scholarly journals Investigating the causal effect of maternal vitamin B12 and folate levels on offspring birthweight

2020 ◽  
Author(s):  
Gunn-Helen Moen ◽  
Robin N Beaumont ◽  
Christine Sommer ◽  
Beverley M. Shields ◽  
Deborah A Lawlor ◽  
...  
Keyword(s):  
Vitamin B12 ◽  
Genetic Variants ◽  
Observational Studies ◽  
Genome Wide Association Study ◽  
Causal Effect ◽  
Meta Analysis ◽  
Serum Vitamin ◽  
Genetic Effects ◽  
Sensitivity Analyses ◽  
A Genome

AbstractLower maternal serum vitamin B12 (B12) and folate levels have been associated with lower offspring birthweight in observational studies. The aim of this study was to investigate whether this relationship is causal.We performed two-sample Mendelian Randomization (MR) using summary data on associations between genotype-B12 (10 genetic variants) or genotype-folate (4 genetic variants) levels from a genome-wide association study of 45,576 individuals (sample 1) and maternal-specific genetic effects on offspring birthweight from the latest EGG consortium meta-analysis with 297,356 individuals reporting their own birthweight and 210,248 women reporting their offspring’s birthweight (sample 2). To investigate the effect of offspring’s own B12 or folate levels on their own birthweight, we performed two-sample MR using the fetal-specific genetic effects from the latest EGG consortium meta-analysis. We used the inverse variance weighted method, and sensitivity analyses to account for pleiotropy, in addition to sensitivity analyses excluding a potentially pleiotropic variant in the FUT2 gene for B12.We did not find evidence for a causal effect of maternal B12 on offspring birthweight, nor evidence for an effect of offspring B12 on their own birthweight using the fetal-specific genetic effect. The results were consistent across the different methods and in sensitivity analyses excluding the FUT2 variant. We found a positive effect of maternal folate on offspring birthweight (0.146 [0.065, 0.227], which corresponds to an increase in birthweight of 71g per 1SD higher folate). We found some evidence for a small inverse effect of fetal folate on their own birthweight (−0.051 [−0.100, −0.003]).In conclusion, our results are consistent with evidence from randomized controlled trials that increased maternal folate levels increase offspring birthweight. We did not find evidence for a causal effect of B12 on offspring birthweight, suggesting previous observational studies may have been due to confounding.

scholarly journals Investigating the causal effect of maternal vitamin B12 and folate levels on offspring birthweight

2020 ◽  
Author(s):  
Gunn-Helen Moen ◽  
Robin N Beaumont ◽  
Niels Grarup ◽  
Christine Sommer ◽  
Beverley M Shields ◽  
...  
Keyword(s):  
Vitamin B12 ◽  
Genetic Variants ◽  
Observational Studies ◽  
Genome Wide Association Study ◽  
Causal Effect ◽  
Meta Analysis ◽  
Serum Vitamin ◽  
Maternal Serum ◽  
Sensitivity Analyses ◽  
A Genome

Abstract Background Lower maternal serum vitamin B12 (B12) and folate levels have been associated with lower offspring birthweight, in observational studies. The aim of this study was to investigate whether this relationship is causal. Methods We performed two-sample Mendelian randomization (MR) using summary data on associations between genotype-B12 (10 genetic variants) or genotype-folate (four genetic variants) levels from: a genome-wide association study of 45 576 individuals (sample 1); and both maternal- and fetal-specific genetic effects on offspring birthweight from the latest Early Growth Genetics consortium meta-analysis with 297 356 individuals reporting their own birthweight and 210 248 women reporting their offspring's birthweight (sample 2). We used the inverse variance weighted method, and sensitivity analyses to account for pleiotropy, in addition to excluding a potentially pleiotropic variant in the FUT2 gene for B12 levels. Results We did not find evidence for a causal effect of maternal or fetal B12 levels on offspring birthweight. The results were consistent across the different methods. We found a positive causal effect of maternal folate levels on offspring birthweight [0.146 (0.065, 0.227), which corresponds to an increase in birthweight of 71 g per 1 standard deviation higher folate]. We found some evidence for a small inverse effect of fetal folate levels on their own birthweight [−0.051 (−0.100, −0.003)]. Conclusions Our results are consistent with evidence from randomized controlled trials that higher maternal folate levels increase offspring birthweight. We did not find evidence for a causal effect of B12 levels on offspring birthweight, suggesting previous observational studies may have been confounded.

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 < 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 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 Using a Two-Sample Mendelian Randomization Method in Assessing the Causal Relationships Between Human Blood Metabolites and Heart Failure

2021 ◽  
Vol 8 ◽  
Author(s):  
Zixian Wang ◽  
Shiyu Chen ◽  
Qian Zhu ◽  
Yonglin Wu ◽  
Guifeng Xu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Human Blood ◽  
Large Scale ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Meta Analysis ◽  
Sensitivity Analyses ◽  
Blood Metabolites ◽  
Causal Relationships

Background: Heart failure (HF) is the main cause of morbidity and mortality worldwide, and metabolic dysfunction is an important factor related to HF pathogenesis and development. However, the causal effect of blood metabolites on HF remains unclear.Objectives: Our chief aim is to investigate the causal relationships between human blood metabolites and HF risk.Methods: We used an unbiased two-sample Mendelian randomization (MR) approach to assess the causal relationships between 486 human blood metabolites and HF risk. Exposure information was obtained from Sample 1, which is the largest metabolome-based genome-wide association study (mGWAS) data containing 7,824 Europeans. Outcome information was obtained from Sample 2, which is based on the results of a large-scale GWAS meta-analysis of HF and contains 47,309 cases and 930,014 controls of Europeans. The inverse variance weighted (IVW) model was used as the primary two-sample MR analysis method and followed the sensitivity analyses, including heterogeneity test, horizontal pleiotropy test, and leave-one-out analysis.Results: We observed that 11 known metabolites were potentially related to the risk of HF after using the IVW method (P < 0.05). After adding another four MR models and performing sensitivity analyses, we found a 1-SD increase in the xenobiotics 4-vinylphenol sulfate was associated with ~22% higher risk of HF (OR [95%CI], 1.22 [1.07–1.38]).Conclusions: We revealed that the 4-vinylphenol sulfate may nominally increase the risk of HF by 22% after using a two-sample MR approach. Our findings may provide novel insights into the pathogenesis underlying HF and novel strategies for HF prevention.

Genome-Wide Association for HbA1c in Malay Identified Deletion on SLC4A1 that Influences HbA1c Independent of Glycemia

2020 ◽  
Vol 105 (12) ◽  
pp. 3854-3864
Author(s):  
Jin-Fang Chai ◽  
Shih-Ling Kao ◽  
Chaolong Wang ◽  
Victor Jun-Yu Lim ◽  
Ing Wei Khor ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Hba1c Level ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Specific Reference ◽  
Genetic Determinants ◽  
Genome Wide ◽  
Whole Exome ◽  
A Genome

Abstract Context Glycated hemoglobin A1c (HbA1c) level is used to screen and diagnose diabetes. Genetic determinants of HbA1c can vary across populations and many of the genetic variants influencing HbA1c level were specific to populations. Objective To discover genetic variants associated with HbA1c level in nondiabetic Malay individuals. Design and Participants We conducted a genome-wide association study (GWAS) analysis for HbA1c using 2 Malay studies, the Singapore Malay Eye Study (SiMES, N = 1721 on GWAS array) and the Living Biobank study (N = 983 on GWAS array and whole-exome sequenced). We built a Malay-specific reference panel to impute ethnic-specific variants and validate the associations with HbA1c at ethnic-specific variants. Results Meta-analysis of the 1000 Genomes imputed array data identified 4 loci at genome-wide significance (P < 5 × 10-8). Of the 4 loci, 3 (ADAM15, LINC02226, JUP) were novel for HbA1c associations. At the previously reported HbA1c locus ATXN7L3-G6PC3, association analysis using the exome data fine-mapped the HbA1c associations to a 27-bp deletion (rs769664228) at SLC4A1 that reduced HbA1c by 0.38 ± 0.06% (P = 3.5 × 10-10). Further imputation of this variant in SiMES confirmed the association with HbA1c at SLC4A1. We also showed that these genetic variants influence HbA1c level independent of glucose level. Conclusion We identified a deletion at SLC4A1 associated with HbA1c in Malay. The nonglycemic lowering of HbA1c at rs769664228 might cause individuals carrying this variant to be underdiagnosed for diabetes or prediabetes when HbA1c is used as the only diagnostic test for diabetes.

scholarly journals Iron Status May Not Affect Amyotrophic Lateral Sclerosis: A Mendelian Randomization Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Jiahao Cai ◽  
Xiong Chen ◽  
Hongxuan Wang ◽  
Zixin Wei ◽  
Mei Li ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Iron Status ◽  
Transferrin Saturation ◽  
Outcome Data ◽  
Sensitivity Analyses ◽  
A Genome ◽  
Lateral Sclerosis

BackgroundObservational studies have shown an association of increased iron status with a higher risk of amyotrophic lateral sclerosis (ALS). Iron status might be a novel target for ALS prevention if a causal relationship exists. We aimed to reveal the causality between iron status and ALS incidence using a large two-sample Mendelian randomization (MR).MethodsSingle nucleotide polymorphisms (SNPs) for iron status were identified from a genome-wide association study (GWAS) on 48,972 individuals. The outcome data came from the largest ALS GWAS to date (20,806 cases; 59,804 controls). We conducted conservative analyses (using SNPs with concordant change of biomarkers of iron status) and liberal analyses (using SNPs associated with at least one of the biomarkers of iron status), with inverse variance weighted (IVW) method as the main analysis. We then performed sensitivity analyses including weighted median, MR-Egger and MR-pleiotropy residual sum and outlier, as well as leave-one-out analysis to detect pleiotropy.ResultsIn the conservative analyses, we found no evidence of association between four biomarkers of iron status and ALS using IVW method with odds ratio (OR) 1.00 [95% confidence interval (CI): 0.90–1.11] per standard deviation (SD) increase in iron, 0.96 (95% CI: 0.77–1.21) in ferritin, 0.99 (95% CI: 0.92–1.07) in transferrin saturation, and 1.04 (95% CI: 0.93–1.16) in transferrin. Findings from liberal analyses were similar, and sensitivity analyses suggested no pleiotropy detected (all p > 0.05).ConclusionOur findings suggest no causal effect between iron status and risk of ALS. Efforts to change the iron status to decrease ALS incidence might be impractical.

scholarly journals A Genome-Wide Association Study and Polygenic Risk Score Analysis of Posttraumatic Stress Disorder and Metabolic Syndrome in a South African Population

2021 ◽  
Vol 15 ◽  
Author(s):  
Patricia C. Swart ◽  
Leigh L. van den Heuvel ◽  
Cathryn M. Lewis ◽  
Soraya Seedat ◽  
Sian M. J. Hemmings
Keyword(s):  
Metabolic Syndrome ◽  
South African ◽  
Genetic Variants ◽  
Genome Wide Association Study ◽  
Stress Disorder ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Polygenic Risk ◽  
Genome Wide ◽  
A Genome

Posttraumatic stress disorder (PTSD) is a trauma-related disorder that frequently co-occurs with metabolic syndrome (MetS). MetS is characterized by obesity, dyslipidemia, and insulin resistance. To provide insight into these co-morbidities, we performed a genome-wide association study (GWAS) meta-analysis to identify genetic variants associated with PTSD, and determined if PTSD polygenic risk scores (PRS) could predict PTSD and MetS in a South African mixed-ancestry sample. The GWAS meta-analysis of PTSD participants (n = 260) and controls (n = 343) revealed no SNPs of genome-wide significance. However, several independent loci, as well as five SNPs in the PARK2 gene, were suggestively associated with PTSD (p < 5 × 10–6). PTSD-PRS was associated with PTSD diagnosis (Nagelkerke’s pseudo R2 = 0.0131, p = 0.00786), PTSD symptom severity [as measured by CAPS-5 total score (R2 = 0.00856, p = 0.0367) and PCL-5 score (R2 = 0.00737, p = 0.0353)], and MetS (Nagelkerke’s pseudo R2 = 0.00969, p = 0.0217). These findings suggest an association between PTSD and PARK2, corresponding with results from the largest PTSD-GWAS conducted to date. PRS analysis suggests that genetic variants associated with PTSD are also involved in the development of MetS. Overall, the results contribute to a broader goal of increasing diversity in psychiatric genetics.

scholarly journals Genetically determined circulating levels ofcytokines and the risk of rheumatoid arthritis

2020 ◽  
Author(s):  
Yu Qian ◽  
Zhixing He ◽  
Sizheng Steven Zhao ◽  
Bin Liu ◽  
Ying Chen ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Observational Studies ◽  
Causal Effect ◽  
Sensitivity Analyses ◽  
European Ancestry ◽  
Effect Estimate ◽  
Inverse Association ◽  
A Genome ◽  
Genetically Determined ◽  
Circulating Levels

Abstract Background: Accumulation of inflammatory leukocytes in articular tissues is the hallmark feature of rheumatoid arthritis (RA). Increasing evidence from observational studies have suggested that several cytokines are relevant in the disease process of RA. However, traditional observational studies are susceptible to bias from confounding and reverse causation; therefore, the potential causal association of individual cytokines with the risk of RA remains elusive. Our study aimed to evaluate whether genetically determined circulating levels of cytokines are associated with the risk of RA by conducting a two-sample Mendelian randomization (MR) study.Methods: We identified single nucleotide polymorphisms (SNPs) associated with circulating levels of cytokines and growth factors from a genome-wide association study (GWAS) including 8,293 participants of European ancestry as instrumental variables (IVs). The association estimates of these IVs with RA were obtained from a GWAS meta-analysis including 14,361 RA cases and 43,923 controls of European ancestry. MR analyses were performed using the random-effects inverse variance-weighted, weighted-median, MR-Egger and MR pleiotropy residual sum and outlier tests. Sensitivity analyses were further performed using restricted IVs excluding potential pleiotropic SNPs.Results: In the primary MR analysis, a total of 270 SNPs associated with circulating levels of 27 cytokines were identified and used as IVs. We found a suggestive inverse association between genetically determined circulating level of macrophage inflammatory protein-1β (MIP-1b) and the risk of RA [odds ratio (OR): 0.97, 95% confidence interval (CI) = 0.92-0.99, P = 0.016]. The association remained statistically significant in alternative MR analyses, and the causal effect estimate from sensitivity analysis using the restricted IVs was similar.Conclusions: Genetically determined elevated circulating level of MIP-1b was associated with a lower risk of RA. Further studies are warranted to determine how this MIP-1b and related pathways contribute to the development of RA.

Association of genetic variants for plasma LRG1 with rapid decline in kidney function in patients with type 2 diabetes

2021 ◽  
Author(s):  
Resham Lal Gurung ◽  
Rajkumar Dorajoo ◽  
M Yiamunaa ◽  
Jian-Jun Liu ◽  
Sharon Li Ting Pek ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Glomerular Filtration ◽  
Kidney Function ◽  
Genetic Variants ◽  
Genome Wide Association Study ◽  
Causal Effect ◽  
Mendelian Randomisation ◽  
Rapid Decline ◽  
A Genome

Abstract Context Elevated levels of plasma Leucine Rich α-2-Glycoprotein 1 (LRG1), a component of TGF-ß signalling, are associated with development and progression of chronic kidney disease in patients with type 2 diabetes (T2D). However, whether this relationship is causal is uncertain. Objectives To identify genetic variants associated with plasma LRG1 levels and determine whether genetically predicted plasma LRG1 contributes to a rapid decline in kidney function (RDKF) in patients with T2D. Design and participants We performed a genome-wide association study (GWAS) of plasma LRG1 among 3,694 T2D individuals [1,881(983 Chinese, 420 Malay and 478 Indian) discovery from SMART2D cohort and 1,813 (Chinese) validation from DN cohort]. One- sample Mendelian randomization analysis was performed among 1,337 T2D Chinese participants with preserved glomerular filtration function (baseline estimated glomerular filtration rate (eGFR) >60ml/min/1.73m 2). RDKF was defined as an eGFR decline of 3 mL/min/1.73 m 2/year or greater. Results We identified rs4806985 variant near LRG1 locus robustly associated with plasma LRG1 levels (MetaP=6.66x10 -16). Among 1,337 participants, 344 (26%) developed RDKF and the rs4806985 variant was associated with higher odds of RDKF (meta odds ratio =1.23, P=0.030 adjusted for age and sex). Mendelian randomisation analysis provided evidence for a potential causal effect of plasma LRG1 on kidney function decline in T2D (P<0.05). Conclusion We demonstrate that genetically influenced plasma LRG1 increases the risk of RDKF in T2D patients suggesting plasma LRG1 as a potential treatment target. However, further studies are warranted to elucidate underlying pathways to provide insight into DKD prevention.

scholarly journals Effect of age at puberty on risk of multiple sclerosis

Neurology ◽  
2019 ◽  
Vol 92 (16) ◽  
pp. e1803-e1810 ◽  
Author(s):  
Adil Harroud ◽  
John A. Morris ◽  
Vincenzo Forgetta ◽  
Ruth Mitchell ◽  
George Davey Smith ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Weight Status ◽  
Genome Wide Association Study ◽  
Causal Effect ◽  
Pubertal Timing ◽  
Sensitivity Analyses ◽  
Age At Menarche ◽  
A Genome ◽  
Age At Puberty ◽  
Effect Of Age

ObjectiveTo investigate the potential for a causal effect of age at puberty on multiple sclerosis (MS) susceptibility using a mendelian randomization (MR) approach.MethodsWe used 372 genetic variants strongly associated with age at menarche in a genome-wide association study (GWAS) involving 329,245 women. The genetic architecture of pubertal timing across both sexes is highly correlated (genetic correlation [rg] = 0.75, p = 1.2 × 10−79), allowing these variants to provide reliable insight into pubertal timing in males as well. The effect of pubertal timing on risk of MS was measured with summary statistics from a GWAS of 14,802 cases with MS and 26,703 controls from the International Multiple Sclerosis Genetics Consortium. Multivariable MR controlling for effects of body mass index (BMI) using genetic data from additional consortia investigated whether pubertal effects on MS were dependent on weight status.ResultsA 1-year increase in genetically predicted age at puberty decreased odds of MS by 8% (odds ratio [OR] 0.92, 95% confidence interval [CI] 0.86–0.99, p = 0.03). However, multivariable MR analysis showed that after accounting for effects on adult BMI, the association of age at puberty with MS susceptibility attenuated (OR 0.96, 95% CI 0.88–1.04, p = 0.36). Similar results were obtained when childhood BMI was incorporated. Sensitivity analyses provided no evidence of major bias from genetic pleiotropy.ConclusionsWe found support for an association between higher age at puberty and decreased risk of MS with a magnitude comparable to that reported in observational studies. This effect appears to be largely mediated by the strong association between age at puberty and obesity. A large causal effect of pubertal timing independent of BMI is unlikely.

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