scholarly journals Genetic and phenotypic analysis of the causal relationship between aging and COVID-19

2021 ◽  
Vol 1 (1) ◽  
Author(s):  
Kejun Ying ◽  
Ranran Zhai ◽  
Timothy V. Pyrkov ◽  
Anastasia V. Shindyapina ◽  
Marco Mariotti ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Immune Cell ◽  
Mendelian Randomization ◽  
Biological Age ◽  
Phenotypic Analysis ◽  
Mendelian Randomization Analysis ◽  
Age Related ◽  
Immune System Development ◽  
Increased Risk ◽  
Randomization Analysis

Abstract Background Epidemiological studies revealed that the elderly and those with comorbidities are most affected by COVID-19, but it is important to investigate shared genetic mechanisms between COVID-19 risk and aging. Methods We conducted a multi-instrument Mendelian Randomization analysis of multiple lifespan-related traits and COVID-19. Aging clock models were applied to the subjects with different COVID-19 conditions in the UK-Biobank cohort. We performed a bivariate genomic scan for age-related COVID-19 and Mendelian Randomization analysis of 389 immune cell traits to investigate their effect on lifespan and COVID-19 risk. Results We show that the genetic variation that supports longer life is significantly associated with the lower risk of COVID-19 infection and hospitalization. The odds ratio is 0.31 (P = 9.7 × 10−6) and 0.46 (P = 3.3 × 10−4), respectively, per additional 10 years of life. We detect an association between biological age acceleration and future incidence and severity of COVID-19 infection. Genetic profiling of age-related COVID-19 infection indicates key contributions of Notch signaling and immune system development. We reveal a negative correlation between the effects of immune cell traits on lifespan and COVID-19 risk. We find that lower B-cell CD19 levels are indicative of an increased risk of COVID-19 and decreased life expectancy, which is further validated by COVID-19 clinical data. Conclusions Our analysis suggests that the factors that accelerate aging lead to an increased COVID-19 risk and point to the importance of Notch signaling and B cells in both. Interventions that target these factors to reduce biological age may reduce the risk of COVID-19.

scholarly journals Genetic and Phenotypic Evidence for the Causal Relationship Between Aging and COVID-19

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 332-332
Author(s):  
Ranran Zhai ◽  
Timothy Pyrkov ◽  
Anastasia Shindyapina ◽  
Marco Mariotti ◽  
Peter Fedichev ◽  
...  
Keyword(s):  
Immune Cell ◽  
The Elderly ◽  
Significant Negative Correlation ◽  
Epidemiological Studies ◽  
Notch Signaling Pathway ◽  
Biological Age ◽  
Risk Of Death ◽  
Age Related ◽  
Increased Risk ◽  
Clock Models

Abstract Epidemiological studies revealed that the elderly and those with comorbidities are most susceptible to COVID-19. To understand how genetics affects the risk of COVID-19, we conducted a multi-instrument Mendelian Randomization (MR) analysis and found that the genetic variation that supports a longer life is significantly associated with the lower risk of COVID-19 infection, as well as being hospitalized after infected. The odds ratio is 0.31 (P = 9.7e-6) and 0.46 (P = 3.3e-4), respectively, per additional 10 years of life. We further applied aging clock models and detected an association between biological age acceleration and future incidence and severity of COVID-19 infection for all subjects and individuals free of chronic disease. Biological age acceleration was also significantly associated with the risk of death in COVID-19 patients. A bivariate genomic scan for age-related COVID-19 infection identified a key contribution of the Notch signaling pathway and immune system. Finally, we performed MR using 389 immune cell traits as exposure and observed a significant negative correlation between their effect on lifespan and COVID-19 risk, especially for B cell-related traits. More specifically, we discovered the lower CD19 level on B cells indicates an increased risk of COVID-19 and potentially decreases the lifespan expectancy, which is further validated in clinical data from COVID-19 patients. Our analysis suggests that the factors that accelerate aging and limit lifespan cause an increased COVID-19 risk. Thus, the interventions target these factors (e.g., reduce biological age), after further validation, may have the opportunity to reduce the risk of COVID-19.

scholarly journals Sleep Duration and Stroke

Stroke ◽  
2020 ◽  
Vol 51 (11) ◽  
pp. 3279-3285
Author(s):  
Olga E. Titova ◽  
Karl Michaëlsson ◽  
Susanna C. Larsson
Keyword(s):  
Ischemic Stroke ◽  
Intracerebral Hemorrhage ◽  
Prospective Study ◽  
Sleep Duration ◽  
Mendelian Randomization ◽  
Short Sleep ◽  
Mendelian Randomization Analysis ◽  
Increased Risk ◽  
Long Sleep ◽  
Randomization Analysis

Background and Purpose: Studies of sleep duration in relation to specific types of stroke are scarce. Moreover, the results are inconclusive and causality remains unclear. Our objective was to investigate whether sleep duration is associated with risk of stroke and its types using observational and Mendelian randomization designs. Methods: The prospective study included 79 881 women and men (45–79 years of age) who were followed up for incident stroke or death over a mean follow-up of 14.6 years (1 164 646 person-years) through linkage to Swedish Registers. For the Mendelian randomization study, single-nucleotide polymorphisms associated with sleep duration were identified from a genome-wide association study. Summarized data for genetic associations with stroke were obtained from publicly available data of the MEGASTROKE and the International Stroke Genetics Consortia. Results: Compared with normal sleep duration, long sleep (≥9 hours per day) was associated with increased risk of total and ischemic stroke (hazard ratios [95% CI], 1.12 [1.03–1.22] and 1.14 [1.03–1.24], respectively), whereas short sleep (<7 h/d) was linked to higher risk of intracerebral hemorrhage (hazard ratio [95% CI], 1.21 [1.03–1.41]). The 2-sample Mendelian randomization analysis supported no causal association of short or long sleep duration with ischemic stroke as a whole. Conclusions: In a prospective study, long sleep duration was associated with increased risk of total and ischemic stroke, whereas short sleep was linked to increased risk of intracerebral hemorrhage. However, the Mendelian randomization analysis did not show a significant detrimental effect of short or long sleep duration on the risk of total stroke or stroke types.

scholarly journals Causal Association of Trauma With Subsequent Psychiatric Disorder: A Mendelian Randomization Study

2021 ◽  
Author(s):  
Dongqing Gu ◽  
Shan Ou ◽  
Guodong Liu
Keyword(s):  
Psychiatric Disorder ◽  
Mood Disorder ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Causal Association ◽  
Post Traumatic Stress ◽  
Mendelian Randomization Analysis ◽  
Increased Risk ◽  
Randomization Analysis

Abstract Objective Trauma has been proposed as a risk factor for the development of psychiatric disorder. This study aimed to determine the causal association between them. Methods Two-sample Mendelian randomization analyses were performed to estimate the causal association between trauma and psychiatric disorder. We obtained summary-level data for genetic variants associated with trauma and the corresponding association with psychiatric disorder from previous genome-wide association studies, and inverse variance weighted was used as the main method in our Mendelian randomization analysis. Results Genetically predisposed trauma was associated with an increased risk of psychiatric disorder (odds ratio [OR] = 1.02, 95% confidence interval [CI], 1.01–1.02,), mood disorder (OR = 1.01, 95% CI, 1.00-1.01) and depression (OR = 1.02, 95% CI, 1.01–1.02) in UK Biobank, as well as increased risk of mood disorder (OR = 1.23, 95% CI, 1.03–1.48), depression (OR = 1.10, 95% CI, 1.04–1.17), bipolar disorder (OR = 1.24, 95% CI, 1.04–1.49) and schizophrenia (OR = 1.47, 95% CI, 1.21–1.78) in data source from MR Base. However, Mendelian randomization evidence did not support an association between trauma and risk of post-traumatic stress disorder, anxiety disorder, sleep disorder, and eating disorder. Conclusions Findings from our Mendelian randomization analysis suggested that trauma might be causally associated with an increased risk of some common psychiatric disorder such as depression.

scholarly journals 25-Hydroxyvitamin D and Risk of Osteoporotic Fractures: Mendelian Randomization Analysis in 2 Large Population-Based Cohorts

2020 ◽  
Vol 66 (5) ◽  
pp. 676-685 ◽  
Author(s):  
Yunus Çolak ◽  
Shoaib Afzal ◽  
Børge G Nordestgaard
Keyword(s):  
Vitamin D ◽  
Mendelian Randomization ◽  
Osteoporotic Fractures ◽  
Population Based ◽  
Hydroxyvitamin D ◽  
Mendelian Randomization Analysis ◽  
Hazard Ratios ◽  
Increased Risk ◽  
25 Hydroxyvitamin D ◽  
Randomization Analysis

Abstract Background Whether low plasma 25-hydroxyvitamin D concentrations cause osteoporotic fractures is unclear. We tested the hypothesis that low plasma 25-hydroxyvitamin D concentrations are associated with increased risk of osteoporotic fractures using a Mendelian randomization analysis. Methods We genotyped 116 335 randomly chosen white Danish persons aged 20–100 years in 2 population-based cohort studies for plasma 25-hydroxyvitamin D decreasing genotypes in CYP2R1 (rs117913124 and rs12794714), DHCR7 (rs7944926 and rs11234027), GEMIN2 (rs2277458), and HAL (rs3819817); 35 833 had information on plasma 25-hydroxyvitamin D. We assessed risk of total, osteoporotic, and anatomically localized fractures from 1981 through 2017. Information on fractures and vital status was obtained from nationwide registries. Results During up to 36 years of follow-up, we observed 17 820 total fractures, 10 861 osteoporotic fractures, and 3472 fractures of hip or femur. Compared with individuals with 25-hydroxyvitamin D ≥ 50nmol/L, multivariable adjusted hazard ratios (95% CIs) for total fractures were 1.03 (0.97–1.09) for individuals with 25–49.9 nmol/L, 1.19 (1.10–1.28) for individuals with 12.5–24.9 nmol/L, and 1.39 (1.21–1.60) for individuals with 25-hydroxyvitamin D &lt; 12.5 nmol/L. Corresponding hazard ratios were 1.07 (1.00–1.15), 1.25 (1.13–1.37), and 1.49 (1.25–1.77) for osteoporotic fractures and 1.09 (0.98–1.22), 1.37 (1.18–1.57), and 1.41 (1.09–1.81) for fractures of hip or femur, respectively. Hazard ratios per 1 increase in vitamin D allele score, corresponding to 3.0% (approximately 1.6 nmol/L) lower 25-hydroxyvitamin D concentrations, were 0.99 (0.98–1.00) for total fractures, 0.99 (0.97–1.00) for osteoporotic fractures, and 0.98 (0.95–1.00) for fractures of hip or femur. Conclusions Low plasma 25-hydroxyvitamin D concentrations were associated with osteoporotic fractures; however, Mendelian randomization analysis provided no evidence supporting a causal role for vitamin D in the risk for osteoporotic fractures.

scholarly journals Association between systemic lupus erythematosus and cancer: findings from cohort studies and Mendelian randomization analysis

2021 ◽  
Author(s):  
Dongqing Gu ◽  
Mingshuang Tang ◽  
Huijie Cui ◽  
Min Zhang ◽  
Yutong Wang ◽  
...  
Keyword(s):  
Cohort Studies ◽  
Lupus Erythematosus ◽  
Odds Ratio ◽  
Observational Studies ◽  
Mendelian Randomization ◽  
Meta Analysis ◽  
European Ancestry ◽  
Mendelian Randomization Analysis ◽  
Increased Risk ◽  
Randomization Analysis

Abstract Background Observational studies suggested that systemic lupus erythematosus (SLE) was associated with an increased risk of cancer, however, the causal effect remains unclear. We aim to determine the causality between SLE and cancer using a meta-analysis and Mendelian randomization (MR) approach. Methods A systematic search was conducted using PubMed to identify cohort studies published before January 21, 2021. Meta-analysis was performed to calculate relative risk (RR) and corresponding 95% confidence intervals (CI), and the potentially causal relationships identified by observational studies were further validated using two-sample Mendelian randomization. Results Through meta-analysis of 43 cohort studies involving 231,499 patients, we observed an increased overall cancer risk among SLE patients (RR = 1.62, 95% CI, 1.47–1.79). Site-specific analysis suggested that SLE patients were associated with an increased risk of 17 cancers. Mendelian randomization analysis indicated that genetically predisposed SLE was causally associated with an increased risk of lymphoma (odds ratio = 1.0004, 95% CI, 1.0001–1.0007, P = 0.0035), whereas a decreased risk of bladder cancer (odds ratio = 0.9996, 95% CI, 0.9994–0.9998, P = 0.00004) in European ancestry. However, no relationship was observed between genetically predisposed SLE and risk of colon, pancreatic, lung, cervical and Non-melanoma skin cancer in European ancestry, liver cancer and lung cancer in Asian ancestry. Conclusions Findings from meta-analysis and Mendelian randomization analysis suggested that SLE might be causally associated with an increased risk of lymphoma. However, inconsistent results were observed between SLE and risk of bladder cancer.

scholarly journals Genetic and Phenotypic Evidence for the Causal Relationship Between Aging and COVID-19

2020 ◽  
Author(s):  
Kejun Ying ◽  
Ranran Zhai ◽  
Timothy V. Pyrkov ◽  
Marco Mariotti ◽  
Peter O. Fedichev ◽  
...  
Keyword(s):  
Mendelian Randomization ◽  
The Elderly ◽  
Epidemiological Studies ◽  
Notch Signaling Pathway ◽  
Biological Age ◽  
Risk Of Death ◽  
Age Related ◽  
Log Odds ◽  
Clock Models ◽  
Randomization Analysis

AbstractEpidemiological studies revealed that the elderly and those with co-morbidities are most susceptible to COVID-19. To understand how genetics affects the risk of COVID-19, we conducted a multi-instrument Mendelian randomization analysis and found that the genetic variation that supports a longer life is significantly associated with the lower risk of COVID-19 infection. The odds ratio is 0.31 (95% CI: 0.18 to 0.52; P = 9.7× 10−6) per additional 10 years of life, and 0.53 (95% CI: 0.43 to 0.65; P = 2.3 × 10−9) per unit higher log odds of surviving to the 90th percentile. On the other hand, there was no association between COVID-19 susceptibility and healthspan (the lifespan free of the top seven age-related morbidities). We further applied aging clock models and detected an association between biological age acceleration and future incidence and severity of COVID-19 infection for all subjects as well as for individuals free of chronic disease. Biological age acceleration was also significantly associated with the risk of death in COVID-19 patients. Finally, a bivariate genomic scan for age-related COVID-19 infection identified a key contribution of the Notch signaling pathway. Our analysis suggests that Notch2 expression is associated with a higher risk of COVID-19 infection, providing a druggable target. More generally, interventions that reduce biological age have the opportunity to reduce the risk of COVID-19.

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