scholarly journals Cleft lip/palate and educational attainment: cause, consequence or correlation? A Mendelian randomization study

2020 ◽  
Vol 49 (4) ◽  
pp. 1282-1293 ◽  
Author(s):  
Christina Dardani ◽  
Laurence J Howe ◽  
Nandita Mukhopadhyay ◽  
Evie Stergiakouli ◽  
Yvonne Wren ◽  
...  
Keyword(s):  
Educational Attainment ◽  
Genetic Correlation ◽  
Cleft Lip ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Meta Analysis ◽  
Genetic Liability ◽  
Performance Factors ◽  
A Genome ◽  
Cleft Lip Palate

Abstract Background Previous studies have found that children born with a non-syndromic orofacial cleft have lower-than-average educational attainment. Differences could be due to a genetic predisposition to low intelligence and academic performance, factors arising due to the cleft phenotype (such as social stigmatization, impaired speech/language development) or confounding by the prenatal environment. A clearer understanding of this mechanism will inform interventions to improve educational attainment in individuals born with a cleft, which could substantially improve their quality of life. We assessed evidence for the hypothesis that common variant genetic liability to non-syndromic cleft lip with or without cleft palate (nsCL/P) influences educational attainment. Methods We performed a genome-wide association study (GWAS) meta-analysis of nsCL/P with 1692 nsCL/P cases and 4259 parental and unrelated controls. Using GWAS summary statistics, we performed Linkage Disequilibrium (LD)-score regression to estimate the genetic correlation between nsCL/P, educational attainment (GWAS n = 766 345) and intelligence (GWAS n = 257 828). We used two-sample Mendelian randomization to evaluate the causal effects of genetic liability to nsCL/P on educational attainment and intelligence. Results There was limited evidence for shared genetic aetiology or causal relationships between nsCL/P and educational attainment [genetic correlation (rg) −0.05, 95% confidence interval (CI) −0.12 to 0.01, P 0.13; MR estimate (βMR) −0.002, 95% CI −0.009 to 0.006, P 0.679) or intelligence (rg −0.04, 95% CI −0.13 to 0.04, P 0.34; βMR −0.009, 95% CI −0.02 to 0.002, P 0.11). Conclusions Common variants are unlikely to predispose individuals born with nsCL/P to low educational attainment or intelligence. This is an important first step towards understanding the aetiology of low educational attainment in this group.

EXPRESS: Effect of genetic liability to visceral adiposity on stroke and its subtypes: a Mendelian randomization study

2021 ◽  
pp. 174749302110062
Author(s):  
Bin Yan ◽  
Jian Yang ◽  
Li Qian ◽  
Fengjie Gao ◽  
Ling Bai ◽  
...  
Keyword(s):  
Sensitivity Analysis ◽  
Ischemic Stroke ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Visceral Adiposity ◽  
Large Artery ◽  
Nucleotide Polymorphisms ◽  
Genetic Liability ◽  
A Genome ◽  
Increased Risk

Background: Observational studies have found an association between visceral adiposity and stroke. Aims: The purpose of this study was to investigate the role and genetic effect of visceral adipose tissue (VAT) accumulation on stroke and its subtypes. Methods: In this two-sample Mendelian randomization (MR) study, genetic variants (221 single nucleotide polymorphisms; P<5×10-8) using as instrumental variables for MR analysis was obtained from a genome-wide association study (GWAS) of VAT. The outcome datasets for stroke and its subtypes were obtained from the MEGASTROKE consortium (up to 67,162 cases and 453,702 controls). MR standard analysis (inverse variance weighted method) was conducted to investigate the effect of genetic liability to visceral adiposity on stroke and its subtypes. Sensitivity analysis (MR-Egger, weighted median, MR-PRESSO) were also utilized to assess horizontal pleiotropy and remove outliers. Multi-variable MR analysis was employed to adjust potential confounders. Results: In the standard MR analysis, genetically determined visceral adiposity (per 1 SD) was significantly associated with a higher risk of stroke (odds ratio [OR] 1.30; 95% confidence interval [CI] 1.21-1.41, P=1.48×10-11), ischemic stroke (OR 1.30; 95% CI 1.20-1.41, P=4.01×10-10), and large artery stroke (OR 1.49; 95% CI 1.22-1.83, P=1.16×10-4). The significant association was also found in sensitivity analysis and multi-variable MR analysis. Conclusions: Genetic liability to visceral adiposity was significantly associated with an increased risk of stroke, ischemic stroke, and large artery stroke. The effect of genetic susceptibility to visceral adiposity on the stroke warrants further investigation.

scholarly journals Mendelian randomization identifies folliculin expression as a mediator of diabetic retinopathy

2020 ◽  
Author(s):  
Andrew D. Skol ◽  
Segun C. Jung ◽  
Ana Marija Sokovic ◽  
Siquan Chen ◽  
Sarah Fazal ◽  
...  
Keyword(s):  
Gene Expression ◽  
Diabetic Retinopathy ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Meta Analysis ◽  
Susceptibility Gene ◽  
Glucose Response ◽  
Aberrant Expression ◽  
Genome Wide ◽  
A Genome

AbstractThe goal of the study was to identify genes whose aberrant expression can contribute to diabetic retinopathy. We determined differential gene expression in response to high glucose in lymphoblastoid cell lines derived from matched individuals with type 1 diabetes (T1D) with and without retinopathy. Those genes exhibiting the largest difference in glucose response between individuals with diabetes with and without retinopathy were assessed for association to diabetic retinopathy utilizing genotype data from a genome-wide association study meta-analysis. All genetic variants associated with gene expression (expression Quantitative Trait Loci, eQTLs) of the glucose response genes were tested for association with diabetic retinopathy. We detected an enrichment of the eQTLs from the glucose response genes among small association p-values and identified folliculin (FLCN) as a susceptibility gene for diabetic retinopathy. We show that expression of FLCN in response to glucose was greater in individuals with diabetic retinopathy compared to individuals with diabetes without retinopathy. Three large, independent cohorts of individuals with diabetes revealed an association of FLCN eQTLs to diabetic retinopathy. Mendelian randomization further confirmed a direct positive effect of increased FLCN expression on retinopathy in individuals with diabetes. Together, our studies integrating genetic association and gene expression implicate FLCN as a disease gene for diabetic retinopathy.

scholarly journals Inflammatory Cytokines and Risk of Ischemic Stroke: A Mendelian Randomization Study

2022 ◽  
Vol 12 ◽  
Author(s):  
Yalan Li ◽  
Jun Lu ◽  
Jie Wang ◽  
Peizhi Deng ◽  
Changjiang Meng ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Inflammatory Cytokines ◽  
Large Scale ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Meta Analysis ◽  
Outcome Data ◽  
Sensitivity Analyses ◽  
A Genome

Background: Observational studies have revealed the association between some inflammatory cytokines and the occurrence of ischemic stroke, but the causal relationships remain unclear.Methods: We conducted a two-sample Mendelian randomization (MR) analysis to assess the causal effects of thirty inflammatory cytokines and the risk of ischemic stroke. For exposure data, we collected genetic variants associated with inflammatory cytokines as instrumental variables (IVs) from a genome-wide association study (GWAS) meta-analysis from Finland (sample size up to 8,293). For the outcome data, we collected summary data of ischemic stroke from a large-scale GWAS meta-analysis involved 17 studies (34,217 cases and 406,111 controls). We further performed a series of sensitivity analyses as validation of primary MR results.Results: According to the primary MR estimations and further sensitivity analyses, we established one robust association after Bonferroni correction: the odds ratio (95% CI) per unit change in genetically increased IL-4 was 0.84 (0.89–0.95) for ischemic stroke. The chemokine MCP3 showed a nominally significant association with ischemic stroke risk (OR: 0.93, 95% CI: 0.88–0.99, unadjusted p &lt; 0.05). There was no evidence of a causal effect of other inflammatory cytokines and the risk of ischemic stroke.Conclusions: Our study suggested that genetically increased IL-4 levels showed a protective effect on the risk of ischemic stroke, which provides important new insights into the potential therapeutic target for preventing ischemic stroke.

scholarly journals Periodontitis and pulmonary function: a Mendelian randomization study

2021 ◽  
Author(s):  
Sebastian-Edgar Baumeister ◽  
Michael Nolde ◽  
Birte Holtfreter ◽  
Hansjörg Baurecht ◽  
Sven Gläser ◽  
...  
Keyword(s):  
Pulmonary Function ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Forced Expiratory Volume ◽  
Sensitivity Analyses ◽  
Observational Research ◽  
Nucleotide Polymorphisms ◽  
Genetic Liability ◽  
A Genome ◽  
The Uk

Abstract Objectives Observational research suggests that periodontitis affects pulmonary function; however, observational studies are subject to confounding and reverse causation, making causal inference and the direction of these associations difficult. We used Mendelian randomization (MR) to assess the potential causal association between genetic liability to periodontitis and pulmonary function. Materials and methods We used six single-nucleotide polymorphisms (SNPs) associated with periodontitis (P < 5 × 10−6) from a genome-wide association study (GWAS) of 17,353 European descent periodontitis cases and 28,210 controls from the GeneLifestyle Interactions in Dental Endpoints consortium and the UK Biobank, and related these to SNPs from a lung function GWAS including 79,055 study participants of the SpiroMeta Consortium. Results MR analysis suggested no effect of periodontitis on the ratio of forced expiratory volume in one second to lower forced vital capacity (standard deviation increment in outcome per doubling of the odds of the exposure (95% confidence interval) =  − 0.004 (− 0.028; 0.020)). Replication analysis using genetic instruments from two different GWAS and sensitivity analyses to address potential pleiotropy led to no substantial changes in estimates. Conclusions Collectively, these findings do not support a relationship between genetic liability for periodontitis and pulmonary function. Clinical relevance Periodontitis does not seem to be a risk factor for worsening of pulmonary function.

scholarly journals Cleft lip/palate and educational attainment: cause, consequence, or correlation? A Mendelian randomization study

2018 ◽  
Author(s):  
Christina Dardani ◽  
Laurence J Howe ◽  
Evie Stergiakouli ◽  
Yvonne Wren ◽  
Kerry Humphries ◽  
...  
Keyword(s):  
Educational Attainment ◽  
Genetic Predisposition ◽  
Genetic Variants ◽  
Cleft Lip ◽  
Mendelian Randomization ◽  
Common Variant ◽  
Genome Wide Association Studies ◽  
Genetic Liability ◽  
Common Genetic Variants ◽  
Family Level

AbstractImportancePrevious studies have found that children born with a non-syndromic form of cleft lip and/or palate have lower-than-average educational attainment. These differences could be due to a genetic predisposition to low intelligence and academic performance, factors arising due to the cleft phenotype (such as school absence, social stigmatization and impaired speech and language development), or confounding by the prenatal environment. A clearer understanding of this mechanism will inform development of interventions to improve educational attainment in individuals born with a cleft, which could have wide-ranging knock-on effects on their quality of life.ObjectiveTo assess evidence for the hypothesis that common variant genetic liability to non-syndromic cleft lip with or without cleft palate (nsCL/P) influences educational attainment.DesignUsing summary data from genome-wide association studies (GWAS), we performed Linkage Disequilibrium (LD)-score regression and two-sample Mendelian randomization to evaluate the relationship between genetic liability to nsCL/P (GWAS n=3,987) and educational attainment (GWAS n=766,345), and intelligence (GWAS n=257,828).ResultsThere was little evidence for shared genetic aetiology between nsCL/P and educational attainment (rg −0.03, 95% CI −0.14 to 0.08, P 0.58; βMR 0.002, 95% CI −0.001 to 0.005, P 0.417) or intelligence (rg −0.01, 95% CI −0.12 to 0.10, P 0.85; βMR 0.002, 95% CI −0.010 to 0.014, P 0.669).Conclusions and relevanceCommon genetic variants are unlikely to predispose individuals born with nsCL/P to low educational attainment or intelligence. This information will help tailor clinical-, school-, social- and family-level interventions to improve educational attainment in this group.Key PointsQuestionDo children born with a non-syndromic cleft lip with or without palate (nsCL/P) have lower-than average academic achievement because of an underlying genetic predisposition to educational attainment and/or intelligence?FindingsThere was little evidence for shared common variant genetic correlation between nsCL/P, educational attainment and intelligence.MeaningCommon genetic variants are unlikely to predispose individuals born with nsCL/P to low educational attainment or intelligence. This information will help tailor clinical-, school-, social- and family-level interventions to improve educational attainment in this group.

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

Rheumatology ◽  
2019 ◽  
Vol 59 (5) ◽  
pp. 940-947 ◽  
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.

scholarly journals Mendelian randomization study shows no causal effects of serum urate levels on the risk of MS

2020 ◽  
Vol 8 (1) ◽  
pp. e920
Author(s):  
Adil Harroud ◽  
J. Brent Richards ◽  
Sergio E. Baranzini
Keyword(s):  
Large Scale ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Meta Analysis ◽  
Serum Urate ◽  
Sensitivity Analyses ◽  
Data Sets ◽  
A Genome ◽  
Mr Study

ObjectiveTo examine whether lifelong genetically increased serum urate levels, a potent antioxidant, contribute to MS susceptibility using Mendelian randomization (MR).MethodsThis 2-sample MR study included 25 independent genetic variants strongly associated with serum urate levels in a genome-wide association study meta-analysis of 140,949 individuals. Effects on the risk of MS were assessed with summary statistics from 3 large-scale MS genetic data sets totaling 61,667 MS cases and 86,806 controls from the International MS Genetic Consortium. Multiple sensitivity analyses were performed to evaluate the assumptions of MR and remove potentially pleiotropic variants.ResultsUsing inverse-variance weighted MR, we found no evidence for a causal effect of serum urate level on the risk of MS in any of the cohorts (MS1: OR 0.99 per each mg/dL unit increase in urate, 95% CI 0.89–1.08, p = 0.76; MS2: OR = 0.99, 95% CI 0.89–1.11, p = 0.90; MS3: OR = 1.00, 95% CI 0.98–1.2, p = 0.91). Pleiotropy robust MR methods yielded consistent estimates.ConclusionThis MR study does not support a clinically relevant causal effect of serum urate levels on the risk of MS.

scholarly journals DNA methylation mediates genetic liability to non-syndromic cleft lip/palate

2018 ◽  
Author(s):  
Laurence J Howe ◽  
Tom G Richardson ◽  
Ryan Arathimos ◽  
Lucas Alvizi ◽  
Maria-Rita Passos-Bueno ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Genetic Risk ◽  
Cleft Lip ◽  
Genome Wide Association Study ◽  
Complex Trait ◽  
Methylation Data ◽  
Protein Coding ◽  
Genetic Liability ◽  
Cleft Lip Palate

AbstractBackgroundNon-syndromic cleft lip/palate (nsCL/P) is a complex trait with genetic and environmental risk factors. Around 40 distinct genetic risk loci have been identified for nsCL/P, but many reside in non-protein-coding regions with an unclear function. We hypothesised that one possibility is that the genetic risk variants influence susceptibility to nsCL/P through gene regulation pathways, such as those involving DNA methylation.MethodsUsing nsCL/P Genome-wide association study summary data and methylation data from four studies, we used Mendelian randomization and joint likelihood mapping to identify putative loci where genetic liability to nsCL/P may be mediated by variation in DNA methylation in blood.ResultsThere was evidence at three independent loci, VAX1 (10q25.3), LOC146880 (17q23.3) and NTN1 (17p13.1), that liability to nsCL/P and variation in DNA methylation might be driven by the same genetic variant. Follow up analyses using DNA methylation data, derived from lip and palate tissue, and gene expression catalogues provided further insight into possible biological mechanisms.ConclusionsGenetic variation may increase liability to nsCL/P by influencing DNA methylation and gene expression at VAX1, LOC146880 and NTN1.

Physical activity and the risk of rheumatoid arthritis: evidence from meta-analysis and Mendelian randomization

2021 ◽  
Author(s):  
Lingling Sun ◽  
Jiahao Zhu ◽  
Yuxiao Ling ◽  
Shuai Mi ◽  
Yasong Li ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Physical Activity ◽  
Observational Studies ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Meta Analysis ◽  
Convincing Evidence ◽  
A Genome ◽  
Summary Relative Risk ◽  
Meta Analyses

Abstract Background There is very little information about the association between physical activity (PA) and the risk of rheumatoid arthritis (RA). The purpose of this study is to understand the effect of PA on subsequent risk of developing RA. Methods A literature search was performed in PubMed and Web of Science up to 19 September 2020. Observational studies examining associations between PA and the RA development were identified. Categorical and dose–response meta-analyses were both performed. Then two-sample Mendelian randomization (MR) analysis was conducted to interrogate the causal relationship by utilizing genetic instruments identified from a genome-wide association study of self-reported and accelerometer-based PA traits. Results Four eligible studies were included in the meta-analyses, involving 4213 RA cases among 255 365 participants. The summary relative risk (RR) of RA risk was 0.79 [95% confidence interval (CI): 0.72, 0.87] for the highest vs the lowest PA, and 0.85 (95% CI: 0.79, 0.92) for PA vs inactivity/occasional PA. However, we found no convincing evidence supporting a causal role of genetically predicted accelerometer-measured PA [odds ratio (OR): 0.97; 95% CI: 0.88, 1.08 per 1-SD unit increment], genetically predicted moderate-to-vigorous PA (OR: 1.08; 95% CI: 0.49, 2.39 per 1-SD unit increment) or genetically predicted vigorous PA ≥3 days/week (OR: 2.63; 95% CI: 0.05, 130.96) with RA risk. Conclusions The meta-analyses of the observational studies indicated that higher PA levels correlate with reduced risk of RA. In contrast to meta-analyses, the MR analyses reported here suggested PA may not help to prevent RA.

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