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

2017 ◽  
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.

scholarly journals Epigenome-wide association study of seizures in childhood and adolescence

2020 ◽  
Vol 12 (1) ◽  
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.

scholarly journals Infant temperament, early-childhood parenting, and early-adolescent development: Testing alternative models of Parenting × Temperament interaction

2021 ◽  
pp. 1-12
Author(s):  
Xiaoya Zhang ◽  
Kristina Sayler ◽  
Sarah Hartman ◽  
Jay Belsky
Keyword(s):  
Early Childhood ◽  
Differential Susceptibility ◽  
Early Adolescent ◽  
Emotional Symptoms ◽  
Supportive Parenting ◽  
Parents And Children ◽  
Parameterized Model ◽  
Using Data ◽  
Childhood Parenting ◽  
Avon Longitudinal Study

Abstract Here we evaluate whether infant difficult temperament (6 months) functions as a vulnerability or more general plasticity factor when investigating effects of early-childhood parenting (8–42 months) on both positive and negative early-adolescent socioemotional development (age 8–11 years). Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC, N = 14,541) and a re-parameterized model-testing approach to distinguish alternative person × environment conceptual models, results indicated that temperament × parenting interacted in predicting externalizing (i.e., hyperactivity, conduct problems), but not other behavior (i.e., emotional symptoms, peer problems), in a (weak) differential susceptibility manner. While more and less supportive parenting predicted, respectively, fewer and more behavior problems, it did so more strongly for children who were more difficult as infants.

scholarly journals Gestation at completion of prenatal questionnaires in ALSPAC

2020 ◽  
Vol 5 ◽  
pp. 100
Author(s):  
Yasmin Iles-Caven ◽  
Kate Northstone ◽  
Jean Golding
Keyword(s):  
Data Collection ◽  
Pregnant Women ◽  
First Trimester ◽  
Environmental Data ◽  
Parents And Children ◽  
Using Data ◽  
Time Critical ◽  
Avon Longitudinal Study ◽  
In Pregnancy ◽  
Made In

Enrolling a cohort in pregnancy can be methodologically difficult in terms of structuring data collection. For example, some exposures of interest may be time-critical while other (often retrospective) data can be collected at any point during pregnancy.  The Avon Longitudinal Study of Parents and Children (ALSPAC) is a prime example of a cohort where certain data were collected at specific time points and others at variable times depending on the gestation at contact.  ALSPAC aimed to enrol as many pregnant women as possible in a geographically defined area with an expected date of delivery between April 1991 and December 1992. The ideal was to enrol women as early in pregnancy as possible, and to collect information, when possible, at two fixed gestational periods (18 and 32 weeks). A variety of methods were used to enrol participants.   Approximately 80% of eligible women resident in the study area were enrolled. Gestation at enrolment ranged from 4-41 (median = 14) weeks of pregnancy. Given this variation in gestation we describe the various decisions that were made in regard to the timing of questionnaires to ensure that appropriate data were obtained from the pregnant women.  45% of women provided data during the first trimester, this is less than ideal but reflects the fact that many women do not acknowledge their pregnancy until the first trimester is safely completed. Data collection from women at specific gestations (18 and 32 weeks) was much more successful (80-85%). Unfortunately, it was difficult to obtain environmental data during the first trimester. Given the time critical nature of exposures during this trimester, researchers must take the gestational age at which environmental data was collected into account. This is particularly important for data collected using the questionnaire named ‘Your Environment’ (using data known as the A files).

scholarly journals Factorial Mendelian randomization: using genetic variants to assess interactions

2019 ◽  
Vol 49 (4) ◽  
pp. 1147-1158 ◽  
Author(s):  
Jessica M B Rees ◽  
Christopher N Foley ◽  
Stephen Burgess
Keyword(s):  
Risk Factors ◽  
Instrumental Variables ◽  
Genetic Variants ◽  
Mendelian Randomization ◽  
Real Data ◽  
Uk Biobank ◽  
Pharmacological Interventions ◽  
Natural Break ◽  
Using Data ◽  
Randomization Analysis

Abstract Background Factorial Mendelian randomization is the use of genetic variants to answer questions about interactions. Although the approach has been used in applied investigations, little methodological advice is available on how to design or perform a factorial Mendelian randomization analysis. Previous analyses have employed a 2 × 2 approach, using dichotomized genetic scores to divide the population into four subgroups as in a factorial randomized trial. Methods We describe two distinct contexts for factorial Mendelian randomization: investigating interactions between risk factors, and investigating interactions between pharmacological interventions on risk factors. We propose two-stage least squares methods using all available genetic variants and their interactions as instrumental variables, and using continuous genetic scores as instrumental variables rather than dichotomized scores. We illustrate our methods using data from UK Biobank to investigate the interaction between body mass index and alcohol consumption on systolic blood pressure. Results Simulated and real data show that efficiency is maximized using the full set of interactions between genetic variants as instruments. In the applied example, between 4- and 10-fold improvement in efficiency is demonstrated over the 2 × 2 approach. Analyses using continuous genetic scores are more efficient than those using dichotomized scores. Efficiency is improved by finding genetic variants that divide the population at a natural break in the distribution of the risk factor, or else divide the population into more equal-sized groups. Conclusions Previous factorial Mendelian randomization analyses may have been underpowered. Efficiency can be improved by using all genetic variants and their interactions as instrumental variables, rather than the 2 × 2 approach.

scholarly journals MR-LDP: a two-sample Mendelian randomization for GWAS summary statistics accounting for linkage disequilibrium and horizontal pleiotropy

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Qing Cheng ◽  
Yi Yang ◽  
Xingjie Shi ◽  
Kar-Fu Yeung ◽  
Can Yang ◽  
...  
Keyword(s):  
Risk Factors ◽  
Linkage Disequilibrium ◽  
Genetic Variants ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Alternative Methods ◽  
Genome Wide Association Studies ◽  
Summary Statistics ◽  
Causal Relationships ◽  
Disease Outcomes

Abstract The proliferation of genome-wide association studies (GWAS) has prompted the use of two-sample Mendelian randomization (MR) with genetic variants as instrumental variables (IVs) for drawing reliable causal relationships between health risk factors and disease outcomes. However, the unique features of GWAS demand that MR methods account for both linkage disequilibrium (LD) and ubiquitously existing horizontal pleiotropy among complex traits, which is the phenomenon wherein a variant affects the outcome through mechanisms other than exclusively through the exposure. Therefore, statistical methods that fail to consider LD and horizontal pleiotropy can lead to biased estimates and false-positive causal relationships. To overcome these limitations, we proposed a probabilistic model for MR analysis in identifying the causal effects between risk factors and disease outcomes using GWAS summary statistics in the presence of LD and to properly account for horizontal pleiotropy among genetic variants (MR-LDP) and develop a computationally efficient algorithm to make the causal inference. We then conducted comprehensive simulation studies to demonstrate the advantages of MR-LDP over the existing methods. Moreover, we used two real exposure–outcome pairs to validate the results from MR-LDP compared with alternative methods, showing that our method is more efficient in using all-instrumental variants in LD. By further applying MR-LDP to lipid traits and body mass index (BMI) as risk factors for complex diseases, we identified multiple pairs of significant causal relationships, including a protective effect of high-density lipoprotein cholesterol on peripheral vascular disease and a positive causal effect of BMI on hemorrhoids.

scholarly journals Epigenome-wide association study of seizures in childhood and adolescence

2019 ◽  
Author(s):  
Doretta Caramaschi ◽  
Charlie Hatcher ◽  
Rosa H. Mulder ◽  
Janine F. Felix ◽  
Charlotte A. M. Cecil ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Genetic Variants ◽  
Cognitive Skills ◽  
Mendelian Randomization ◽  
Independent Study ◽  
Childhood And Adolescence ◽  
Parents And Children ◽  
Genome Wide ◽  
Common Genetic Variants ◽  
The Brain

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 analysed 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 analysed 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 addition, seizure-associated methylation changes could affect other outcomes such as growth, cognitive skills and educational attainment. In conclusion, we present a link between seizures and DNA methylation which suggests that DNA methylation changes might mediate some of the effects of seizures on growth and neurodevelopment.

scholarly journals 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 ◽  
2012 ◽  
Vol 7 (12) ◽  
pp. e51084 ◽  
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

scholarly journals Why the Son-bias in Caregiving? Testing Sex-differences in the Associations Between Paternal Caregiving and Child Outcomes in England

2020 ◽  
pp. 0192513X2094190
Author(s):  
Emily H. Emmott ◽  
Ruth Mace
Keyword(s):  
Sex Differences ◽  
Test Scores ◽  
Child Outcomes ◽  
Behavioral Difficulties ◽  
Ecological Framework ◽  
Parents And Children ◽  
Behavioral Difficulty ◽  
More Care ◽  
Using Data ◽  
Avon Longitudinal Study

Studies show that fathers across Western populations tend to provide more care to sons than daughters. Following a human behavioral ecological framework, we hypothesize that son-biases in fathering may (at least in part) be due to differences in fitness returns to paternal direct investments by child’s sex. In this study, we investigate sex-differences in the associations between paternal caregiving and children’s outcomes in stable, two-parent families. Using data from the Avon Longitudinal Study of Parents and Children, we test whether paternal caregiving in early childhood is associated with different effects on children’s school test scores and behavioral difficulties by children’s sex. Overall, we find that paternal caregiving is associated with higher school test scores and lower behavioral difficulty scores, but the association between paternal caregiving and school test scores was stronger for boys. Our findings highlight possible sex-differences in returns to paternal caregiving for certain domains of child outcomes in England.

scholarly journals MR-LDP: a two-sample Mendelian randomization for GWAS summary statistics accounting for linkage disequilibrium and horizontal pleiotropy

2019 ◽  
Author(s):  
Qing Cheng ◽  
Yi Yang ◽  
Xingjie Shi ◽  
Kar-Fu Yeung ◽  
Can Yang ◽  
...  
Keyword(s):  
Risk Factors ◽  
Body Mass Index ◽  
Linkage Disequilibrium ◽  
Body Mass ◽  
Genetic Variants ◽  
Mendelian Randomization ◽  
Alternative Methods ◽  
Summary Statistics ◽  
Causal Relationships ◽  
Disease Outcomes

AbstractThe proliferation of genome-wide association studies (GWAS) has prompted the use of two-sample Mendelian randomization (MR) with genetic variants as instrumental variables (IV) for drawing reliable causal relationships between health risk factors and disease outcomes. However, the unique features of GWAS demand that MR methods account for both linkage disequilibrium (LD) and ubiquitously existing horizontal pleiotropy among complex traits, which is the phenomenon wherein a variant affects the outcome through mechanisms other than exclusively through the exposure. Therefore, statistical methods that fail to consider LD and horizontal pleiotropy can lead to biased estimates and false-positive causal relationships. To overcome these limitations, we propose a probabilistic model for MR analysis to identify the casual effects between risk factors and disease outcomes using GWAS summary statistics in the presence of LD and to properly account for horizontal pleiotropy among genetic variants (MR-LDP). MR-LDP utilizes a computationally efficient parameter-expanded variational Bayes expectation-maximization (PX-VBEM) algorithm to estimate the parameter of interest and further calibrates the evidence lower bound (ELBO) for a likelihood ratio test. We then conducted comprehensive simulation studies to demonstrate the advantages of MR-LDP over the existing methods in terms of both type-I error control and point estimates. Moreover, we used two real exposure-outcome pairs (CAD-CAD and Height-Height; CAD for coronary artery disease) to validate the results from MR-LDP compared with alternative methods, showing that our method is more efficient in using all instrumental variants in LD. By further applying MR-LDP to lipid traits and body mass index (BMI) as risk factors for complex diseases, we identified multiple pairs of significant causal relationships, including a protective effect of high-density lipoprotein cholesterol (HDL-C) on peripheral vascular disease (PVD), and a positive causal effect of body mass index (BMI) on hemorrhoids.

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