Age by Single Nucleotide Polymorphism Interactions on Bronchodilator Response in Asthmatics

An unaddressed and important issue is the role age plays in modulating response to short acting β2-agonists in individuals with asthma. The objective of this study was to identify whether age modifies genetic associations of single nucleotide polymorphisms (SNPs) with bronchodilator response (BDR) to β2-agonists. Using three cohorts with a total of 892 subjects, we ran a genome wide interaction study (GWIS) for each cohort to examine SNP by age interactions with BDR. A fixed effect meta-analysis was used to combine the results. In order to determine if previously identified BDR SNPs had an age interaction, we also examined 16 polymorphisms in candidate genes from two published genome wide association studies (GWAS) of BDR. There were no significant SNP by age interactions on BDR using the genome wide significance level of 5 × 10−8. Using a suggestive significance level of 5 × 10−6, three interactions, including one for a SNP within PRAG1 (rs4840337), were significant and replicated at the significance level of 0.05. Considering candidate genes from two previous GWAS of BDR, three SNPs (rs10476900 (near ADRB2) [p-value = 0.009], rs10827492 (CREM) [p-value = 0.02], and rs72646209 (NCOA3) [p-value = 0.02]) had a marginally significant interaction with age on BDR (p < 0.05). Our results suggest age may be an important modifier of genetic associations for BDR in asthma.

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Reproducibility in the UK Biobank of Genome-Wide Significant Signals Discovered in Earlier Genome-wide Association Studies

10.1101/2020.06.24.20139576 ◽

2020 ◽

Cited By ~ 1

Author(s):

Jack W. O’Sullivan ◽

John P. A. Ioannidis

Keyword(s):

Effect Size ◽

Association Studies ◽

Genome Wide Association ◽

P Value ◽

Genome Wide Association Studies ◽

Uk Biobank ◽

Single Nucleotide ◽

Genome Wide ◽

The Uk ◽

Open Question

AbstractWith the establishment of large biobanks, discovery of single nucleotide polymorphism (SNPs) that are associated with various phenotypes has been accelerated. An open question is whether SNPs identified with genome-wide significance in earlier genome-wide association studies (GWAS) are replicated also in later GWAS conducted in biobanks. To address this question, the authors examined a publicly available GWAS database and identified two, independent GWAS on the same phenotype (an earlier, “discovery” GWAS and a later, replication GWAS done in the UK biobank). The analysis evaluated 136,318,924 SNPs (of which 6,289 had reached p<5e-8 in the discovery GWAS) from 4,397,962 participants across nine phenotypes. The overall replication rate was 85.0% and it was lower for binary than for quantitative phenotypes (58.1% versus 94.8% respectively). There was a18.0% decrease in SNP effect size for binary phenotypes, but a 12.0% increase for quantitative phenotypes. Using the discovery SNP effect size, phenotype trait (binary or quantitative), and discovery p-value, we built and validated a model that predicted SNP replication with area under the Receiver Operator Curve = 0.90. While non-replication may often reflect lack of power rather than genuine false-positive findings, these results provide insights about which discovered associations are likely to be seen again across subsequent GWAS.

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Haplotypes within tandemly duplicated candidate genes at BnaA9.MRP5 modulate phytate concentration in canola (Brassica napus L.)

10.22541/au.161165160.08519096/v1 ◽

2021 ◽

Author(s):

Haijiang Liu ◽

xiaojuan Li ◽

Qianwen Zhang ◽

pan yuan ◽

Lei Liu ◽

...

Keyword(s):

Candidate Genes ◽

Oilseed Rape ◽

Genome Wide Association Study ◽

Mineral Elements ◽

Nucleotide Polymorphisms ◽

Brassica Napus L ◽

Single Nucleotide ◽

Genome Wide ◽

A Genome ◽

Phytate Content

Phytate is the storage form of phosphorus in angiosperm seeds and plays vitally important roles during seed development. However, in crop plants phytate decreases bioavailability of seed-sourced mineral elements for humans, livestock and poultry, and contributes to phosphate-related water pollution. However, there is little knowledge about this trait in oilseed rape B. napus (oilseed rape). Here, a panel of 505 diverse B. napus accessions was screened in a genome-wide association study (GWAS) using 3.28 x 106 single nucleotide polymorphisms (SNPs). This identified 119 SNPs significantly associated with phytate concentration (PA_Conc) and phytate content (PA_Cont) and six candidate genes were identified. Of these, BnaA9.MRP5 represented the candidate gene for the significant SNP chrA09_5198034 (27kb) for both PA_Cont and PA_Conc. Transcription of BnaA9.MRP5 in a low -phytate variety (LPA20) was significantly elevated compared with a high -phytate variety (HPA972). Association and haplotype analysis indicated that inbred lines carrying specific SNP haplotypes within BnaA9.MRP5 were associated with high- and low-phytate phenotypes. No significant differences in seed germination and seed yield were detected between low and high phytate cultivars examined. Candidate genes, favorable haplotypes and the low phytate varieties identified in this study will be useful for low-phytate breeding of B. napus.

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Genome-Wide Association Study Meta-Analysis of Stroke in 22 000 Individuals of African Descent Identifies Novel Associations With Stroke

Stroke ◽

10.1161/strokeaha.120.029123 ◽

2020 ◽

Vol 51 (8) ◽

pp. 2454-2463

Author(s):

Keith L. Keene ◽

Hyacinth I. Hyacinth ◽

Joshua C. Bis ◽

Steven J. Kittner ◽

Braxton D. Mitchell ◽

...

Keyword(s):

Single Nucleotide Polymorphism ◽

Meta Analysis ◽

African Descent ◽

Genome Wide Association ◽

Minority Population ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphism ◽

Single Nucleotide ◽

Genome Wide ◽

A Genome

Background and Purpose: Stroke is a complex disease with multiple genetic and environmental risk factors. Blacks endure a nearly 2-fold greater risk of stroke and are 2× to 3× more likely to die from stroke than European Americans. Methods: The COMPASS (Consortium of Minority Population Genome-Wide Association Studies of Stroke) has conducted a genome-wide association meta-analysis of stroke in >22 000 individuals of African ancestry (3734 cases, 18 317 controls) from 13 cohorts. Results: In meta-analyses, we identified one single nucleotide polymorphism (rs55931441) near the HNF1A gene that reached genome-wide significance ( P =4.62×10 −8 ) and an additional 29 variants with suggestive evidence of association ( P <1×10 −6 ), representing 24 unique loci. For validation, a look-up analysis for a 100 kb region flanking the COMPASS single nucleotide polymorphism was performed in SiGN (Stroke Genetics Network) Europeans, SiGN Hispanics, and METASTROKE (Europeans). Using a stringent Bonferroni correction P value of 2.08×10 −3 (0.05/24 unique loci), we were able to validate associations at the HNF1A locus in both SiGN ( P =8.18×10 −4 ) and METASTROKE ( P =1.72×10 −3 ) European populations. Overall, 16 of 24 loci showed evidence for validation across multiple populations. Previous studies have reported associations between variants in the HNF1A gene and lipids, C-reactive protein, and risk of coronary artery disease and stroke. Suggestive associations with variants in the SFXN4 and TMEM108 genes represent potential novel ischemic stroke loci. Conclusions: These findings represent the most thorough investigation of genetic determinants of stroke in individuals of African descent, to date.

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Genome-Wide Association Studies of Leaf Angle in Maize

10.21203/rs.3.rs-329481/v1 ◽

2021 ◽

Author(s):

Bo Peng ◽

Xiaolei Zhao ◽

Yi Wang ◽

Chunhui Li ◽

Yongxiang Li ◽

...

Keyword(s):

Candidate Genes ◽

Phenotypic Variation ◽

Genetic Basis ◽

Genome Wide Association ◽

Leaf Angle ◽

Genome Wide Association Studies ◽

Major Qtls ◽

Genome Wide ◽

Population Structure Analysis ◽

A Genome

Abstract Compact plant-type with small leaf angle has increased canopy light interception, which is conducive to the photosynthesis of the population and higher population yield at high density planting in maize. In this study, a panel of 285 diverse maize inbred lines genotyped with 56,000 SNPs was used to investigate the genetic basis of leaf angle across three consecutive years using a genome-wide association study (GWAS). The leaf angle showed broad phenotypic variation and high heritability across different years. Population structure analysis subdivided the panel into four subgroups that correspond to the four major empirical germplasm origins in China, i.e., Tangsipingtou, Reid, Lancaster and P. When tested with the optimal GWAS model, we found that the Q+K model was the best in reducing false positive. In total, 96 SNPs accounting for 5.54%-10.44% of phenotypic variation were significantly (P<0.0001) associated with leaf angle across three years. According to the linkage disequilibrium decay distance, 96 SNPs were binned in 43 QTLs for leaf angle. Seven major QTLs with R2>8% stably detected in at least two years and BLUP values were clustered in four genomic regions (bins 2.01, 2.07, 5.06, and 10.04). Seven important candidate genes, Zm00001d001961, Zm00001d006348, Zm00001d006463, Zm00001d017618, Zm00001d024919, Zm00001d025018, and Zm00001d025033 were predicted for the seven stable major QTLs, respectively. The markers identified in this study can be used for molecular breeding for leaf angle, and the candidate genes would contribute to further understanding of the genetic basis of leaf angle.

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Genome-Wide Association Studies for Immunoglobulins in Colostrum and Serum in Chinese Holstein

10.21203/rs.3.rs-40831/v1 ◽

2020 ◽

Author(s):

Shan Lin ◽

Cuncun Ke ◽

Lin Liu ◽

Yahui Gao ◽

Lingna Xu ◽

...

Keyword(s):

Immune Response ◽

Dairy Cattle ◽

Candidate Genes ◽

Functional Enrichment ◽

Genome Wide Association ◽

Holstein Cows ◽

Genome Wide Association Studies ◽

Chinese Holstein ◽

Genome Wide ◽

A Genome

Abstract BackgroundImmunoglobulins (Igs) are important components of the innate immune system, and fight pathogens as a part of the first defense line. Newborn dairy calves get maternal antibodies from colostrum. Therefore, contents of immunoglobulins in colostrum and serum of cows are essential traits when estimating potential natural disease resistance of calves. In this study, a genome-wide association study (GWAS) was performed to identify candidate genes that are responsible for the observed genetic variation of immunoglobulins contents in colostrum and blood in Holstein cows.ResultsColostrum, blood and hair follicle samples were collected from the 620 Chinese Holstein cows within 24 hours after calving. The concentration of IgG, IgG1, IgG2, IgA and IgM in both colostrum and serum were detected via ELISA methods, respectively. Using GCTA software, GWASs were performed with 88,934 SNPs genotyped by using Illumina 50K (54,609 SNPs) and GeneSeek 150K (140,668 SNPs) chips in which 50K chip were imputed to 150K SNPs with BEAGLE 3.0.4 software. As a result, 20 and 5 SNPs were detected genome-wide significantly associated with contents of the IgG and IgM in colostrum and serum (P<3.16E–6). In addition, 57, 11 and 10 SNPs were suggestive significantly associated with IgG, IgA and IgM traits (P<6.32E–5). Next, a total of 1,083 functional genes were identified that included or adjacent to these significant SNPs with a distance less than 1 Mb. Functional enrichment analysis showed that these genes were involved in immune related pathways, such as immune response, Fc gamma R-mediated phagocytosis, negative regulation of immunoglobulin secretion, humoral immune response, Fc-epsilon receptor and NF-kappaB signaling pathways. By integrating analysis of the functional enrichment and the known QTL data, we identified 21 candidate genes associated with contents of immunoglobulins in colostrum and serum, including ABR, TIMM22, CRK, MYO1C, RILP, SERPINF2, AKT1, BCL11B, HHIPL1, DYNC1H1, HSP90AA1, TRAF3, KLC1, IL6, PYCARD, ITGAM, TGFB1I1, GUSB, CRCP, RABGEF1 and SBDS.ConclusionsIn this study, we identified 21 candidate genes associated with immunoglobulins level in colostrum and serum in dairy cattle. This founding demonstrated the possibility of increasing immunity through selective breeding and provided an important information for molecular breeding of dairy cattle.

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A Genome-Wide Association Study for Partial Resistance to Maize Common Rust

Phytopathology ◽

10.1094/phyto-11-15-0305-r ◽

2016 ◽

Vol 106 (7) ◽

pp. 745-751 ◽

Cited By ~ 19

Author(s):

Bode A. Olukolu ◽

William F. Tracy ◽

Randall Wisser ◽

Brian De Vries ◽

Peter J. Balint-Kurti

Keyword(s):

Candidate Genes ◽

Genome Wide Association Study ◽

Quantitative Resistance ◽

Mixed Linear Model ◽

Genome Wide Association ◽

Cell Wall Modification ◽

Single Nucleotide ◽

Puccinia Sorghi ◽

Genome Wide ◽

A Genome

Quantitative resistance to maize common rust (causal agent Puccinia sorghi) was assessed in an association mapping population of 274 diverse inbred lines. Resistance to common rust was found to be moderately correlated with resistance to three other diseases and with the severity of the hypersensitive defense response previously assessed in the same population. Using a mixed linear model accounting for the confounding effects of population structure and flowering time, genome-wide association tests were performed based at 246,497 single-nucleotide polymorphism loci. Three loci associated with maize common rust resistance were identified. Candidate genes at each locus had predicted roles, mainly in cell wall modification. Other candidate genes included a resistance gene and a gene with a predicted role in regulating accumulation of reactive oxygen species.

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Meta-Analysis of Allergy Genome-Wide Association Studies

10.1101/2020.12.24.424368 ◽

2020 ◽

Author(s):

Ronin Sharma

Keyword(s):

Association Studies ◽

Meta Analysis ◽

Genetic Association Studies ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Significance Level ◽

Genome Wide ◽

Linear Regressions

AbstractAllergies are complex conditions involving both environmental and genetic factors. The genetic basis underlying allergic disease is investigated through genetic association studies. Genome-wide association studies (GWAS) leverage sequenced data to identify genetic mutations, such as single-nucleotide polymorphisms (SNPs), associated with phenotypes of interest. Machine learning can be used to analyze large datasets and generate predictive models. In this study, several classification models were created to predict the significance level of SNPs associated with allergies. Summary statistics were obtained from the GWAS Catalog and combined from several studies. Biological features such as chromosomal location, base pair location, effect allele, and odds ratio were used to train the models. The models ranged from simple linear regressions to multi-layer neural networks. The final models reached accuracies of 80% and reflect the features that have the largest impact on a SNP’s association level.

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Genome-wide association studies of mineral and phytic acid concentrations in pea (Pisum sativum L.) to evaluate biofortification potential

G3 Genes|Genome|Genetics ◽

10.1093/g3journal/jkab227 ◽

2021 ◽

Author(s):

Sarah Powers ◽

J Lucas Boatwright ◽

Dil Thavarajah

Keyword(s):

Pisum Sativum ◽

Candidate Genes ◽

Phytic Acid ◽

Reference Genome ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Single Plant ◽

Pisum Sativum L ◽

Genome Wide ◽

A Genome

Abstract Pea (Pisum sativum L.) is an important cool season food legume for sustainable food production and human nutrition due to its nitrogen fixation capabilities and nutrient-dense seed. However, minimal breeding research has been conducted to improve the nutritional quality of the seed for biofortification, and most genomic-assisted breeding studies utilize small populations with few single nucleotide polymorphisms (SNPs). Genomic resources for pea have lagged behind those of other grain crops, but the recent release of the Pea Single Plant Plus Collection (PSPPC) and the pea reference genome provide new tools to study nutritional traits for biofortification. Calcium, phosphorus, potassium, iron, zinc, and phytic acid concentrations were measured in a study population of 299 different accessions grown under greenhouse conditions. Broad phenotypic variation was detected for all parameters except phytic acid. Calcium exhibited moderate broad-sense heritability (H2) estimates, at 50%, while all other minerals exhibited low heritability. Of the accessions used, 267 were previously genotyped in the PSPPC release by the USDA, and we mapped the genotyping data to the pea reference genome for the first time. This study generated 54,344 high-quality SNPs used to investigate the population structure of the Pea Single Plant Plus Collection and perform a genome-wide association study to identify genomic loci associated with mineral concentrations in mature pea seed. Overall, we were able to identify multiple significant SNPs and candidate genes for iron, phosphorus, and zinc. These results can be used for genetic improvement in pea for nutritional traits and biofortification, and the candidate genes provide insight into mineral metabolism.

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Abstract P126: Sex Interacts With Chromosome 6p24 on Coronary Artery Calcium but Not Chromosome 9p21

Circulation ◽

10.1161/circ.137.suppl_1.p126 ◽

2018 ◽

Vol 137 (suppl_1) ◽

Author(s):

Sharon M Lutz ◽

Dawn DeMeo ◽

Matthew Budoff ◽

John E Hokanson

Keyword(s):

Coronary Artery ◽

Coronary Artery Calcium ◽

Significant Interaction ◽

Genome Wide Association ◽

Smoking History ◽

P Value ◽

Genome Wide Association Studies ◽

Chromosome 9P21 ◽

Genome Wide ◽

A Genome

Introduction: Coronary artery calcium (CAC) is a marker of subclinical atherosclerosis. CAC has been shown to strongly correlate with the amount of atherosclerotic plaque and predicts future coronary disease events and mortality. CAC is a complex heritable trait and levels differ by sex. We investigated the interaction between sex and genome wide association study (GWAS) signals on chromosome 6p24 and 9p21 on Coronary Artery Calcium (CAC) in the COPDGene study. Hypothesis: We assessed the hypothesis that sex would interact with the GWAS signals on CAC. Methods: The COPDGene is a study of 10,192 current and former smokers with at least 10 pack-years of smoking history. CAC was measured using high dose, inspiration chest CT scans, following an established protocol in 8,739 individuals (6,150 non-Hispanic Whites (NHW) and 2,589 African Americans (AA)). We considered sex by SNP interactions on CAC for our previously identified GWAS signals on chromosome 6p24 and chromosome 9p21 using R software adjusting for genetic ancestry using principal components as well as recognized risk factors (age, pack-years of smoking history, BMI, diabetes, high blood pressure, high cholesterol, and steroid use). We used the log transformation of CAC plus 1 as the quantitative phenotype. Results: There was a significant interaction between sex and chromosome 6p24 PHACTR1 [rs9349379] (p=0.023) on CAC among NHW subjects in the COPDGene study. There was a genome-wide significant association for rs9349379 with CAC among male NHW subjects [p-value= 1.21E-8] but not among female NHW subjects [p-value= 0.02]. Overall there was no genome-wide significant association for rs9349379 with CAC among all NHW subjects [p-value= 6.39E-7]. There was no significant interaction between sex and chromosome 9p21 CDKN2B-AS1 [rs10757272] (p-value=0.25) on CAC among NHW COPDGene subjects. Among AA subjects in the COPDGene study, there was not a significant interaction between sex and rs9349379 [ PHACTR1 ] (p-value=0.48) or sex and rs10757272 [ CDKN2B-AS1 ] (p-value=0.21) on CAC. Conclusions: There was a SNP by sex interaction on CAC for chromosome 6p24 with a genome wide significant signal for NHW men but not for NHW women. The chromosome 9p21 signal for CAC did not significantly differ by sex. This study demonstrates the importance of considering gene by sex interactions in genome wide association studies of cardiovascular disease risk.

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Genome-Wide Association Studies and Transcriptome Changes during Acclimation and Deacclimation in Divergent Brassica napus Varieties

International Journal of Molecular Sciences ◽

10.3390/ijms21239148 ◽

2020 ◽

Vol 21 (23) ◽

pp. 9148 ◽

Cited By ~ 1

Author(s):

David P. Horvath ◽

Jiaping Zhang ◽

Wun S. Chao ◽

Ashok Mandal ◽

Mukhlesur Rahman ◽

...

Keyword(s):

Oxidative Stress ◽

Cold Acclimation ◽

Candidate Genes ◽

Calcium Binding ◽

Association Studies ◽

Differentially Expressed ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Genome Wide ◽

A Genome

Information concerning genes and signals regulating cold acclimation processes in plants is abundant; however, less is known about genes and signals regulating the deacclimation process. A population of primarily winter B. napus varieties was used to conduct a genome-wide association study and to compare the transcriptomes from two winter B. napus varieties showing time-dependent differences in response to cold acclimation and deacclimation treatments. These studies helped to identify loci, candidate genes, and signaling processes impacting deacclimation in B. napus. GWAS identified polymorphisms at five different loci associated with freezing tolerance following deacclimation. Local linkage decay rates near these polymorphisms identified 38 possible candidate genes. Several of these genes have been reported as differentially regulated by cold stress in arabidopsis (Arabidopsis thaliana), including a calcium-binding EF-hand family protein (encoded by BnaCnng10250D) that was also differentially expressed during deacclimation in this study. Thousands of other genes differentially expressed during the acclimation and deacclimation treatments implicated processes involving oxidative stress, photosynthesis, light-regulated diurnal responses, and growth regulation. Generally, responses observed during acclimation were reversed within one week of deacclimation. The primary differences between the two winter B. napus varieties with differential deacclimation responses involved protection from oxidative stress and the ability to maintain photosynthesis.

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