scholarly journals Using symptom-based case predictions to identify host genetic factors that contribute to COVID-19 susceptibility

PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0255402
Author(s):  
Irene V. van Blokland ◽  
Pauline Lanting ◽  
Anil P. S. Ori ◽  
Judith M. Vonk ◽  
Robert C. A. Warmerdam ◽  
...  
Keyword(s):  
Prediction Model ◽  
Genetic Associations ◽  
Cross Sectional ◽  
Genetic Studies ◽  
Genome Wide ◽  
Host Genetic ◽  
Consistent Performance ◽  
Testing Policies ◽  
Genome Wide Significance ◽  
Limited Testing

Epidemiological and genetic studies on COVID-19 are currently hindered by inconsistent and limited testing policies to confirm SARS-CoV-2 infection. Recently, it was shown that it is possible to predict COVID-19 cases using cross-sectional self-reported disease-related symptoms. Here, we demonstrate that this COVID-19 prediction model has reasonable and consistent performance across multiple independent cohorts and that our attempt to improve upon this model did not result in improved predictions. Using the existing COVID-19 prediction model, we then conducted a GWAS on the predicted phenotype using a total of 1,865 predicted cases and 29,174 controls. While we did not find any common, large-effect variants that reached genome-wide significance, we do observe suggestive genetic associations at two SNPs (rs11844522, p = 1.9x10-7; rs5798227, p = 2.2x10-7). Explorative analyses furthermore suggest that genetic variants associated with other viral infectious diseases do not overlap with COVID-19 susceptibility and that severity of COVID-19 may have a different genetic architecture compared to COVID-19 susceptibility. This study represents a first effort that uses a symptom-based predicted phenotype as a proxy for COVID-19 in our pursuit of understanding the genetic susceptibility of the disease. We conclude that the inclusion of symptom-based predicted cases could be a useful strategy in a scenario of limited testing, either during the current COVID-19 pandemic or any future viral outbreak.

scholarly journals Using symptom-based case predictions to identify host genetic factors that contribute to COVID-19 susceptibility

2020 ◽  
Author(s):  
Irene V van Blokland ◽  
Pauline Lanting ◽  
Anil PS Ori ◽  
Judith M Vonk ◽  
Robert CA Warmerdam ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Genetic Architecture ◽  
Genetic Factors ◽  
Added Value ◽  
Cross Sectional ◽  
Genetic Studies ◽  
Host Genetic ◽  
Testing Policies ◽  
Larger Sample ◽  
Limited Testing

Epidemiological and genetic studies on COVID-19 are hindered by inconsistent and limited testing policies to confirm SARS-CoV-2 infection. Recently, it was shown that it is possible to predict potential COVID-19 cases using cross-sectional self-reported disease-related symptoms. Using a previously reported COVID-19 prediction model, we show that it is possible to conduct a GWAS on predicted COVID-19 which benefits from a larger sample size in order to gain new insights into the genetic susceptibility of the disease. Furthermore, we find suggestive evidence that genetic variants for other viral infectious diseases do not overlap with COVID-19 susceptibility and that severity of COVID-19 may have a different genetic architecture compared to COVID-19 susceptibility. Our findings demonstrate the added value of using self-reported symptom assessments to quickly monitor novel endemic viral outbreaks in a scenario of limited testing. Should there be another outbreak of a novel infectious disease, then we recommend repeatedly collecting data of disease-related symptoms.

scholarly journals Detecting Genetic Associations betweenATG5and Lupus Nephritis bytrans-eQTL

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Yue-miao Zhang ◽  
Fa-juan Cheng ◽  
Xu-jie Zhou ◽  
Yuan-yuan Qi ◽  
Ping Hou ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Lupus Erythematosus ◽  
Clinical Information ◽  
Nucleotide Polymorphisms ◽  
Genetic Associations ◽  
Single Nucleotide ◽  
Genetic Studies ◽  
Genome Wide ◽  
Custom Made ◽  
Regulatory Effects

Objectives. Numerous loci were identified to perturb gene expression intrans. As elevatedATG5expression was observed in systemic lupus erythematosus (SLE), the study was conducted to analyze the genome-wide genetic regulatory mechanisms associated withATG5expression in a Chinese population with lupus nephritis (LN).Methods. The online expression quantitative trait loci database was searched fortrans-expression single nucleotide polymorphisms (trans-eSNPs) ofATG5. Taggingtrans-eSNPs were genotyped by a custom-made genotyping chip in 280 patients and 199 controls. For positive findings, clinical information and bioinformation analyses were performed.Results. Fourtrans-eSNPs were observed to be associated with susceptibility to LN (P< 0.05), including ANKRD50 rs17008504, AGA rs2271100, PAK7 rs6056923, and TET2 rs1391441, while seven othertrans-eSNPs showed marginal significant associations (0.05 <P< 0.1). Correlations between thetrans-eSNPs andATG5expression and different expression levels ofATG5in SLE patients and controls were validated, and their regulatory effects were annotated. However, no significant associations were observed between different genotypes oftrans-eSNPs and severity or outcome of the patients.Conclusion. Using the new systemic genetics approach, we identified 10 loci associated with susceptibility to LN potentially, which may be complementary to future pathway based genetic studies.

scholarly journals Genetic Associations with Subjective Well-Being Also Implicate Depression and Neuroticism

2015 ◽  
Author(s):  
Aysu Okbay ◽  
Bart M. L. Baselmans ◽  
Jan-Emmanuel De Neve ◽  
Patrick Turley ◽  
Michel G. Nivard ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Genome Wide Association Study ◽  
Well Being ◽  
Genome Wide Association ◽  
Subjective Well Being ◽  
Genetic Associations ◽  
Genome Wide ◽  
A Genome ◽  
Genome Wide Significance

We conducted a genome-wide association study of subjective well-being (SWB) in 298,420 individuals. We also performed auxiliary analyses of depressive symptoms ("DS";N= 161,460) and neuroticism (N= 170,910), both of which have a substantial genetic correlation with SWB (ρ≈-0.8). We identify three SNPs associated with SWB at genome-wide significance. Two of them are significantly associated with DS in an independent sample. In our auxiliary analyses, we identify 13 additional genome-wide-significant associations: two with DS and eleven with neuroticism, including two inversion polymorphisms. Across our phenotypes, loci regulating expression in central nervous system and adrenal/pancreas tissues are enriched. The discovery of genetic loci associated with the three phenotypes we study has proven elusive; our findings illustrate the payoffs from studying them jointly.

scholarly journals A year of COVID-19 GWAS results from the GRASP portal reveals potential SARS-CoV-2 modifiers

2021 ◽  
Author(s):  
Florian Thibord ◽  
Melissa V Chan ◽  
Ming-Huei Chen ◽  
Andrew D Johnson
Keyword(s):  
Genetic Architecture ◽  
Association Studies ◽  
Therapeutic Strategies ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Genetic Associations ◽  
Independent Dataset ◽  
Genome Wide ◽  
Data Release ◽  
Host Genetic

Host genetic variants influence the susceptibility and severity of several infectious diseases, and the discovery of novel genetic associations with Covid-19 phenotypes could help developing new therapeutic strategies to reduce its burden. Between May 2020 and February 2021, we used Covid-19 data released periodically by UK Biobank and performed over 400 Genome-Wide Association Studies (GWAS) of Covid-19 susceptibility (N=15,738 cases), hospitalization (N=1,916), severe outcomes (N=935) and death (N=828), stratified by ancestry and sex. In coherence with previous studies, we observed 2 independent signals at the chr3p21.31 locus (rs73062389-A, OR=1.22, P=7.64E-14 and rs13092887-A, OR=1.73, P=2.38E-8, in Europeans) modulating susceptibility and severity, respectively, and a signal influencing susceptibility at the ABO locus (rs9411378-A, OR=1.10, P =7.36E-10, in Europeans), which was more significant in men than in women (P=0.01). In addition, we detected 7 genome-wide significant signals in the last data release analyzed (on February 24th 2021), of which 4 were associated with susceptibility (SCRT2, LRMDA, chr15q24.2, MIR3681HG), 2 with hospitalization (ANKS1A, chr12p13.31) and 1 for severity (ADGRE1). Finally, we identified over 300 associations which increased in significance over time, and reached at least P<10-5 in the last data release analyzed. We replicated 2 of these signals in an independent dataset: a variant downstream of CCL3 (rs2011959) associated with severity in men, and a variant located in an ATP5PO intron (rs12482569) associated with hospitalization. These results, freely available on the GRASP portal, provide new insights on the host genetic architecture of Covid-19 phenotypes.

scholarly journals Association between Genetic Variants and Cisplatin-Induced Nephrotoxicity: A Genome-Wide Approach and Validation Study

2021 ◽  
Vol 11 (11) ◽  
pp. 1233
Author(s):  
Zulfan Zazuli ◽  
Corine de de Jong ◽  
Wei Xu ◽  
Susanne J. H. Vijverberg ◽  
Rosalinde Masereeuw ◽  
...  
Keyword(s):  
Candidate Gene ◽  
Genetic Risk ◽  
Validation Cohort ◽  
Genotype Imputation ◽  
Candidate Gene Approach ◽  
Genetic Associations ◽  
Discovery Cohort ◽  
Genome Wide ◽  
A Genome ◽  
Genome Wide Significance

This study aims to evaluate genetic risk factors for cisplatin-induced nephrotoxicity by investigating not previously studied genetic risk variants and further examining previously reported genetic associations. A genome-wide study (GWAS) was conducted in genetically estimated Europeans in a discovery cohort of cisplatin-treated adults from Toronto, Canada, followed by a candidate gene approach in a validation cohort from the Netherlands. In addition, previously reported genetic associations were further examined in both the discovery and validation cohorts. The outcome, nephrotoxicity, was assessed in two ways: (i) decreased estimated glomerular filtration rate (eGFR), calculated using the Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI) and (ii) increased serum creatinine according to the Common Terminology Criteria for Adverse Events v4.03 for acute kidney injury (AKI-CTCAE). Four different Illumina arrays were used for genotyping. Standard quality control was applied for pre- and post-genotype imputation data. In the discovery cohort (n = 608), five single-nucleotide polymorphisms (SNPs) reached genome-wide significance. The A allele in rs4388268 (minor allele frequency = 0.23), an intronic variant of the BACH2 gene, was consistently associated with increased risk of cisplatin-induced nephrotoxicity in both definitions, meeting genome-wide significance (β = −8.4, 95% CI −11.4–−5.4, p = 3.9 × 10−8) for decreased eGFR and reaching suggestive association (OR = 3.9, 95% CI 2.3–6.7, p = 7.4 × 10−7) by AKI-CTCAE. In the validation cohort of 149 patients, this variant was identified with the same direction of effect (eGFR: β = −1.5, 95% CI −5.3–2.4, AKI-CTCAE: OR = 1.7, 95% CI 0.8–3.5). Findings of our previously published candidate gene study could not be confirmed after correction for multiple testing. Genetic predisposition of BACH2 (rs4388268) might be important in the development of cisplatin-induced nephrotoxicity, indicating opportunities for mechanistic understanding, tailored therapy and preventive strategies.

scholarly journals Genetic variation in RCOR1 is associated with tinnitus in UK Biobank

2020 ◽  
Author(s):  
Helena Rose Rees Wells ◽  
Fatin N Zainul Abidin ◽  
Maxim Freydin ◽  
Frances MK Williams ◽  
Sally J Dawson
Keyword(s):  
Molecular Mechanisms ◽  
Genome Wide Association Study ◽  
Uk Biobank ◽  
Genetic Studies ◽  
Significance Threshold ◽  
Genome Wide ◽  
Neuronal Gene ◽  
Close Proximity ◽  
Repressor Complex ◽  
Genome Wide Significance

Tinnitus is a prevalent condition in which perception of sound occurs without an external stimulus. It is often associated with pre-existing hearing loss or noise-induced damage to the auditory system. In some individuals it occurs frequently or even continuously and leads to considerable distress and difficulty sleeping. There is little knowledge of the molecular mechanisms involved in tinnitus which has hindered the development of treatments. Evidence suggests that tinnitus has a heritable component although previous genetic studies have not established specific risk factors. We performed a case-control genome-wide association study for self-reported tinnitus in 172,608 UK Biobank volunteers. Three variants in close proximity to the RCOR1 gene reached genome wide significance: rs4906228 (p=1.7E-08), rs4900545 (p=1.8E-08) and 14:103042287_CT_C (p=3.50E-08). RCOR1 encodes REST Corepressor 1, a component of a co-repressor complex involved in repressing neuronal gene expression in non-neuronal cells. Eleven other independent genetic loci reached a suggestive significance threshold of p<1E-06.

scholarly journals Genetic Associations of Chronotype in the Finnish General Population

2020 ◽  
Vol 35 (5) ◽  
pp. 501-511
Author(s):  
Mirkka Maukonen ◽  
Aki S. Havulinna ◽  
Satu Männistö ◽  
Noora Kanerva ◽  
Veikko Salomaa ◽  
...  
Keyword(s):  
Clock Gene ◽  
Genome Wide Association Study ◽  
Clock Genes ◽  
Genetic Risk Score ◽  
Assessment Methods ◽  
Candidate Gene Approach ◽  
Nucleotide Polymorphisms ◽  
Genetic Associations ◽  
Cross Sectional ◽  
Genome Wide

Individuals with a later chronotype (evening types) tend to have unhealthier behaviors and increased morbidity and mortality as compared with those with an earlier chronotype (morning types). However, the role of genetics in explaining evening types’ adverse health and health behavior is unclear. Our aim was to study genetic associations of chronotype among 8433 Finns from the cross-sectional National FINRISK 2007 and 2012 studies. First, we studied associations between chronotype and 20 key clock genes with a candidate-gene approach and then performed a full genome-wide association study (GWAS) of chronotype. We also developed a genetic risk score (GRS) for chronotype based on 313 single nucleotide polymorphisms (SNPs) that have previously been associated with chronotype. Chronotype was assessed with a shortened version of Horne and Östberg’s Morningness-Eveningness Questionnaire (sMEQ), and for comparison, we also used the single self-evaluation question on chronotype from the questionnaire. Linear and logistic regression was used for statistical analysis assuming additive effects. The clock gene analysis revealed 1 independent association signal within NR1D2 (lead SNP rs4131403) that was associated with chronotype ( p < 0.05; as based on both chronotype assessment methods). The GWAS analysis did not yield any genome-wide significant associations ( p > 5 × 10−8). However, higher GRS was associated with evening chronotype ( p < 0.001; as based on both chronotype assessment methods). In conclusion, our findings indicated novel genetic associations between chronotype and the NR1D2 clock gene, which has previously been associated with carbohydrate and lipid metabolism. Furthermore, the GRS was able to capture the genetic aspect of chronotype in our study population. These findings expand our knowledge of the genetic basis of chronotype.

scholarly journals Association of genetic variants with prostate cancer in Africa: a concise review

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Emmanuel Acheampong ◽  
Evans Asamoah Adu ◽  
Christian Obirikorang ◽  
George Amoah ◽  
Osei Owusu Afriyie ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Genetic Variants ◽  
Association Studies ◽  
African Ancestry ◽  
Candidate Gene Approach ◽  
Main Body ◽  
Genome Wide Association Studies ◽  
Genetic Associations ◽  
Genetic Studies ◽  
Genome Wide

Abstract Background Prostate cancer (PCa) has one of the highest heritability of all major cancers, where the genetic contribution has been documented, and knowledge about the molecular genetics of the disease is increasing. However, the extent and aspects to which genetic variants explain PCa heritability in Africa are limited. Main body In this review, we summarize studies that highlight how identified genetic variants explain differences in PCa incidence and presentation across ethnic groups. We also present the knowledge gaps in PCa genetics in Africa and why Africa represents an untapped potential ground for genetic studies on PCa. A significant number of genome-wide association studies, linkage, and fine-mapping analyses have been conducted globally, and that explains 30–33% of PCa heritability. The African ancestry has a significant mention in PCa incidence and presentation. To date, the candidate gene approach has replicated 23 polymorphisms including dinucleotide and trinucleotide repeats in 16 genes. CYP17-rs743572, CYP3A4-rs2740574, CYP3A5-rs776746, CYP3A43-rs501275, and haplotype blocks, containing these variants, are significantly associated with PCa among some population groups but not others. With the few existing studies, the extent of genetic diversity in Africa suggests that genetic associations of PCa to African ancestry go beyond nucleotide sequence polymorphisms, to a level of environmental adaptation, which may interpret genetic risk profiles. Also, the shreds of evidence suggest that evolutionary history contributes to the high rates of PCa relative to African ancestry, and genetic associations do not always replicate across populations. Conclusion The genetic architecture of PCa in Africa provides important contributions to the global understanding of PCa specifically the African-ancestry hypothesis. There is a need for more prostate cancer consortiums to justify the heritable certainties of PCa among Africans, and emphasis should be placed on the genetic epidemiological model of PCa in Africa.

scholarly journals Many QTLs with minor additive effects are associated with a large difference in growth between two selection lines in chickens

2005 ◽  
Vol 86 (2) ◽  
pp. 115-125 ◽  
Author(s):  
LINA JACOBSSON ◽  
HEE-BOK PARK ◽  
PER WAHLBERG ◽  
ROBERT FREDRIKSSON ◽  
MIGUEL PEREZ-ENCISO ◽  
...  
Keyword(s):  
Body Weight ◽  
Phenotypic Variance ◽  
Additive Effects ◽  
Founder Population ◽  
Phenotypic Difference ◽  
Genetic Studies ◽  
Metabolic Characteristics ◽  
Red Junglefowl ◽  
Genome Wide ◽  
Genome Wide Significance

Two growth-selected lines in chickens have been developed from a single founder population by divergent selection for body weight at 56 days of age. After more than 40 generations of selection they show a nine-fold difference in body weight at selection age and large differences in growth rate, appetite, fat deposition and metabolic characteristics. We have generated a large intercross between these lines comprising more than 800 F2 birds. QTL mapping revealed 13 loci affecting growth. The most striking observation was that the allele in the high weight line in all cases was associated with enhanced growth, but each locus explained only a small proportion of the phenotypic variance using a standard QTL model (1·3–3·1%). This result is in sharp contrast to our previous study where we reported that the two-fold difference in adult body size between the red junglefowl and White Leghorn domestic chickens is explained by a small number of QTLs with large additive effects. Furthermore, no QTLs for anorexia or antibody response were detected despite large differences for these traits between the founder lines. The result is an excellent example where a large phenotypic difference between populations occurs in the apparent absence of any single locus with large phenotypic effects. The study underscores the need for powerful experimental designs in genetic studies of multifactorial traits. No QTL at all would have reached genome-wide significance using a less powerful design (e.g. approx. 200 F2 individuals) regardless of the nine-fold phenotypic difference between the founder lines for the selected trait.

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