 in LIPC on TG level. The H6 in CETP (β = 0.52, p = 0.015; odds ratio (OR) = 1.87, p = 0.009) and H5 in LIPC (β = 0.56, p < 0.001; OR = 1.51, p = 0.002) have a significant increasing effect on TG/HDL-C ratio and have shown higher prevalence among the Roma, as compared to Hungarian general population. The H2 in the CETP gene has a decreasing effect on the TG/HDL-C ratio (OR = 0.58, p = 0.019) and is significantly less frequent among the Roma. Conclusions: Accumulation of harmful haplotypes in CETP and LIPC genes might have a role in the elevated TG/HDL-C ratio in the Roma population, which contributes to a higher risk in the development of cardiovascular diseases.

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

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Catherine Igartua ◽  
Sahar V. Mozaffari ◽  
Dan L. Nicolae ◽  
Carole Ober
Keyword(s):  
Plasma Lipid ◽  
Founder Population ◽  
Coding Variants

scholarly journals Comprehensive Genome-Wide Association Analysis Reveals the Genetic Basis of Root System Architecture in Soybean

2020 ◽  
Vol 11 ◽  
Author(s):  
Waldiodio Seck ◽  
Davoud Torkamaneh ◽  
François Belzile
Keyword(s):  
Root System ◽  
System Architecture ◽  
Phenotypic Variation ◽  
Genetic Basis ◽  
Genome Wide Association Study ◽  
Primary Root ◽  
Root System Architecture ◽  
Genome Wide Association ◽  
Nucleotide Polymorphisms ◽  
Genome Wide

Increasing the understanding genetic basis of the variability in root system architecture (RSA) is essential to improve resource-use efficiency in agriculture systems and to develop climate-resilient crop cultivars. Roots being underground, their direct observation and detailed characterization are challenging. Here, were characterized twelve RSA-related traits in a panel of 137 early maturing soybean lines (Canadian soybean core collection) using rhizoboxes and two-dimensional imaging. Significant phenotypic variation (P &lt; 0.001) was observed among these lines for different RSA-related traits. This panel was genotyped with 2.18 million genome-wide single-nucleotide polymorphisms (SNPs) using a combination of genotyping-by-sequencing and whole-genome sequencing. A total of 10 quantitative trait locus (QTL) regions were detected for root total length and primary root diameter through a comprehensive genome-wide association study. These QTL regions explained from 15 to 25% of the phenotypic variation and contained two putative candidate genes with homology to genes previously reported to play a role in RSA in other species. These genes can serve to accelerate future efforts aimed to dissect genetic architecture of RSA and breed more resilient varieties.

scholarly journals Cardiovascular disease and osteoporosis: is there a link between lipids and bone?

2002 ◽  
Vol 39 (3) ◽  
pp. 203-210 ◽  
Author(s):  
John R Burnett ◽  
Samuel D Vasikaran
Keyword(s):  
Cardiovascular Disease ◽  
Bone Density ◽  
Vascular Calcification ◽  
Cholesterol Biosynthesis ◽  
Hormone Replacement ◽  
Plasma Lipid ◽  
Clinical Effects ◽  
Cardiovascular Morbidity And Mortality ◽  
The Relationship

Atherosclerotic heart disease and osteoporosis are both diseases of old age. Evidence is accumulating for a link between vascular and bone disease. Calcification is a common feature of atherosclerotic plaques, and osteoporosis is associated with both atherosclerosis and vascular calcification. However, the relationship of vascular calcification to the pathogenesis of atherosclerosis remains incompletely understood. Hormone replacement therapy has beneficial effects in the prevention of both atherosclerosis and osteoporosis. Bisphosphonates inhibit bone resorption and are used in the treatment of osteoporosis, whereas the statins inhibit cholesterol biosynthesis and are used for the treatment of atherosclerosis. We have reviewed recent advances in the knowledge of the actions of bisphosphonates and statins at the cellular, molecular and end-organ levels in order to examine the relationship between cardiovascular disease and osteoporosis and to explore the link between lipids and bones. These studies suggest that the mechanism of actions of these two classes of drugs at the cellular level may not be mutually exclusive. There are some early clinical data to complement these findings, suggesting that statins increase bone density and bisphosphonates may have a beneficial effect in vivo on plasma lipid levels and on the atherosclerotic process. Properly designed prospective studies that examine the effect of statins on bone density and fractures, as well as the effects of bisphosphonates on lipid profiles, atherosclerotic progression and cardiovascular morbidity and mortality are needed to define clearly the clinical effects and potential new roles for these agents.

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.

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