Maternal and offspring fasting glucose and type 2 diabetes-associated genetic variants and cognitive function at age 8: a Mendelian randomization study in the Avon Longitudinal Study of Parents and Children

Abstract Background Observational studies suggest poorer glycemic traits and type 2 diabetes associated with coronavirus disease 2019 (COVID-19) risk although these findings could be confounded by socioeconomic position. We conducted a two-sample Mendelian randomization to clarify their role in COVID-19 risk and specific COVID-19 phenotypes (hospitalized and severe cases). Method We identified genetic instruments for fasting glucose (n = 133,010), 2 h glucose (n = 42,854), glycated hemoglobin (n = 123,665), and type 2 diabetes (74,124 cases and 824,006 controls) from genome wide association studies and applied them to COVID-19 Host Genetics Initiative summary statistics (17,965 COVID-19 cases and 1,370,547 population controls). We used inverse variance weighting to obtain the causal estimates of glycemic traits and genetic predisposition to type 2 diabetes in COVID-19 risk. Sensitivity analyses included MR-Egger and weighted median method. Results We found genetic predisposition to type 2 diabetes was not associated with any COVID-19 phenotype (OR: 1.00 per unit increase in log odds of having diabetes, 95%CI 0.97 to 1.04 for overall COVID-19; OR: 1.02, 95%CI 0.95 to 1.09 for hospitalized COVID-19; and OR: 1.00, 95%CI 0.93 to 1.08 for severe COVID-19). There were no strong evidence for an association of glycemic traits in COVID-19 phenotypes, apart from a potential inverse association for fasting glucose albeit with wide confidence interval. Conclusion We provide some genetic evidence that poorer glycemic traits and predisposition to type 2 diabetes unlikely increase the risk of COVID-19. Although our study did not indicate glycemic traits increase severity of COVID-19, additional studies are needed to verify our findings.

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Epigenome-wide association study of seizures in childhood and adolescence

Clinical Epigenetics ◽

10.1186/s13148-019-0793-z ◽

2020 ◽

Vol 12 (1) ◽

Cited By ~ 2

Author(s):

Doretta Caramaschi ◽

Charlie Hatcher ◽

Rosa H. Mulder ◽

Janine F. Felix ◽

Charlotte A. M. Cecil ◽

...

Keyword(s):

Dna Methylation ◽

Genetic Variants ◽

Mendelian Randomization ◽

Independent Study ◽

Childhood And Adolescence ◽

Parents And Children ◽

Genome Wide ◽

Common Genetic Variants ◽

The Brain ◽

Avon Longitudinal Study

AbstractThe occurrence of seizures in childhood is often associated with neurodevelopmental impairments and school underachievement. Common genetic variants associated with epilepsy have been identified and epigenetic mechanisms have also been suggested to play a role. In this study, we analyzed the association of genome-wide blood DNA methylation with the occurrence of seizures in ~ 800 children from the Avon Longitudinal Study of Parents and Children, UK, at birth (cord blood), during childhood, and adolescence (peripheral blood). We also analyzed the association between the lifetime occurrence of any seizures before age 13 with blood DNA methylation levels. We sought replication of the findings in the Generation R Study and explored causality using Mendelian randomization, i.e., using genetic variants as proxies. The results showed five CpG sites which were associated cross-sectionally with seizures either in childhood or adolescence (1–5% absolute methylation difference at pFDR < 0.05), although the evidence of replication in an independent study was weak. One of these sites was located in the BDNF gene, which is highly expressed in the brain, and showed high correspondence with brain methylation levels. The Mendelian randomization analyses suggested that seizures might be causal for changes in methylation rather than vice-versa. In conclusion, we show a suggestive link between seizures and blood DNA methylation while at the same time exploring the limitations of conducting such study.

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Vitamin B-12 Status during Pregnancy and Child’s IQ at Age 8: A Mendelian Randomization Study in the Avon Longitudinal Study of Parents and Children

PLoS ONE ◽

10.1371/journal.pone.0051084 ◽

2012 ◽

Vol 7 (12) ◽

pp. e51084 ◽

Cited By ~ 19

Author(s):

Carolina Bonilla ◽

Debbie A. Lawlor ◽

Amy E. Taylor ◽

David J. Gunnell ◽

Yoav Ben–Shlomo ◽

...

Keyword(s):

Longitudinal Study ◽

Mendelian Randomization ◽

Vitamin B ◽

Parents And Children ◽

Vitamin B 12 ◽

Avon Longitudinal Study

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Association of physical activity and sedentary behavior with type 2 diabetes and glycemic traits: a two-sample Mendelian randomization study

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2020-001896 ◽

2020 ◽

Vol 8 (2) ◽

pp. e001896

Author(s):

Christa Meisinger ◽

Jakob Linseisen ◽

Michael Leitzmann ◽

Hansjoerg Baurecht ◽

Sebastian Edgar Baumeister

Keyword(s):

Physical Activity ◽

Type 2 Diabetes ◽

Sedentary Behavior ◽

Mendelian Randomization ◽

Fasting Glucose ◽

Vigorous Physical Activity ◽

Model Assessment ◽

Homeostasis Model Assessment ◽

A Genome

IntroductionObservational studies suggest that physical activity lowers and sedentary behavior increases the risk of type 2 diabetes. Despite of some supportive trial data for physical activity, it is largely unresolved whether these relations are causal or due to bias.ObjectiveWe investigated the associations between accelerometer-based physical activity and sedentary behavior with type 2 diabetes and several glycemic traits using two-sample Mendelian randomization analysis.Research design and methodsSingle nucleotide polymorphisms (SNPs) associated at p<5×10−8 with accelerometer-based physical activity average accelerations, vigorous physical activity (fraction of accelerations >425 milligravities), and sedentary behavior (metabolic equivalent task ≤1.5) in a genome-wide analysis of the UK Biobank served as instrumental variables.OutcomesType 2 diabetes, hemoglobin A1c (HbA1c), fasting glucose, homeostasis model assessment of beta-cell function (HOMA-B), and homeostasis model assessment of insulin resistance (HOMA-IR).ResultsPhysical activity and sedentary behavior were unrelated to type 2 diabetes, HbA1c, fasting glucose, HOMA-B, and HOMA-IR. The inverse variance weighted ORs per SD increment for the association between average accelerations and vigorous physical activity with type 2 diabetes were 1.00 (95% CI 0.94 to 1.07, p=0.948) and 0.83 (95% CI 0.56 to 1.23, p=0.357), respectively. These results were confirmed by sensitivity analyses using alternative MR-methods to test the robustness of our findings.ConclusionsBased on these results, genetically predicted objectively measured average or vigorous physical activity and sedentary behavior is not associated with type 2 diabetes risk or with glycemic traits in the general population. Further research is required to deepen the understanding of the biological pathways of physical activity.

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A Mendelian Randomization Study of Metabolite Profiles, Fasting Glucose, and Type 2 Diabetes

Diabetes ◽

10.2337/db17-0199 ◽

2017 ◽

Vol 66 (11) ◽

pp. 2915-2926 ◽

Cited By ~ 20

Author(s):

Jun Liu ◽

Jan Bert van Klinken ◽

Sabina Semiz ◽

Ko Willems van Dijk ◽

Aswin Verhoeven ◽

...

Keyword(s):

Type 2 Diabetes ◽

Mendelian Randomization ◽

Fasting Glucose ◽

Metabolite Profiles

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Effects of 16 Genetic Variants on Fasting Glucose and Type 2 Diabetes in South Asians: ADCY5 and GLIS3 Variants May Predispose to Type 2 Diabetes

PLoS ONE ◽

10.1371/journal.pone.0024710 ◽

2011 ◽

Vol 6 (9) ◽

pp. e24710 ◽

Cited By ~ 39

Author(s):

Simon D. Rees ◽

M. Zafar I. Hydrie ◽

J. Paul O'Hare ◽

Sudhesh Kumar ◽

A. Samad Shera ◽

...

Keyword(s):

Type 2 Diabetes ◽

Genetic Variants ◽

Fasting Glucose ◽

South Asians

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Testing the principles of Mendelian randomization: Opportunities and complications on a genomewide scale

10.1101/124362 ◽

2017 ◽

Cited By ~ 2

Author(s):

M Taylor ◽

KE Tansey ◽

DA Lawlor ◽

J Bowden ◽

DM Evans ◽

...

Keyword(s):

Genetic Variants ◽

Mendelian Randomization ◽

Phenotypic Correlation ◽

Causal Relationships ◽

Biological Phenomena ◽

Parents And Children ◽

Multiple Variables ◽

Using Data ◽

Avon Longitudinal Study ◽

Gwas Catalog

ABSTRACTBackgroundMendelian randomization (MR) uses genetic variants as instrumental variables to assess whether observational associations between exposures and disease reflect causal relationships. MR requires genetic variants to be independent of factors that confound observational associations.MethodsUsing data from the Avon Longitudinal Study of Parents and Children, associations within and between 121 phenotypes and 13,720 genetic variants (from the NHGRI-EBI GWAS catalog) were examined to assess the validity of MR assumptions.ResultsAmongst 7,260 pairwise comparisons between the 121 phenotypes, 2,188 (30%) provided evidence of association, where 363 were expected at the 5% level (observed:expected ratio=6.03; 95% CI: 5.42, 6.70; χ2=9682.29; d.f. =1, P≤1x10-50). Amongst 1,660,120 pairwise associations between phenotypes and genotypes, 86,748 (5.2%) gave evidence of association at the same threshold, where 83,006 were expected (observed:expected ratio=1.05; 95% CI: 1.04, 1.05; χ2=117.57; d.f. =1, P=2.15x10-27). Amongst 1,171,764 pairwise associations between the phenotypes and LD pruned independent genetic variants, 60,136 (5.1%) gave evidence of association, where 58,588 were expected (observed:expected ratio=1.03; 95% CI: 1.03, 1.08; χ2= 43.05; d.f. = 1, P=5.33x10-11).ConclusionThese results confirm previously observed patterns of phenotypic correlation. They also provide evidence of a substantially lower level of association between genetic variants and phenotypes, with residual inflation the likely product of indistinguishable real genetic association, multiple variables measuring the same biological phenomena, or pleiotropy. These results reflect the favorable properties of genetic instruments for estimating causal relationships, but confirm the need for functional information or analytical methods to account for pleiotropic events.

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Genetic Correlation and Bidirectional Causal Association Between Type 2 Diabetes and Pulmonary Function

Frontiers in Endocrinology ◽

10.3389/fendo.2021.777487 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jiahao Zhu ◽

Huanling Zhao ◽

Dingwan Chen ◽

Lap Ah Tse ◽

Sanjay Kinra ◽

...

Keyword(s):

Type 2 Diabetes ◽

Pulmonary Function ◽

Genetic Correlation ◽

Mendelian Randomization ◽

Fasting Glucose ◽

Genetic Correlations ◽

Fasting Insulin ◽

Causal Association ◽

Bidirectional Association

BackgroundObservational studies have shown possible bidirectional association between type 2 diabetes (T2D) and pulmonary function, but the causality is not well defined. The purpose of this study is to investigate genetic correlation and causal relationship of T2D and glycemic traits with pulmonary function.MethodsBy leveraging summary statistics from large-scale genome-wide association studies, linkage disequilibrium score regression was first implemented to quantify genetic correlations between T2D, glycemic traits, and several spirometry indices. Then both univariable and multivariable Mendelian randomization analyses along with multiple pleiotropy-robust methods were performed in two directions to assess the causal nature of these relationships.ResultsForced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) showed significant genetic correlations with T2D and fasting insulin levels and suggestive genetic correlations with fasting glucose and hemoglobin A1c. In Mendelian randomization analyses, genetically predicted higher FEV1 (OR = 0.77; 95% CI = 0.63, 0.94) and FVC (OR = 0.82; 95% CI = 0.68, 0.99) were significantly associated with lower risk of T2D. Conversely, genetic predisposition to higher risk of T2D exhibited strong association with reduced FEV1 (beta = −0.062; 95% CI = −0.100, −0.024) and FEV1 (beta = −0.088; 95% CI = −0.126, −0.050) and increased FEV1/FVC ratio (beta = 0.045; 95% CI = 0.012, 0.078). We also found a suggestive causal effect of fasting glucose on pulmonary function and of pulmonary function on fasting insulin and proinsulin.ConclusionsThe present study provided supportive evidence for genetic correlation and bidirectional causal association between T2D and pulmonary function. Further studies are warranted to clarify possible mechanisms related to lung dysfunction and T2D, thus offering a new strategy for the management of the two comorbid diseases.

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Combined Effect of Nonalcoholic Fatty Liver Disease and Impaired Fasting Glucose on the Development of Type 2 Diabetes: A 4-year retrospective longitudinal study

Diabetes Care ◽

10.2337/dc10-1991 ◽

2011 ◽

Vol 34 (3) ◽

pp. 727-729 ◽

Cited By ~ 90

Author(s):

J. C. Bae ◽

E. J. Rhee ◽

W. Y. Lee ◽

S. E. Park ◽

C. Y. Park ◽

...

Keyword(s):

Type 2 Diabetes ◽

Liver Disease ◽

Longitudinal Study ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Impaired Fasting Glucose ◽

Fatty Liver Disease ◽

Fasting Glucose ◽

Nonalcoholic Fatty Liver

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Mendelian randomization studies of biomarkers and type 2 diabetes

Endocrine Connections ◽

10.1530/ec-15-0087 ◽

2015 ◽

Vol 4 (4) ◽

pp. 249-260 ◽

Cited By ~ 12

Author(s):

Ali Abbasi

Keyword(s):

Type 2 Diabetes ◽

Genetic Variants ◽

Large Scale ◽

Mendelian Randomization ◽

Association Studies ◽

Causal Effects ◽

Current Evidence ◽

Genome Wide Association Studies ◽

Glycaemic Traits

Many biomarkers are associated with type 2 diabetes (T2D) risk in epidemiological observations. The aim of this study was to identify and summarize current evidence for causal effects of biomarkers on T2D. A systematic literature search in PubMed and EMBASE (until April 2015) was done to identify Mendelian randomization studies that examined potential causal effects of biomarkers on T2D. To replicate the findings of identified studies, data from two large-scale, genome-wide association studies (GWAS) were used: DIAbetes Genetics Replication And Meta-analysis (DIAGRAMv3) for T2D and the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) for glycaemic traits. GWAS summary statistics were extracted for the same genetic variants (or proxy variants), which were used in the original Mendelian randomization studies. Of the 21 biomarkers (from 28 studies), ten have been reported to be causally associated with T2D in Mendelian randomization. Most biomarkers were investigated in a single cohort study or population. Of the ten biomarkers that were identified, nominally significant associations with T2D or glycaemic traits were reached for those genetic variants related to bilirubin, pro-B-type natriuretic peptide, delta-6 desaturase and dimethylglycine based on the summary data from DIAGRAMv3 or MAGIC. Several Mendelian randomization studies investigated the nature of associations of biomarkers with T2D. However, there were only a few biomarkers that may have causal effects on T2D. Further research is needed to broadly evaluate the causal effects of multiple biomarkers on T2D and glycaemic traits using data from large-scale cohorts or GWAS including many different genetic variants.

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