Non-Causal Effects of Asthma on COVID-19 Susceptibility and Severity

Background: Asthma is observationally associated with an increased risk of COVID-19, but the causality remains unclear. We aim to determine whether there is a casual role of asthma in susceptibility to SARS-CoV-2 infection or COVID-19 severity.Methods: Instrumental variables (IVs) for asthma and moderate-to-severe asthma were obtained from publicly available summary statistics from the most recent and largest genome-wide association study (GWAS), including 394 283 and 57 695 participants of European ancestry, respectively. The corresponding data for COVID-19 susceptibility, hospitalization and severe-disease were derived from the COVID-19 Host Genetics Initiative GWAS meta-analysis of up to 1 683 768 individuals of European descent. Causality was inferred between correlated traits by Mendelian Randomization analyses. Inverse-variance weighted method was used as the primary MR estimates and multiple alternate approaches and several sensitivity analyses were also conducted.Results: Our MR analysis revealed no causal effects of asthma on COVID-19 susceptibility, hospitalization or severe disease, with odds ratio (OR) of 0.994 (95% CI: 0.962–1.027), 1.020 (95% CI: 0.955–1.089), and 0.929 (95% CI: 0.836–1.032), respectively. Furthermore, using genetic variants for moderate-to-severe asthma, a similar pattern of results was observed for COVID-19 susceptibility (OR: 0.988, 95% CI: 0.946–1.031), hospitalization (OR: 0.967, 95% CI: 0.906–1.031), and severe disease (OR: 0.911, 95% CI: 0.823–1.009). The association of asthma and moderate-to-severe asthma with COVID-19 was overall robust to sensitivity analyses.Conclusion: Genetically predicted asthma was not associated with susceptibility to, or severity of, COVID-19 disease, indicating that asthma is unlikely to be a causal factor in the development of COVID-19.

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Association of telomere length with risk of rheumatoid arthritis: a meta-analysis and Mendelian randomization

Rheumatology ◽

10.1093/rheumatology/kez524 ◽

2019 ◽

Vol 59 (5) ◽

pp. 940-947 ◽

Cited By ~ 1

Author(s):

Zhen Zeng ◽

Wanting Zhang ◽

Yu Qian ◽

Huijun Huang ◽

David J H Wu ◽

...

Keyword(s):

Genome Wide Association Study ◽

Mendelian Randomization ◽

Meta Analysis ◽

Genome Wide Association ◽

Sensitivity Analyses ◽

Causal Association ◽

Genome Wide ◽

Inverse Variance ◽

A Genome ◽

Mean Differences

Abstract Objective To evaluate the telomere length (TL) in patients with RA relative to that in controls and to test whether TL is causally associated with risk of RA. Methods Systematic review and meta-analysis of relevant literature was conducted to evaluate the association between TL and RA. Standardized mean differences with 95% CIs of TL in RA patients relative to controls were pooled using fixed or random-effects models. TL-related single-nucleotide polymorphisms were selected from a genome-wide association study of 37 684 individuals, and summary statistics of RA were obtained from a genome-wide association study meta-analysis including 14 361 RA patients and 43 923 controls. Mendelian randomization was performed using the inverse-variance weighted, weighted-median and likelihood-based methods. Sensitivity analyses were performed to test the robustness of the association. Results In the meta-analysis of 911 RA patients and 2498 controls, we found that patients with RA had a significantly shorter TL compared with controls (standardized mean differences = −0.50; 95% CI −0.88, −0.11; P = 0.012). In the Mendelian randomization analysis, we found that genetically predicted longer TL was associated with a reduced risk of RA [odds ratio = 0.68; 95% CI 0.54, 0.86; P = 0.002 using the inverse-variance weighted method]. Sensitivity analyses using alternative Mendelian randomization approaches yielded similar findings, suggesting the robustness of the causal association. Conclusion Our study provides evidence for a negative causal association of TL with risk of RA. Further studies are warranted to elucidate the underlying mechanism for the role of telomeres in the development of RA.

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Abstract 14182: Genome Wide Association Study for High Sensitive Cardiac Troponin T Levels Identifies a Novel Gene in Europeans With Type 1 Diabetes

Circulation ◽

10.1161/circ.142.suppl_3.14182 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Tarunveer S Ahluwalia ◽

Frederik Persson ◽

Tine W Hansen ◽

Lise Tarnow ◽

Hans-Henrik Parving ◽

...

Keyword(s):

Type 1 Diabetes ◽

Association Study ◽

Gene Locus ◽

Genome Wide Association Study ◽

Troponin T ◽

Genome Wide Association ◽

European Ancestry ◽

Genome Wide ◽

Increased Risk

Introduction: Adults with diabetes have a two to four folds increased risk of dying with heart disease compared to those without diabetes. Higher cardiac troponins, especially Troponin T (TnT) is a specific biomarker for cardiac injury also guiding management of chest pain and associated with increased risk of heart failure. Hypothesis: There is limited knowledge on genes regulating cardiac TnT levels. We conducted a genome wide association study (GWAS) for circulating cardiac TnT levels among individuals with type 1 diabetes (T1D). Methods: The study included 849 T1D individuals recruited from the outpatient clinic at Steno Diabetes Center Copenhagen, Denmark. Serum high sensitive TnT (hsTnT) levels were measured and log transformed for normalization after check for outliers (mean ± 4 SD). Genotyping on 538,448 single nucleotide variants (SNVs) was done using Illumina Human Core Exome Chip. After quality control filters: hardy weinberg equilibrium (p >10 -6 ), European ancestry, genotype call rates >95%, common variants were examined in 740 individuals with hs TnT data. We ran linear regression based additive genetic models adjusting for age, sex, diabetes duration and population sub structure using Plink and R statistical programs. P <5 x 10 -8 was genome wide significant (GWS) while 5 x 10 -8 < p < 1 x 10 -6 was considered suggestive. Results: Participants had a mean (SD) age of 43.7 (11.1) years, 57.4% were men, with diabetes duration of 28.0 (9.5) years, HbA1c 8.9 (1.3) % and 50.5% with diabetic nephropathy. Median (IQR) hsTnT levels were 64.7 (29.2-175.6) pg/ml. We identified a GWS missense common variant in the CISD3 gene locus on chromosome 17 (p=1.7 x 10 -8 ) for cardiac hsTnT levels. This gene codes CDGSH Iron Sulfur Domain 3 protein also called Mitochondrial Inner NEET Protein. Two suggestive loci were PTPRD (Protein Tyrosine Phosphatase Receptor Type D; p=4.9 x 10 -7 ) and DCC (DCC Netrin 1 Receptor; 6.6 x 10 -7 ) on chromosomes 9 and 18. PTPRD is a known GWS locus for hsTnT that we reconfirm among T1D individuals. Conclusions: We identify a novel gene locus for circulating cardiac hsTnT levels among T1D individuals of European ancestry. CISD3 is expressed in heart tissue regulating mitochondrial functions. Further validation is suggested.

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Genetically Determined Levels of Serum Metabolites and Risk of Neuroticism: A Mendelian Randomization Study

The International Journal of Neuropsychopharmacology ◽

10.1093/ijnp/pyaa062 ◽

2020 ◽

Author(s):

Li Qian ◽

Yajuan Fan ◽

Fengjie Gao ◽

Binbin Zhao ◽

Bin Yan ◽

...

Keyword(s):

Uric Acid ◽

Lower Risk ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Strong Predictor ◽

Causal Effects ◽

Sensitivity Analyses ◽

Nucleotide Polymorphisms ◽

Genetic Associations ◽

Inverse Variance

Abstract Background Neuroticism is a strong predictor for a variety of social and behavioral outcomes, but the etiology is still unknown. Our study aims to provide a comprehensive investigation of causal effects of serum metabolome phenotypes on risk of neuroticism using Mendelian randomization (MR) approaches. Methods Genetic associations with 486 metabolic traits were utilized as exposures, and data from a large genome-wide association study of neuroticism were selected as outcome. For MR analysis, we used the standard inverse-variance weighted (IVW) method for primary MR analysis and 3 additional MR methods (MR-Egger, weighted median, and MR pleiotropy residual sum and outlier) for sensitivity analyses. Results Our study identified 31 metabolites that might have causal effects on neuroticism. Of the 31 metabolites, uric acid and paraxanthine showed robustly significant association with neuroticism in all MR methods. Using single nucleotide polymorphisms as instrumental variables, a 1-SD increase in uric acid was associated with approximately 30% lower risk of neuroticism (OR: 0.77; 95% CI: 0.62–0.95; PIVW = 0.0145), whereas a 1-SD increase in paraxanthine was associated with a 7% higher risk of neuroticism (OR: 1.07; 95% CI: 1.01–1.12; PIVW = .0145). Discussion Our study suggested an increased level of uric acid was associated with lower risk of neuroticism, whereas paraxanthine showed the contrary effect. Our study provided novel insight by combining metabolomics with genomics to help understand the pathogenesis of neuroticism.

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The International SSRI Pharmacogenomics Consortium (ISPC): a genome-wide association study of antidepressant treatment response

Translational Psychiatry ◽

10.1038/tp.2015.47 ◽

2015 ◽

Vol 5 (4) ◽

pp. e553-e553 ◽

Cited By ~ 75

Author(s):

J M Biernacka ◽

K Sangkuhl ◽

G Jenkins ◽

R M Whaley ◽

P Barman ◽

...

Keyword(s):

Association Study ◽

Selective Serotonin Reuptake Inhibitors ◽

Genome Wide Association Study ◽

Transmembrane Domain ◽

Meta Analysis ◽

Genome Wide Association ◽

Research Network ◽

Genome Wide ◽

A Genome ◽

Increased Risk

Abstract Response to treatment with selective serotonin reuptake inhibitors (SSRIs) varies considerably between patients. The International SSRI Pharmacogenomics Consortium (ISPC) was formed with the primary goal of identifying genetic variation that may contribute to response to SSRI treatment of major depressive disorder. A genome-wide association study of 4-week treatment outcomes, measured using the 17-item Hamilton Rating Scale for Depression (HRSD-17), was performed using data from 865 subjects from seven sites. The primary outcomes were percent change in HRSD-17 score and response, defined as at least 50% reduction in HRSD-17. Data from two prior studies, the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomics Study (PGRN-AMPS) and the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, were used for replication, and a meta-analysis of the three studies was performed (N=2394). Although many top association signals in the ISPC analysis map to interesting candidate genes, none were significant at the genome-wide level and the associations were not replicated using PGRN-AMPS and STAR*D data. Top association results in the meta-analysis of response included single-nucleotide polymorphisms (SNPs) in the HPRTP4 (hypoxanthine phosphoribosyltransferase pseudogene 4)/VSTM5 (V-set and transmembrane domain containing 5) region, which approached genome-wide significance (P=5.03E−08) and SNPs 5’ upstream of the neuregulin-1 gene, NRG1 (P=1.20E−06). NRG1 is involved in many aspects of brain development, including neuronal maturation and variations in this gene have been shown to be associated with increased risk for mental disorders, particularly schizophrenia. Replication and functional studies of these findings are warranted.

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Causal Effects of Homocysteine, Folate, and Cobalamin on Kidney Function: A Mendelian Randomization Study

Nutrients ◽

10.3390/nu13030906 ◽

2021 ◽

Vol 13 (3) ◽

pp. 906

Author(s):

Sehoon Park ◽

Soojin Lee ◽

Yaerim Kim ◽

Semin Cho ◽

Kwangsoo Kim ◽

...

Keyword(s):

Kidney Function ◽

Estimated Glomerular Filtration Rate ◽

Mendelian Randomization ◽

Homocysteine Level ◽

Meta Analysis ◽

Causal Effects ◽

European Ancestry ◽

Genome Wide ◽

Function Impairment ◽

Genetic Instruments

Blood homocysteine level and related vitamin levels are associated with various health outcomes. We aimed to assess causal effects of blood homocysteine, folate, and cobalamin on kidney function in the general population by performing Mendelian randomization (MR) analysis. Genetic instruments for blood homocysteine, folate, and cobalamin levels were introduced from a previous genome-wide association (GWAS) meta-analysis of European individuals. Summary-level MR analysis was performed for the estimated glomerular filtration rate (eGFR) from the CKDGen consortium GWAS that included 567,460 European ancestry individuals. For replication, allele-score-based MR was performed with an independent U.K. Biobank cohort of 337,138 individuals of white British ancestry. In summary-level MR for the CKDGen data, high genetically predicted homocysteine levels were significantly associated with low eGFR (per 1 standard deviation, beta for eGFR change −0.95 (−1.21, −0.69) %), supported by pleiotropy-robust MR sensitivity analysis. Genetically predicted high folate levels were significantly associated with high eGFR change (0.86 (0.30, 1.42) %); however, causal estimates from cobalamin were nonsignificant (−0.11 (−0.33, 0.11) %). In the U.K. Biobank data, the results were consistently identified. Therefore, a high blood homocysteine level causally decreases eGFR. Future trials with appropriate homocysteine-lowering interventions may be helpful for the primary prevention of kidney function impairment.

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Genome-Wide Association Study of Circulating Interleukin 6 Levels Identifies Novel Loci

Human Molecular Genetics ◽

10.1093/hmg/ddab023 ◽

2021 ◽

Author(s):

Tarunveer S Ahluwalia ◽

Bram P Prins ◽

Mohammadreza Abdollahi ◽

Nicola J Armstrong ◽

Stella Aslibekyan ◽

...

Keyword(s):

Association Study ◽

Interleukin 6 ◽

Fixed Effects ◽

Complex Disease ◽

Genome Wide Association Study ◽

Heritability Estimate ◽

Genome Wide Association ◽

European Ancestry ◽

Genome Wide ◽

Increased Risk

Abstract Interleukin-6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery, and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed-effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on Chromosome (Chr) 2q14, (pcombined = 1.8 × 10−11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (pcombined = 1.5 × 10−10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (pcombined = 1.2 × 10−122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.

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Causal Effect of Obstructive Sleep Apnea on Atrial Fibrillation: A Mendelian Randomization Study

Journal of the American Heart Association ◽

10.1161/jaha.121.022560 ◽

2021 ◽

Author(s):

Weiqi Chen ◽

Xueli Cai ◽

Hongyi Yan ◽

Yuesong Pan

Keyword(s):

Atrial Fibrillation ◽

Obstructive Sleep Apnea ◽

Mendelian Randomization ◽

Causal Effect ◽

Genome Wide Association ◽

Sensitivity Analyses ◽

Genome Wide ◽

Inverse Variance ◽

Obstructive Sleep ◽

Increased Risk

Background Obstructive sleep apnea (OSA) has shown to be associated with an increased risk of atrial fibrillation in observational studies. Whether this association reflect causal effect is still unclear. The aim of this study was to evaluate the causal effect of OSA on atrial fibrillation. Methods and Results We used a 2‐sample Mendelian randomization (MR) method to evaluate the causal effect of OSA on atrial fibrillation. Summary data on genetic variant‐OSA association were obtained from a recently published genome‐wide association studies with up to 217 955 individuals and data on variant‐atrial fibrillation association from another genome‐wide association study with up to 1 030 836 individuals. Effect estimates were evaluated using inverse‐variance weighted method. Other MR analyses, including penalized inverse‐variance weighted, penalized robust inverse‐variance weighted, MR‐Egger, simple median, weighted median, weighted mode‐based estimate and Mendelian Randomization Pleiotropy Residual Sum and Outlier methods were performed in sensitivity analyses. The MR analyses in both the fixed‐effect and random‐effect inverse‐variance weighted models showed that genetically predicted OSA was associated with an increased risk of atrial fibrillation (odds ratio [OR], 1.21; 95% CI, 1.12–1.31, P <0.001; OR, 1.21; 95% CI, 1.11–1.32, P <0.001) using 5 single nucleotide polymorphisms as the instruments. MR‐Egger indicated no evidence of genetic pleiotropy (intercept, −0.014; 95% CI, −0.033 to 0.005, P =0.14). Results were robust using other MR methods in sensitivity analyses. Conclusions This MR analysis found that genetically predicted OSA had causal effect on an increased risk of atrial fibrillation.

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Genomic Characterization of Host Factors Related to SARS-CoV-2 Infection in People with Dementia and Control Populations: The GR@ACE/DEGESCO Study

Journal of Personalized Medicine ◽

10.3390/jpm11121318 ◽

2021 ◽

Vol 11 (12) ◽

pp. 1318

Author(s):

Itziar de Rojas ◽

Isabel Hernández ◽

Laura Montrreal ◽

Inés Quintela ◽

Miguel Calero ◽

...

Keyword(s):

Genome Wide Association Study ◽

Meta Analysis ◽

Fatal Outcome ◽

Disease Status ◽

Sensitivity Analyses ◽

People With Dementia ◽

Genome Wide ◽

Genomic Characterization ◽

Apoe Locus ◽

And Control

Emerging studies have suggested several chromosomal regions as potential host genetic factors involved in the susceptibility to SARS-CoV-2 infection and disease outcome. We nested a COVID-19 genome-wide association study using the GR@ACE/DEGESCO study, searching for susceptibility factors associated with COVID-19 disease. To this end, we compared 221 COVID-19 confirmed cases with 17,035 individuals in whom the COVID-19 disease status was unknown. Then, we performed a meta-analysis with the publicly available data from the COVID-19 Host Genetics Initiative. Because the APOE locus has been suggested as a potential modifier of COVID-19 disease, we added sensitivity analyses stratifying by dementia status or by disease severity. We confirmed the existence of the 3p21.31 region (LZTFL1, SLC6A20) implicated in the susceptibility to SARS-CoV-2 infection and TYK2 gene might be involved in COVID-19 severity. Nevertheless, no statistically significant association was observed in the COVID-19 fatal outcome or in the stratified analyses (dementia-only and non-dementia strata) for the APOE locus not supporting its involvement in SARS-CoV-2 pathobiology or COVID-19 prognosis.

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Periodontal disease increases the host susceptibility to COVID-19 and its severity: a Mendelian randomization study

Journal of Translational Medicine ◽

10.1186/s12967-021-03198-2 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Yi Wang ◽

Hui Deng ◽

Yihuai Pan ◽

Lijian Jin ◽

Rongdang Hu ◽

...

Keyword(s):

Periodontal Disease ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Host Susceptibility ◽

Sensitivity Analyses ◽

Nucleotide Polymorphisms ◽

Genome Wide ◽

Inverse Variance ◽

Weighted Median ◽

First Time

Abstract Background Emerging evidence shows that periodontal disease (PD) may increase the risk of Coronavirus disease 2019 (COVID-19) complications. Here, we undertook a two-sample Mendelian randomization (MR) study, and investigated for the first time the possible causal impact of PD on host susceptibility to COVID-19 and its severity. Methods Summary statistics of COVID-19 susceptibility and severity were retrieved from the COVID-19 Host Genetics Initiative and used as outcomes. Single nucleotide polymorphisms associated with PD in Genome-wide association study were included as exposure. Inverse-variance weighted (IVW) method was employed as the main approach to analyze the causal relationships between PD and COVID-19. Three additional methods were adopted, allowing the existence of horizontal pleiotropy, including MR-Egger regression, weighted median and weighted mode methods. Comprehensive sensitivity analyses were also conducted for estimating the robustness of the identified associations. Results The MR estimates showed that PD was significantly associated with significantly higher susceptibility to COVID-19 using IVW (OR = 1.024, P = 0.017, 95% CI 1.004–1.045) and weighted median method (OR = 1.029, P = 0.024, 95% CI 1.003–1.055). Furthermore, it revealed that PD was significantly linked to COVID-19 severity based on the comparison of hospitalization versus population controls (IVW, OR = 1.025, P = 0.039, 95% CI 1.001–1.049; weighted median, OR = 1.030, P = 0.027, 95% CI 1.003–1.058). No such association was observed in the cohort of highly severe cases confirmed versus those not hospitalized due to COVID-19. Conclusions We provide evidence on the possible causality of PD accounting for the susceptibility and severity of COVID-19, highlighting the importance of oral/periodontal healthcare for general wellbeing during the pandemic and beyond.

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The genome-wide supported CACNA1C gene polymorphisms and the risk of schizophrenia: an updated meta-analysis

10.21203/rs.2.24453/v2 ◽

2020 ◽

Author(s):

Yongping Liu ◽

Xue Wu ◽

Xi Xia ◽

Jun Yao ◽

Bao-jie Wang

Keyword(s):

Genome Wide Association Study ◽

Meta Analysis ◽

European Ancestry ◽

Bias Analysis ◽

Influence Model ◽

Asian Populations ◽

Model Study ◽

Genome Wide ◽

Meta Analyses ◽

European Populations

Abstract Background: The CACNA1C gene was defined as a risk gene for schizophrenia in a large genome-wide association study of European ancestry performed by the Psychiatric Genomics Consortium. Previous meta-analyses focused on the association between the CACNA1C gene rs1006737 and schizophrenia. The present study focused on whether there was a racial difference in the effect of the CACNA1C gene rs1006737 on schizophrenia. rs2007044 and rs4765905 were analyzed for their effect on the risk of schizophrenia. Methods: Pooled, subgroup, sensitivity, and publication bias analysis were conducted.Results: A total of 18 studies met the inclusion criteria, including fourteen rs1006737 studies (15,213 cases, 19,412 controls), three rs2007044 studies (6,007 cases, 6,518 controls), and two rs4765905 studies (2,435 cases, 2,639 controls). An allele model study also related rs2007044 and rs4765905 to schizophrenia. The overall meta-analysis for rs1006737, which included the allele contrast, dominant, recessive, codominance, and complete overdominance models, showed significant differences between rs1006737 and schizophrenia. However, the race-based subgroup analysis for rs1006737 found that the genotypes GG and GG + GA were only protective factors for schizophrenia in European populations. In contrast, the rs1006737 GA genotype only reduced the risk of schizophrenia in Asian populations. Conclusions: Rs1006737, rs2007044, and rs4765905 of the CACNA1C gene were associated with susceptibility to schizophrenia. However, the influence model for rs1006737 on schizophrenia in Asian and European populations demonstrated both similarities and differences between the two populations.

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