Genetic variants are identified to increase risk of COVID-19 related mortality from UK Biobank data

AbstractBackgroundThe severity of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly heterogenous. Studies have reported that males and some ethnic groups are at increased risk of death from COVID-19, which implies that individual risk of death might be influenced by host genetic factors.MethodsIn this project, we consider the mortality as the trait of interest and perform a genome-wide association study (GWAS) of data for 1,778 infected cases (445 deaths, 25.03%) distributed by the UK Biobank. Traditional GWAS failed to identify any genome-wide significant genetic variants from this dataset. To enhance the power of GWAS and account for possible multi-loci interactions, we adopt the concept of super-variant for the detection of genetic factors. A discovery-validation procedure is used for verifying the potential associations.ResultsWe find 8 super-variants that are consistently identified across multiple replications as susceptibility loci for COVID-19 mortality. The identified risk factors on Chromosomes 2, 6, 7, 8, 10, 16, and 17 contain genetic variants and genes related to cilia dysfunctions (DNAH7 and CLUAP1), cardiovascular diseases (DES and SPEG), thromboembolic disease (STXBP5), mitochondrial dysfunctions (TOMM7), and innate immune system (WSB1). It is noteworthy that DNAH7 has been reported recently as the most downregulated gene after infecting human bronchial epithelial cells with SARS-CoV2.ConclusionsEight genetic variants are identified to significantly increase risk of COVID-19 mortality among the patients with white British ancestry. These findings may provide timely evidence and clues for better understanding the molecular pathogenesis of COVID-19 and genetic basis of heterogeneous susceptibility, with potential impact on new therapeutic options.

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Genetic variants are identified to increase risk of COVID-19 related mortality from UK Biobank data

Human Genomics ◽

10.1186/s40246-021-00306-7 ◽

2021 ◽

Vol 15 (1) ◽

Author(s):

Jianchang Hu ◽

Cai Li ◽

Shiying Wang ◽

Ting Li ◽

Heping Zhang

Keyword(s):

Genetic Variants ◽

Genetic Factors ◽

Genome Wide Association Study ◽

Individual Risk ◽

Uk Biobank ◽

Risk Of Death ◽

Genome Wide ◽

A Genome ◽

Increased Risk ◽

The Uk

Abstract Background The severity of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly heterogeneous. Studies have reported that males and some ethnic groups are at increased risk of death from COVID-19, which implies that individual risk of death might be influenced by host genetic factors. Methods In this project, we consider the mortality as the trait of interest and perform a genome-wide association study (GWAS) of data for 1778 infected cases (445 deaths, 25.03%) distributed by the UK Biobank. Traditional GWAS fails to identify any genome-wide significant genetic variants from this dataset. To enhance the power of GWAS and account for possible multi-loci interactions, we adopt the concept of super variant for the detection of genetic factors. A discovery-validation procedure is used for verifying the potential associations. Results We find 8 super variants that are consistently identified across multiple replications as susceptibility loci for COVID-19 mortality. The identified risk factors on chromosomes 2, 6, 7, 8, 10, 16, and 17 contain genetic variants and genes related to cilia dysfunctions (DNAH7 and CLUAP1), cardiovascular diseases (DES and SPEG), thromboembolic disease (STXBP5), mitochondrial dysfunctions (TOMM7), and innate immune system (WSB1). It is noteworthy that DNAH7 has been reported recently as the most downregulated gene after infecting human bronchial epithelial cells with SARS-CoV-2. Conclusions Eight genetic variants are identified to significantly increase the risk of COVID-19 mortality among the patients with white British ancestry. These findings may provide timely clues and potential directions for better understanding the molecular pathogenesis of COVID-19 and the genetic basis of heterogeneous susceptibility, with potential impact on new therapeutic options.

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Effect of HLA-DRB1 alleles and genetic variants on the development of neutralizing antibodies to interferon beta in the BEYOND and BENEFIT trials

Multiple Sclerosis Journal ◽

10.1177/1352458518763089 ◽

2018 ◽

Vol 25 (4) ◽

pp. 565-573 ◽

Cited By ~ 4

Author(s):

Dorothea Buck ◽

Till FM Andlauer ◽

Wilmar Igl ◽

Eva-Maria Wicklein ◽

Mark Mühlau ◽

...

Keyword(s):

Multiple Sclerosis ◽

Genetic Variants ◽

Neutralizing Antibodies ◽

Genome Wide Association Study ◽

Phase Iii ◽

Interferon Β ◽

Hla Alleles ◽

Genome Wide ◽

A Genome ◽

Increased Risk

Background: Treatment of multiple sclerosis (MS) with interferon β can lead to the development of antibodies directed against interferon β that interfere with treatment efficacy. Several observational studies have proposed different HLA alleles and genetic variants associated with the development of antibodies against interferon β. Objective: To validate the proposed genetic markers and to identify new markers. Methods: Associations of genetic candidate markers with antibody presence and development were examined in a post hoc analysis in 941 patients treated with interferon β-1b in the Betaferon® Efficacy Yielding Outcomes of a New Dose (BEYOND) and BEtaseron®/BEtaferon® in Newly Emerging multiple sclerosis For Initial Treatment (BENEFIT) prospective phase III trials. All patients were treated with interferon β-1b for at least 6 months. In addition, a genome-wide association study was conducted to identify new genetic variants. Results: We confirmed an increased risk for carriers of HLA-DRB1*04:01 (odds ratio (OR) = 3.3, p = 6.9 × 10−4) and HLA-DRB1*07:01 (OR = 1.8, p = 3.5 × 10−3) for developing neutralizing antibodies (NAbs). Several additional, previously proposed HLA alleles and genetic variants showed nominally significant associations. In the exploratory analysis, variants in the HLA region were associated with NAb development at genome-wide significance (OR = 2.6, p = 2.30 × 10−15). Conclusion: The contribution of HLA alleles and HLA-associated single-nucleotide polymorphisms (SNPs) to the development and titer of antibodies against interferon β was confirmed in the combined analysis of two multi-national, multi-center studies.

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A genome-wide association study finds genetic variants associated with neck or shoulder pain in UK Biobank

Human Molecular Genetics ◽

10.1093/hmg/ddaa058 ◽

2020 ◽

Vol 29 (8) ◽

pp. 1396-1404 ◽

Cited By ~ 2

Author(s):

Weihua Meng ◽

Brian W Chan ◽

Cameron Harris ◽

Maxim B Freidin ◽

Harry L Hebert ◽

...

Keyword(s):

Association Study ◽

Shoulder Pain ◽

Genetic Variants ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Uk Biobank ◽

Genome Wide ◽

A Genome ◽

Significant Locus ◽

The Uk

Abstract Background Common types of musculoskeletal conditions include pain in the neck and shoulder areas. This study seeks to identify the genetic variants associated with neck or shoulder pain based on a genome-wide association approach using 203 309 subjects from the UK Biobank cohort and look for replication evidence from the Generation Scotland: Scottish Family Health Study (GS:SFHS) and TwinsUK. Methods A genome-wide association study was performed adjusting for age, sex, BMI and nine population principal components. Significant and independent genetic variants were then sent to GS:SFHS and TwinsUK for replication. Results We identified three genetic loci that were associated with neck or shoulder pain in the UK Biobank samples. The most significant locus was in an intergenic region in chromosome 17, rs12453010, having P = 1.66 × 10−11. The second most significant locus was located in the FOXP2 gene in chromosome 7 with P = 2.38 × 10−10 for rs34291892. The third locus was located in the LINC01572 gene in chromosome 16 with P = 4.50 × 10−8 for rs62053992. In the replication stage, among four significant and independent genetic variants, rs2049604 in the FOXP2 gene and rs62053992 in the LINC01572 gene were weakly replicated in GS:SFHS (P = 0.0240 and P = 0.0202, respectively). Conclusions We have identified three loci associated with neck or shoulder pain in the UK Biobank cohort, two of which were weakly supported in a replication cohort. Further evidence is needed to confirm their roles in neck or shoulder pain.

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Correction: Genetic Variants Associated with Increased Risk of Malignant Pleural Mesothelioma: A Genome-Wide Association Study

PLoS ONE ◽

10.1371/journal.pone.0130109 ◽

2015 ◽

Vol 10 (6) ◽

pp. e0130109 ◽

Cited By ~ 1

Author(s):

Giuseppe Matullo ◽

Simonetta Guarrera ◽

Marta Betti ◽

Giovanni Fiorito ◽

Daniela Ferrante ◽

...

Keyword(s):

Association Study ◽

Malignant Pleural Mesothelioma ◽

Genetic Variants ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Pleural Mesothelioma ◽

Genome Wide ◽

A Genome ◽

Increased Risk

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A Genome-Wide Association Study of Novel Genetic Variants Associated With Anthropometric Traits in Koreans

Frontiers in Genetics ◽

10.3389/fgene.2021.669215 ◽

2021 ◽

Vol 12 ◽

Author(s):

Hye-Won Cho ◽

Hyun-Seok Jin ◽

Yong-Bin Eom

Keyword(s):

Genetic Variants ◽

Genetic Factors ◽

Genome Wide Association Study ◽

Association Studies ◽

Fat Distribution ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Genome Wide ◽

A Genome

Most previous genome-wide association studies (GWAS) have identified genetic variants associated with anthropometric traits. However, most of the evidence were reported in European populations. Anthropometric traits such as height and body fat distribution are significantly affected by gender and genetic factors. Here we performed GWAS involving 64,193 Koreans to identify the genetic factors associated with anthropometric phenotypes including height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip ratio. We found nine novel single-nucleotide polymorphisms (SNPs) and 59 independent genetic signals in genomic regions that were reported previously. Of the 19 SNPs reported previously, eight genetic variants at RP11-513I15.6 and one genetic variant at the RP11-977G19.10 region and six Asian-specific genetic variants were newly found. We compared our findings with those of previous studies in other populations. Five overlapping genetic regions (PAN2, ANKRD52, RNF41, HGMA1, and C6orf106) had been reported previously but none of the SNPs were independently identified in the current study. Seven of the nine newly found novel loci associated with height in women revealed a statistically significant skeletal expression of quantitative trait loci. Our study provides additional insight into the genetic effects of anthropometric phenotypes in East Asians.

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Common susceptibility alleles are unlikely to contribute as strongly as the FV and ABO loci to VTE risk: results from a GWAS approach

Blood ◽

10.1182/blood-2008-11-190389 ◽

2009 ◽

Vol 113 (21) ◽

pp. 5298-5303 ◽

Cited By ~ 194

Author(s):

David-Alexandre Trégouët ◽

Simon Heath ◽

Noémie Saut ◽

Christine Biron-Andreani ◽

Jean-François Schved ◽

...

Keyword(s):

Complex Disease ◽

Genetic Factors ◽

Genome Wide Association Study ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Genome Wide ◽

A Genome ◽

Increased Risk ◽

Fv Leiden ◽

Gwas Approach

Abstract Venous thromboembolism (VTE) is a complex disease that has a major genetic component of risk. To identify genetic factors that may modify the risk of VTE, we conducted a genome-wide association study by analyzing approximately 317 000 single nucleotide polymorphisms (SNPs) in 453 VTE cases and 1327 controls. Only 3 SNPs located in the FV and ABO blood group genes were found associated with VTE at a genome-wide significant level of 1.7 × 10−7. Detailed analysis of these SNPs in additional cohorts of more than 1700 cases and 1400 controls revealed that the association observed at the FV locus was the result of the increased risk mediated by the FV Leiden mutation, whereas O and A2 blood groups were found to be at lower risk for VTE. Apart from the FV and ABO loci, no other locus was found strongly associated with VTE. However, using this large cohort of subjects, we were able to replicate the mild effects of 2 nonsynonymous SNPs, rs1613662 in GP6 and rs13146272 in CYP4V2, recently suspected to be associated with VTE.

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A genome-wide association study finds genetic variants associated with neck or shoulder pain in UK Biobank

10.1101/2020.01.20.913228 ◽

2020 ◽

Author(s):

Weihua Meng ◽

Brian W Chan ◽

Cameron Harris ◽

Maxim B Freidin ◽

Harry L Hebert ◽

...

Keyword(s):

Association Study ◽

Shoulder Pain ◽

Genetic Variants ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Chromosome 17 ◽

Uk Biobank ◽

Genome Wide ◽

A Genome ◽

The Uk

ABSTRACTBackgroundCommon types of musculoskeletal conditions include pain in the neck and shoulder areas. This study seeks to identify the genetic variants associated with neck or shoulder pain based on a genome-wide association approach using 203,309 subjects from the UK Biobank cohort and look for replication evidence from the Generation Scotland: Scottish Family Health Study (GS:SFHS) and TwinsUK.MethodsCases in the UK Biobank were determined by a question which asked the participants if they had experienced pain in the neck or shoulder in the previous month influencing daily activities. Controls were the UK Biobank participants who reported no pain anywhere in the last month. A genome-wide association study was performed adjusting for age, sex, BMI and 9 population principal components. Significant and independent genetic variants were then sent to GS:SFHS and TwinsUK for replication.ResultsWe identified 3 genetic loci that were associated with neck or shoulder pain in the UK Biobank samples. The most significant locus was in an intergenic region in chromosome 17, rs12453010, having P = 1.66 × 10-11. The second most significant locus was located in the FOXP2 gene in chromosome 7 with P = 2.38 × 10-10 for rs34291892. The third locus was located in the LINC01572 gene in chromosome 16 with P = 4.50 × 10-8 for rs62053992. In the replication stage, among 4 significant and independent genetic variants, rs2049604 in the FOXP2 gene and rs62053992 in the LINC01572 gene were weakly replicated in GS:SFHS (P = 0.0240 and P = 0.0202, respectively). None of the single nucleotide polymorphisms (SNPs) were replicated in the TwinsUK cohort (P > 0.05).ConclusionsWe have identified 3 loci associated with neck or shoulder pain in the UK Biobank cohort, two of which were weakly supported in a replication cohort. Further evidence is needed to confirm their roles in neck or shoulder pain.SignificanceThis is the first genome-wide association study on neck or shoulder pain. We have identified 3 genetic loci (an intergenic region in chromosome 17, the FOXP2 gene in chromosome 7, and the LINC01572 gene in chromosome 16) that are associated with neck or shoulder pain using the UK Biobank cohort, among which the FOXP2 gene and the LINC01572 gene were weakly replicated by the Generation Scotland: Scottish Family Health Study (P < 0.05). The SNP heritability was 0.11, indicating neck or shoulder pain is a heritable trait. The tissue expression analysis suggested that neck or shoulder pain was related to multiple brain tissues, indicating the involvement of neuron function. The results will inform further research in the characterisation of the mechanisms of neck or shoulder pain.

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