Genetic regulation of OAS1 nonsense-mediated decay underlies association with risk of severe COVID-19

Genomic regions have been associated with COVID-19 susceptibility and outcomes, including the chr12q24.13 locus encoding antiviral proteins OAS1-3. Here, we report genetic, functional, and clinical insights into genetic associations within this locus. In Europeans, the risk of hospitalized vs. non-hospitalized COVID-19 was associated with a single 19Kb-haplotype comprised of 76 OAS1 variants included in a 95% credible set within a large genomic fragment introgressed from Neandertals. The risk haplotype was also associated with impaired spontaneous but not treatment-induced SARS-CoV-2 clearance in a clinical trial with pegIFN-λ1. We demonstrate that two exonic variants, rs10774671 and rs1131454, affect splicing and nonsense-mediated decay of OAS1. We suggest that genetically-regulated loss of OAS1 expression contributes to impaired spontaneous clearance of SARS-CoV-2 and elevated risk of hospitalization for COVID-19. Our results provide the rationale for further clinical studies using interferons to compensate for impaired spontaneous SARS-CoV-2 clearance, particularly in carriers of the OAS1 risk haplotypes.

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Genetic association studies of alterations in protein function expose recessive effects on cancer predisposition

Scientific Reports ◽

10.1038/s41598-021-94252-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Nadav Brandes ◽

Nathan Linial ◽

Michal Linial

Keyword(s):

Cancer Risk ◽

Protein Function ◽

Association Studies ◽

Genetic Effects ◽

Cancer Predisposition ◽

Genome Wide Association Studies ◽

Genetic Associations ◽

Functional Interpretation ◽

Gene Damage ◽

Genomic Regions

AbstractThe characterization of germline genetic variation affecting cancer risk, known as cancer predisposition, is fundamental to preventive and personalized medicine. Studies of genetic cancer predisposition typically identify significant genomic regions based on family-based cohorts or genome-wide association studies (GWAS). However, the results of such studies rarely provide biological insight or functional interpretation. In this study, we conducted a comprehensive analysis of cancer predisposition in the UK Biobank cohort using a new gene-based method for detecting protein-coding genes that are functionally interpretable. Specifically, we conducted proteome-wide association studies (PWAS) to identify genetic associations mediated by alterations to protein function. With PWAS, we identified 110 significant gene-cancer associations in 70 unique genomic regions across nine cancer types and pan-cancer. In 48 of the 110 PWAS associations (44%), estimated gene damage is associated with reduced rather than elevated cancer risk, suggesting a protective effect. Together with standard GWAS, we implicated 145 unique genomic loci with cancer risk. While most of these genomic regions are supported by external evidence, our results also highlight many novel loci. Based on the capacity of PWAS to detect non-additive genetic effects, we found that 46% of the PWAS-significant cancer regions exhibited exclusive recessive inheritance. These results highlight the importance of recessive genetic effects, without relying on familial studies. Finally, we show that many of the detected genes exert substantial cancer risk in the studied cohort determined by a quantitative functional description, suggesting their relevance for diagnosis and genetic consulting.

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Large-scale phenome-wide association study of PCSK9 loss-of-function variants demonstrates protection against ischemic stroke

10.1101/210302 ◽

2017 ◽

Author(s):

Abhiram S. Rao ◽

Daniel Lindholm ◽

Manuel A. Rivas ◽

Joshua W. Knowles ◽

Stephen B. Montgomery ◽

...

Keyword(s):

Clinical Trial ◽

Coronary Heart Disease ◽

Heart Disease ◽

Ischemic Stroke ◽

Protective Effect ◽

Large Scale ◽

Artery Bypass ◽

Bypass Graft ◽

Genetic Associations ◽

Loss Of Function

AbstractPCSK9 inhibitors are a potent new therapy for hypercholesterolemia and have been shown to decrease risk of coronary heart disease. Although short-term clinical trial results have not demonstrated major adverse effects, long-term data will not be available for some time. Genetic studies in large well-phenotyped biobanks offer a unique opportunity to predict drug effects and provide context for the evaluation of future clinical trial outcomes. We tested association of the PCSK9 loss-of-function variant rsll591147 (R46L) in a hypothesis-driven 11 phenotype set and a hypothesis-generating 278 phenotype set in 337,536 individuals of British ancestry in the United Kingdom Biobank (UKB), with independent discovery (n = 225K) and replication (n = 112K). In addition to the known association with lipid levels (OR 0.63) and coronary heart disease (OR 0.73), the T allele of rs11591147 showed a protective effect on ischemic stroke (OR 0.61, p = 0.002) but not hemorrhagic stroke in the hypothesis-driven screen. We did not observe an association with type 2 diabetes, cataracts, heart failure, atrial fibrillation, and cognitive dysfunction. In the phenome-wide screen, the variant was associated with a reduction in metabolic disorders, ischemic heart disease, coronary artery bypass graft operations, percutaneous coronary interventions and history of angina. A single variant analysis of UKB data using TreeWAS, a Bayesian analysis framework to study genetic associations leveraging phenotype correlations, also showed evidence of association with cerebral infarction and vascular occlusion. This result represents the first genetic evidence in a large cohort for the protective effect of PCSK9 inhibition on ischemic stroke, and corroborates exploratory evidence from clinical trials. PCSK9 inhibition was not associated with variables other than those related to low density lipoprotein cholesterol and atherosclerosis, suggesting that other effects are either small or absent.

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Genetics of Germination and Seedling Traits under Drought Stress in a MAGIC Population of Maize

Plants ◽

10.3390/plants10091786 ◽

2021 ◽

Vol 10 (9) ◽

pp. 1786

Author(s):

Soumeya Rida ◽

Oula Maafi ◽

Ana López-Malvar ◽

Pedro Revilla ◽

Meriem Riache ◽

...

Keyword(s):

Drought Tolerance ◽

Genome Wide Association Study ◽

Genetic Regulation ◽

Breeding Programs ◽

Seedling Traits ◽

Genome Wide ◽

A Genome ◽

Positive Correlations ◽

Genomic Regions ◽

Magic Population

Drought is one of the most detrimental abiotic stresses hampering seed germination, development, and productivity. Maize is more sensitive to drought than other cereals, especially at seedling stage. Our objective was to study genetic regulation of drought tolerance at germination and during seedling growth in maize. We evaluated 420 RIL with their parents from a multi-parent advanced generation inter-cross (MAGIC) population with PEG-induced drought at germination and seedling establishment. A genome-wide association study (GWAS) was carried out to identify genomic regions associated with drought tolerance. GWAS identified 28 and 16 SNPs significantly associated with germination and seedling traits under stress and well-watered conditions, respectively. Among the SNPs detected, two SNPs had significant associations with several traits with high positive correlations, suggesting a pleiotropic genetic control. Other SNPs were located in regions that harbored major QTLs in previous studies, and co-located with QTLs for cold tolerance previously published for this MAGIC population. The genomic regions comprised several candidate genes related to stresses and plant development. These included numerous drought-responsive genes and transcription factors implicated in germination, seedling traits, and drought tolerance. The current analyses provide information and tools for subsequent studies and breeding programs for improving drought tolerance.

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Protein QTL analysis of IGF-I and its binding proteins provides insights into growth biology

10.1101/2020.03.25.007724 ◽

2020 ◽

Author(s):

Eric Bartell ◽

Masanobu Fujimoto ◽

Jane C. Khoury ◽

Philip R. Khoury ◽

Sailaja Vedantam ◽

...

Keyword(s):

Birth Weight ◽

Association Studies ◽

Genetic Regulation ◽

Human Growth ◽

Serum Levels ◽

Genome Wide Association Studies ◽

Genetic Associations ◽

Protein Levels ◽

Igf I ◽

Igfbp 3

AbstractThe growth hormone and insulin-like growth factor (IGF) system is integral to human growth. Genome-wide association studies (GWAS) have identified variants associated with height and located near the genes in this pathway. However, mechanisms underlying these genetic associations are not understood. To investigate the regulation of the genes in this pathway and mechanisms by which regulation could affect growth, we performed GWAS of measured serum protein levels of IGF-I, IGFBP-3, PAPP-A2, IGF-II, and IGFBP-5 in 839 children (3-18 years) from the Cincinnati Genomic Control Cohort. We identified variants associated with protein levels near IGFBP3 and IGFBP5 genes, which contain multiple signals of association with height and other skeletal growth phenotypes. Surprisingly, variants that associate with protein levels at these two loci do not colocalize with height associations, confirmed through conditional analysis. Rather, the IGFBP3 signal (associated with total IGFBP-3 and IGF-II levels) colocalizes with an association with sitting height ratio (SHR); the IGFBP5 signal (associated with IGFBP-5 levels) colocalizes with birth weight. Indeed, height-associated SNPs near genes encoding other proteins in this pathway are not associated with serum levels, possibly excluding PAPP-A2. Mendelian randomization supports a stronger relationship of measured serum levels with SHR (for IGFBP-3) and birth weight (for IGFBP-5) than with height. In conclusion, we begin to characterize the genetic regulation of serum levels of IGF-related proteins in childhood. Furthermore, our data strongly suggest the existence of growth-regulating mechanisms acting through IGF-related genes in ways that are not reflected in measured serum levels of the corresponding proteins.

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Genetic Associations in Four Decades of Multi-Environment Trials Reveal Agronomic Trait Evolution in Common Bean

10.1101/734087 ◽

2019 ◽

Author(s):

Alice H. MacQueen ◽

Jeffrey W. White ◽

Rian Lee ◽

Juan M. Osorno ◽

Jeremy Schmutz ◽

...

Keyword(s):

Common Bean ◽

Crop Improvement ◽

Genetic Research ◽

The United States ◽

Genetic Effects ◽

Data Sets ◽

Genetic Associations ◽

Phenotypic Data ◽

Multiple Phenotypes ◽

Genomic Regions

AbstractMulti-environment trials (METs) are widely used to assess the performance of promising crop germplasm. Though seldom designed to elucidate genetic mechanisms, MET datasets are often much larger than could be duplicated for genetic research and, given proper interpretation, may offer valuable insights into the genetics of adaptation across time and space. The Cooperative Dry Bean Nursery (CDBN) is a MET for common bean (Phaseolus vulgaris) grown for over 70 years in the United States and Canada, consisting of 20 to 50 entries each year at 10 to 20 locations. The CBDN provides a rich source of phenotypic data across entries, years, and locations that is amenable to genetic analysis. To study stable genetic effects segregating in this MET, we conducted genome-wide association (GWAS) using best linear unbiased predictions (BLUPs) derived across years and locations for 21 CDBN phenotypes and genotypic data (1.2M SNPs) for 327 CDBN genotypes. The value of this approach was confirmed by the discovery of three candidate genes and genomic regions previously identified in balanced GWAS. Multivariate adaptive shrinkage (mash) analysis, which increased our power to detect significant correlated effects, found significant effects for all phenotypes. The first use of mash on an agricultural dataset discovered two genomic regions with pleiotropic effects on multiple phenotypes, likely selected on in pursuit of a crop ideotype. Overall, our results demonstrate that by applying multiple statistical genomic approaches on data mined from MET phenotypic data sets, significant genetic effects that define genomic regions associated with crop improvement can be discovered.

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A Test of Neutrality Based on Interlocus Associations

Genetics ◽

10.1093/genetics/146.3.1197 ◽

1997 ◽

Vol 146 (3) ◽

pp. 1197-1206 ◽

Cited By ~ 23

Author(s):

John K Kelly

Keyword(s):

Drosophila Melanogaster ◽

Natural Selection ◽

Neutral Theory ◽

Upper Bounds ◽

Statistical Properties ◽

Neutral Model ◽

Genetic Associations ◽

Evolutionary Processes ◽

Expected Values ◽

Genomic Regions

The evolutionary processes governing variability within genomic regions of low recombination have been the focus of many studies. Here, I investigate the statistical properties of a measure of intrlocus genetic associations under the assumption that mutations are selectively neutral and sites are completely linked. This measure, denoted ZnS, is based on the squared correlation of allelic identity at pairs of polymorphic sites. Upper bounds for ZnS are determined by simulations. Various deviations from the neutral model, including several different forms of natural selection, will inflate the value of ZnS relative to its neutral theory expectations. Larger than expected values of ZnS are observed in genetic samples from the yellow-ac-scute and Adh regions of Drosophila melanogaster.

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Genetic Associations in Four Decades of Multienvironment Trials Reveal Agronomic Trait Evolution in Common Bean

Genetics ◽

10.1534/genetics.120.303038 ◽

2020 ◽

Vol 215 (1) ◽

pp. 267-284 ◽

Cited By ~ 8

Author(s):

Alice H. MacQueen ◽

Jeffrey W. White ◽

Rian Lee ◽

Juan M. Osorno ◽

Jeremy Schmutz ◽

...

Keyword(s):

Common Bean ◽

Association Studies ◽

Crop Improvement ◽

Genetic Research ◽

The United States ◽

Genetic Effects ◽

Genome Wide Association Studies ◽

Genetic Associations ◽

Phenotypic Data ◽

Genomic Regions

Multienvironment trials (METs) are widely used to assess the performance of promising crop germplasm. Though seldom designed to elucidate genetic mechanisms, MET data sets are often much larger than could be duplicated for genetic research and, given proper interpretation, may offer valuable insights into the genetics of adaptation across time and space. The Cooperative Dry Bean Nursery (CDBN) is a MET for common bean (Phaseolus vulgaris) grown for > 70 years in the United States and Canada, consisting of 20–50 entries each year at 10–20 locations. The CDBN provides a rich source of phenotypic data across entries, years, and locations that is amenable to genetic analysis. To study stable genetic effects segregating in this MET, we conducted genome-wide association studies (GWAS) using best linear unbiased predictions derived across years and locations for 21 CDBN phenotypes and genotypic data (1.2 million SNPs) for 327 CDBN genotypes. The value of this approach was confirmed by the discovery of three candidate genes and genomic regions previously identified in balanced GWAS. Multivariate adaptive shrinkage (mash) analysis, which increased our power to detect significant correlated effects, found significant effects for all phenotypes. Mash found two large genomic regions with effects on multiple phenotypes, supporting a hypothesis of pleiotropic or linked effects that were likely selected on in pursuit of a crop ideotype. Overall, our results demonstrate that statistical genomics approaches can be used on MET phenotypic data to discover significant genetic effects and to define genomic regions associated with crop improvement.

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Genomic regions affecting fitness of the sweet corn mutant sugary1

The Journal of Agricultural Science ◽

10.1017/s0021859612000391 ◽

2012 ◽

Vol 151 (3) ◽

pp. 396-406 ◽

Cited By ~ 7

Author(s):

A. DJEMEL ◽

M. C. ROMAY ◽

P. REVILLA ◽

L. KHELIFI ◽

A. ORDÁS ◽

...

Keyword(s):

Inbred Line ◽

Sweet Corn ◽

Recombinant Inbred Lines ◽

Genetic Regulation ◽

Theoretical Point ◽

Nucleotide Polymorphisms ◽

Multiple Traits ◽

Wild Allele ◽

Major Interest ◽

Genomic Regions

SUMMARYMutants often reduce fitness when incorporated into some genotypes, as is the case of the mutant gene sugary1 (su1) in maize (Zea mays L.). Understanding the genetic factors affecting variation in the fitness of a mutant is of major interest from a theoretical point of view and also from a breeder's perspective. The genetic regulation of su1 behaviour was examined in two independent materials. First, populations of two recombinant inbred lines (RIL) were used, belonging to the Nested Association Mapping (NAM) design produced from crosses between the maize inbred B73 and two sweet corn lines (P39 and Il14h) that were genotyped with 1106 single nucleotide polymorphisms (SNPs). These RILs had a group of lines with the su1 allele and another group with the wild allele. At each marker, the allele frequencies of both groups of RILs were compared. Second, an F2 population derived from the cross between A619 (a field maize inbred line) and P39 (a sweet corn inbred line) was characterized with 295 simple sequence repeats (SSRs). In addition, the population was phenotyped for several traits related to viability. A large linkage block was detected around su1 in the RILs belonging to the NAM. Furthermore, significant genomic regions associated with su1 fitness were detected along the 10 maize chromosomes, although the detected effects were small. Quantitative trait loci (QTLs) with effects in multiple traits related to su1 fitness were detected in the F2 population, for example at bin 5·04. Therefore, the present results suggest that the su1 fitness depends on many genes of small effect distributed along the genome, with pleiotropic effects on multiple traits.

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Genetic dysregulation of gene expression and splicing during a ten-year period of human aging

10.1101/519520 ◽

2019 ◽

Cited By ~ 2

Author(s):

Brunilda Balliu ◽

Matthew Durrant ◽

Olivia de Goede ◽

Nathan Abell ◽

Xin Li ◽

...

Keyword(s):

Gene Expression ◽

Alternative Splicing ◽

Expression Profiles ◽

Genetic Regulation ◽

Older Age ◽

Small Subset ◽

Genetic Associations ◽

Cross Sectional ◽

Age Related ◽

Alternatively Spliced

SummaryMolecular and cellular changes are intrinsic to aging and age-related diseases. Prior cross-sectional studies have investigated the combined effects of age and genetics on gene expression and alternative splicing; however, there has been no long-term, longitudinal characterization of these molecular changes, especially in older age. We performed RNA sequencing in whole-blood from the same individuals from the PIVUS study at ages 70 and 80 to quantify how gene expression, alternative splicing, and their genetic regulation are altered during this 10-year period of advanced aging. We observe that individuals are more similar to their own expression profiles later in life than profiles of other individuals their own age; 93% of samples cluster with their own measurement at another age, and there is a strong correlation of genetic effects on expression between the two ages (median ρG = 0.96). Despite this, we identify 1,291 and 294 genes differentially expressed and alternatively spliced with age, as well as 529 genes with outlying individual trajectories of aging. Further, 7.8% and 9.6% of tested genes show a reduction in genetic associations with expression and alternative splicing in older age, with impacted genes enriched in DNA repair pathways. Together these findings indicate that, although gene expression and alternative splicing and their genetic regulation are mostly stable late in life, a small subset of genes is dynamic and is characterized by changes in expression and splicing and a reduction in genetic regulation.

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Abstract 465: Deciphering the Genetic Regulation of ADAMTS7 , a Novel Locus for Coronary Artery Disease

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.34.suppl_1.465 ◽

2014 ◽

Vol 34 (suppl_1) ◽

Author(s):

Kristy Ou ◽

Robert C Bauer ◽

Xuan Zhang ◽

Jian Cui ◽

Daniel J Rader ◽

...

Keyword(s):

Coronary Artery Disease ◽

Smooth Muscle ◽

Coronary Artery ◽

Smooth Muscle Cells ◽

Cell Lines ◽

Genetic Regulation ◽

Muscle Cells ◽

Cell Types ◽

Artery Disease ◽

Genomic Regions

Recent genome-wide association studies (GWAS) have identified an association between the ADAMTS7 locus and coronary artery disease (CAD) in humans. While ADAMTS7 is proposed to play a role in vascular smooth muscle cell (VSMC) migration and neointimal formation, the molecular regulation of human ADAMTS7 gene expression has not yet been explored. We assessed ADAMTS7 expression levels in primary mouse aortic smooth muscle cells (mAoSMC) as well as primary human coronary and human pulmonary artery smooth muscle cells (hCASMC, hPASMC) in response to treatment with various stimulatory agents. No differences in ADAMTS7 expression were observed upon treatment with PDGF, angiotensin II, and nicotine in any of the cell lines tested. However, TNFα upregulated ADAMTS7 by 4-fold in mAoSMC but not in human VSMCs while H 2 O 2 upregulated ADAMTS7 by 4-fold in hCASMC but not mAoSMCs. No agents modulated expression in hPASMC. Basal levels of ADAMTS7 varied among different VSMC lines; hCASMC had 2-fold greater levels of ADAMTS7 when compared to hPASMC and hAoSMC. These data demonstrate that ADAMTS7 is differentially regulated not only across different species, but also among different VSMC types, underscoring the complex genetic regulation of ADAMTS7 . In an attempt to elucidate important regulatory genomic regions controlling ADAMTS7 expression, we utilized data from the ENCODE project to identify regions surrounding ADAMTS7 that are enriched for regulatory domains, e.g. DNase hypsersensitivity (DHS) and H3K27 acetylation, in relevant cell types. We then overlayed data from CARDIoGRAM and C4D CAD GWAS to look for CAD-associated SNPs in these potential enhancers. Ultimately we selected 5 regions of interest (e.g., rs5029904 lies in region with increased H3K27 acetylation in ENCODE layered 7 cell lines, DHS peaks in serum fed and starved hAoSMCs, binding peaks for transcription factors via ENCODE ChIP-Seq experiments) for further studies in luciferase reporter assays multiple cell types to look for tissue specific expression mediated by these genomic regions. GWAS variants in these domains may affect the transcriptional regulation of ADAMTS7 , thus providing insight into the role for ADAMTS7 in human atherosclerosis.

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