scholarly journals Epigenome-wide association of father’s smoking with offspring DNA methylation: a hypothesis-generating study

2019 ◽  
Vol 5 (4) ◽  
Author(s):  
G T Mørkve Knudsen ◽  
F I Rezwan ◽  
A Johannessen ◽  
S M Skulstad ◽  
R J Bertelsen ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Linear Models ◽  
Association Studies ◽  
Null Distribution ◽  
Acid Synthesis ◽  
Epidemiological Studies ◽  
Population Based ◽  
Sensitivity Analyses ◽  
Paternal Line ◽  
Paternal Smoking

Abstract Epidemiological studies suggest that father’s smoking might influence their future children’s health, but few studies have addressed whether paternal line effects might be related to altered DNA methylation patterns in the offspring. To investigate a potential association between fathers’ smoking exposures and offspring DNA methylation using epigenome-wide association studies. We used data from 195 males and females (11–54 years) participating in two population-based cohorts. DNA methylation was quantified in whole blood using Illumina Infinium MethylationEPIC Beadchip. Comb-p was used to analyse differentially methylated regions (DMRs). Robust multivariate linear models, adjusted for personal/maternal smoking and cell-type proportion, were used to analyse offspring differentially associated probes (DMPs) related to paternal smoking. In sensitivity analyses, we adjusted for socio-economic position and clustering by family. Adjustment for inflation was based on estimation of the empirical null distribution in BACON. Enrichment and pathway analyses were performed on genes annotated to cytosine-phosphate-guanine (CpG) sites using the gometh function in missMethyl. We identified six significant DMRs (Sidak-corrected P values: 0.0006–0.0173), associated with paternal smoking, annotated to genes involved in innate and adaptive immunity, fatty acid synthesis, development and function of neuronal systems and cellular processes. DMP analysis identified 33 CpGs [false discovery rate (FDR)  < 0.05]. Following adjustment for genomic control (λ = 1.462), no DMPs remained epigenome-wide significant (FDR < 0.05). This hypothesis-generating study found that fathers’ smoking was associated with differential methylation in their adolescent and adult offspring. Future studies are needed to explore the intriguing hypothesis that fathers’ exposures might persistently modify their future offspring’s epigenome.

scholarly journals Comparison of DNA Methylation Profiles of Hemostatic Genes between Liver Tissue and Peripheral Blood within Individuals

2020 ◽  
Author(s):  
Annelie Angerfors ◽  
Martina Olsson Lindvall ◽  
Björn Andersson ◽  
Staffan Nilsson ◽  
Marcela Davila Lopez ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Peripheral Blood ◽  
Liver Tissue ◽  
Association Studies ◽  
Epidemiological Studies ◽  
Methylation Pattern ◽  
Cpg Dinucleotides ◽  
Phenotypic Differences ◽  
Targeted Bisulfite Sequencing ◽  
Hemostatic Genes

AbstractDNA methylation has become increasingly recognized in the etiology of complex diseases, including thrombotic disorders. Blood is often collected in epidemiological studies for genotyping and has recently also been used to examine DNA methylation in epigenome-wide association studies. DNA methylation patterns are often tissue-specific, thus, peripheral blood may not accurately reflect the methylation pattern in the tissue of relevance. Here, we collected paired liver and blood samples concurrently from 27 individuals undergoing liver surgery. We performed targeted bisulfite sequencing for a set of 35 hemostatic genes primarily expressed in liver to analyze DNA methylation levels of >10,000 cytosine-phosphate-guanine (CpG) dinucleotides. We evaluated whether DNA methylation in blood could serve as a proxy for DNA methylation in liver at individual CpGs. Approximately 30% of CpGs were nonvariable and were predominantly hypo- (<25%) or hypermethylated (>70%) in both tissues. While blood can serve as a proxy for liver at these CpGs, the low variability renders these unlikely to explain phenotypic differences. We therefore focused on CpG sites with variable methylation levels in liver. The level of blood–liver tissue correlation varied widely across these variable CpGs; moderate correlations (0.5 ≤ r < 0.75) were detected for 6% and strong correlations (r ≥ 0.75) for a further 4%. Our findings indicate that it is essential to study the concordance of DNA methylation between blood and liver at individual CpGs. This paired blood–liver dataset is intended as a resource to aid interpretation of blood-based DNA methylation results.

scholarly journals Epigenome-wide associations between observed maternal sensitivity and offspring DNA methylation: a population-based prospective study in children

2020 ◽  
pp. 1-11
Author(s):  
Lorenza Dall’ Aglio ◽  
Jolien Rijlaarsdam ◽  
Rosa H. Mulder ◽  
Alexander Neumann ◽  
Janine F. Felix ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Stress Responses ◽  
Association Studies ◽  
Maternal Sensitivity ◽  
Population Based ◽  
Epigenetic Mechanism ◽  
Developmental Problems ◽  
Maternal Caregiving ◽  
Typical Variation

Abstract Background Experimental work in animals has shown that DNA methylation (DNAm), an epigenetic mechanism regulating gene expression, is influenced by typical variation in maternal care. While emerging research in humans supports a similar association, studies to date have been limited to candidate gene and cross-sectional approaches, with a focus on extreme deviations in the caregiving environment. Methods Here, we explored the prospective association between typical variation in maternal sensitivity and offspring epigenome-wide DNAm, in a population-based cohort of children (N = 235). Maternal sensitivity was observed when children were 3- and 4-years-old. DNAm, quantified with the Infinium 450 K array, was extracted at age 6 (whole blood). The influence of methylation quantitative trait loci (mQTLs), DNAm at birth (cord blood), and confounders (socioeconomic status, maternal psychopathology) was considered in follow-up analyses. Results Genome-wide significant associations between maternal sensitivity and offspring DNAm were observed at 13 regions (p < 1.06 × 10−07), but not at single sites. Follow-up analyses indicated that associations at these regions were in part related to genetic factors, confounders, and baseline DNAm levels at birth, as evidenced by the presence of mQTLs at five regions and estimate attenuations. Robust associations with maternal sensitivity were found at four regions, annotated to ZBTB22, TAPBP, ZBTB12, and DOCK4. Conclusions These findings provide novel leads into the relationship between typical variation in maternal caregiving and offspring DNAm in humans, highlighting robust regions of associations, previously implicated in psychological and developmental problems, immune functioning, and stress responses.

scholarly journals A review of HLA and COVID-19 association studies

2020 ◽  
Vol 3 (2) ◽  
pp. 25-30
Author(s):  
Renata Zunec
Keyword(s):  
Large Scale ◽  
Association Studies ◽  
Human Leukocyte ◽  
Genetic System ◽  
Epidemiological Studies ◽  
Population Based ◽  
Case Control ◽  
Case Control Studies ◽  
First Case ◽  
Scale Population

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is reported to vary across different populations in the prevalence of infection, in the death rate of patients, in the severity of symptoms and in the drug response of patients. Among host genetic factors that can influence all these attributes human leukocyte antigen (HLA) genetic system stands out as one of the leading candidates. Case-control studies, large-scale population-based studies, as well as experimental bioinformatics studies are of utmost importance to confirm HLA susceptibility spectrum of COVID-19. This review presents the results of the first case-control and epidemiological studies performed in several populations, early after the pandemic breakout. The results are pointing to several susceptible and protective HLA alleles and haplotypes associations with COVID-19, some of which might be of interest for the future studies in Croatia, due to its common presence in the population. However, further multiple investigations from around the world, as numerous as possible, are needed to confirm or deteriorate these preliminary results.

scholarly journals Validation of Coding Algorithms for the Identification of Patients with Primary Biliary Cirrhosis Using Administrative Data

2010 ◽  
Vol 24 (3) ◽  
pp. 175-182 ◽  
Author(s):  
Robert P Myers ◽  
Abdel Aziz M Shaheen ◽  
Andrew Fong ◽  
Alex F Wan ◽  
Mark G Swain ◽  
...  
Keyword(s):  
Primary Biliary Cirrhosis ◽  
Administrative Data ◽  
Large Scale ◽  
Optimal Algorithm ◽  
Epidemiological Studies ◽  
Population Based ◽  
Sensitivity Analyses ◽  
Administrative Databases ◽  
Biliary Cirrhosis ◽  
Predictive Values

BACKGROUND: Large-scale epidemiological studies of primary biliary cirrhosis (PBC) have been hindered by difficulties in case ascertainment.OBJECTIVE: To develop coding algorithms for identifying PBC patients using administrative data – a widely available data source.METHODS: Population-based administrative databases were used to identify patients with a diagnosis code for PBC from 1994 to 2002. Coding algorithms for confirmed PBC (two or more of antimitochondrial antibody positivity, cholestatic liver biochemistry and/or compatible liver histology) were derived using chart abstraction data as the reference. Patients with a recorded PBC diagnosis but insufficient confirmatory data were classified as ‘suspected PBC’.RESULTS: Of 189 potential PBC cases, 119 (60%) had confirmed PBC and 28 (14%) had suspected PBC. The optimal algorithm including two or more uses of a PBC code had a sensitivity of 94% (95% CI 71% to 100%) and positive predictive values of 73% (95% CI 61% to 75%) for confirmed PBC, and 89% (95% CI 82% to 94%) for confirmed or suspected PBC. Sensitivity analyses revealed greater accuracy among women, and with the use of multiple data sources and one or more years of data. Inclusion of diagnosis codes for conditions frequently misclassified as PBC did not improve algorithm performance.CONCLUSIONS: Administrative databases can reliably identify patients with PBC and may facilitate epidemiological investigations of this condition.

scholarly journals Cardiometabolic risk factors for COVID-19 susceptibility and severity: A Mendelian randomization analysis

PLoS Medicine ◽  
2021 ◽  
Vol 18 (3) ◽  
pp. e1003553
Author(s):  
Aaron Leong ◽  
Joanne B. Cole ◽  
Laura N. Brenner ◽  
James B. Meigs ◽  
Jose C. Florez ◽  
...  
Keyword(s):  
Odds Ratio ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Statistical Significance ◽  
Epidemiological Studies ◽  
Population Based ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
The Uk

Background Epidemiological studies report associations of diverse cardiometabolic conditions including obesity with COVID-19 illness, but causality has not been established. We sought to evaluate the associations of 17 cardiometabolic traits with COVID-19 susceptibility and severity using 2-sample Mendelian randomization (MR) analyses. Methods and findings We selected genetic variants associated with each exposure, including body mass index (BMI), at p < 5 × 10−8 from genome-wide association studies (GWASs). We then calculated inverse-variance-weighted averages of variant-specific estimates using summary statistics for susceptibility and severity from the COVID-19 Host Genetics Initiative GWAS meta-analyses of population-based cohorts and hospital registries comprising individuals with self-reported or genetically inferred European ancestry. Susceptibility was defined as testing positive for COVID-19 and severity was defined as hospitalization with COVID-19 versus population controls (anyone not a case in contributing cohorts). We repeated the analysis for BMI with effect estimates from the UK Biobank and performed pairwise multivariable MR to estimate the direct effects and indirect effects of BMI through obesity-related cardiometabolic diseases. Using p < 0.05/34 tests = 0.0015 to declare statistical significance, we found a nonsignificant association of genetically higher BMI with testing positive for COVID-19 (14,134 COVID-19 cases/1,284,876 controls, p = 0.002; UK Biobank: odds ratio 1.06 [95% CI 1.02, 1.10] per kg/m2; p = 0.004]) and a statistically significant association with higher risk of COVID-19 hospitalization (6,406 hospitalized COVID-19 cases/902,088 controls, p = 4.3 × 10−5; UK Biobank: odds ratio 1.14 [95% CI 1.07, 1.21] per kg/m2, p = 2.1 × 10−5). The implied direct effect of BMI was abolished upon conditioning on the effect on type 2 diabetes, coronary artery disease, stroke, and chronic kidney disease. No other cardiometabolic exposures tested were associated with a higher risk of poorer COVID-19 outcomes. Small study samples and weak genetic instruments could have limited the detection of modest associations, and pleiotropy may have biased effect estimates away from the null. Conclusions In this study, we found genetic evidence to support higher BMI as a causal risk factor for COVID-19 susceptibility and severity. These results raise the possibility that obesity could amplify COVID-19 disease burden independently or through its cardiometabolic consequences and suggest that targeting obesity may be a strategy to reduce the risk of severe COVID-19 outcomes.

scholarly journals The EWAS Catalog: a database of epigenome-wide association studies

2021 ◽  
Author(s):  
Thomas Battram ◽  
Paul Yousefi ◽  
Gemma Crawford ◽  
Claire Prince ◽  
Mahsa Sheikhali Babei ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Association Studies ◽  
R Package ◽  
Population Based ◽  
Case Control Studies ◽  
Web Based ◽  
Parents And Children ◽  
The Impact ◽  
Avon Longitudinal Study ◽  
Insight Into

Epigenome-wide association studies (EWAS) seek to quantify associations between traits/exposures and DNA methylation measured at thousands or millions of CpG sites across the genome. In recent years, the increase in availability of DNA methylation measures in population-based cohorts and case-control studies has resulted in a dramatic expansion of the number of EWAS being performed and pub-lished. To make this rich source of results more accessible, we have manually curated a database of CpG-trait associations (with p&lt;1x10-4) from published EWAS, each assaying over 100,000 CpGs in at least 100 individuals. From 2021-01-29, The EWAS Catalog contained 1,045,303 associations from over 1000 EWAS. This includes 652,530 associations from 264 peer-reviewed publications. In addi-tion, it also contains summary statistics for 392,773 associations from 428 EWAS, performed in data from the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Gene Expression Om-nibus (GEO). The database is accompanied by a web-based tool and R package, giving researchers the opportunity to quickly and easily query EWAS associations and gain insight into the molecular under-pinnings of disease as well as the impact of traits and exposures on the DNA methylome. The EWAS Catalog is available at: http://www.ewascatalog.org.

scholarly journals Orienting the causal relationship between imprecisely measured traits using genetic instruments

2017 ◽  
Author(s):  
Gibran Hemani ◽  
Kate Tilling ◽  
George Davey Smith
Keyword(s):  
Dna Methylation ◽  
Measurement Error ◽  
Causal Structure ◽  
Association Studies ◽  
Sensitivity Analyses ◽  
Mendelian Randomisation ◽  
Genome Wide Association Studies ◽  
Genetic Associations ◽  
Wrong Answer ◽  
Causal Direction

AbstractInference of the causal structure that induces correlations between two traits can be achieved by combining genetic associations with a mediation-based approach, as is done in the causal inference test (CIT) and others. However, we show that measurement error in the phenotypes can lead to mediation-based approaches inferring the wrong causal direction, and that increasing sample sizes has the adverse effect of increasing confidence in the wrong answer. Here we introduce an extension to Mendelian randomisation, a method that uses genetic associations in an instrumentation framework, that enables inference of the causal direction between traits, with some advantages. First, it is less susceptible to bias in the presence of measurement error; second, it is more statistically efficient; third, it can be performed using only summary level data from genome-wide association studies; and fourth, its sensitivity to measurement error can be evaluated. We apply the method to infer the causal direction between DNA methylation and gene expression levels. Our results demonstrate that, in general, DNA methylation is more likely to be the causal factor, but this result is highly susceptible to bias induced by systematic differences in measurement error between the platforms. We emphasise that, where possible, implementing MR and appropriate sensitivity analyses alongside other approaches such as CIT is important to triangulate reliable conclusions about causality.

scholarly journals Grandmaternal smoking during pregnancy is associated with differential DNA methylation in their grandchildren

2021 ◽  
Author(s):  
Sarah Holmes Watkins ◽  
Yasmin Iles-Caven ◽  
Marcus Pembrey ◽  
Jean Golding ◽  
Matthew Suderman
Keyword(s):  
Dna Methylation ◽  
Binding Sites ◽  
Association Studies ◽  
Epidemiological Studies ◽  
Limited Evidence ◽  
Smoking During Pregnancy ◽  
Cpg Sites ◽  
Specific Effects ◽  
Imprinting Control Region ◽  
First Time

AbstractThe idea that information can be transmitted to subsequent generation(s) by epigenetic means has been studied for decades but remains controversial in humans. Epidemiological studies have established that grandparental exposures are associated with health outcomes in their grandchildren, often with sex-specific effects; however the mechanism of transmission is still unclear. We conducted Epigenome Wide Association Studies (EWAS) to test whether grandmaternal smoking during pregnancy is associated with altered DNA methylation (DNAm) in their adolescent grandchildren. We used data from a birth cohort, with discovery and replication datasets of 1225 and 708 individuals (respectively), aged 15-17 years, and tested replication in the same individuals at birth and 7 years. We show for the first time that DNAm at a small number of loci is associated with grandmaternal smoking in humans, and their locations in the genome suggest hypotheses of transmission. We observe and replicate sex-specific associations at two sites on the X chromosome, one located in an imprinting control region and both within transcription factor binding sites (TFBSs). In fact, we observe enrichment for TFBSs among the CpG sites with the strongest associations, suggesting that TFBSs may be a mechanism by which grandmaternal exposures influence offspring DNA methylation. There is limited evidence that these associations appear at earlier timepoints, so effects are not static throughout development. The implication of this work is that effects of smoking during pregnancy may induce DNAm changes in later generations and that these changes are often sex-specific, in line with observational associations.

Strong Association between Serotonin Transporter 5-HTTVNTR Variant and Psychoactive Substance (Nicotine) Use in the Turkish Cypriot Population

2020 ◽  
Vol 21 (6) ◽  
pp. 466-470
Author(s):  
Emine Kandemis ◽  
Gulten Tuncel ◽  
Ozen Asut ◽  
Sehime G. Temel ◽  
Mahmut C. Ergoren
Keyword(s):  
Serotonin Transporter ◽  
Association Studies ◽  
Strong Association ◽  
Smoking Behavior ◽  
Population Based ◽  
Genome Wide Association Studies ◽  
Genotype Distribution ◽  
Psychological Traits ◽  
Wide Range ◽  
Turkish Cypriot

Background: The use of psychoactive substances is one of the most dangerous social problems worldwide. Nicotine dependence results from the interaction between neurobiological, environmental and genetic factors. Serotonin is a neurotransmitter that has a wide range of central nervous system activities. The serotonin transporter gene has been previously linked to psychological traits. Objective: A variable number of tandem repeats within the serotonin transporter-linked polymorphic gene region are believed to alter the transcriptional efficiency of the 5-HTT gene. Therefore, we aimed to investigate the association between this polymorphic site and smoking behavior in the Turkish Cypriot population. Methods: A total of 259 (100 smokers, 100 non-smokers and 59 ex-smokers) Turkish Cypriots were included in this population-based cross-sectional study. Genomic DNA was extracted from peripheral blood samples and the 5-HTTVNTR2 polymorphisms were determined by the PCR-RFLP. Results: The allelic frequency and genotype distribution results of this study showed a strong association (P<0.0001) between smokers and non-smokers. No statistical significance was found between non-smokers and ex-smokers. Conclusion: This is the first genetic epidemiology study to investigate the allelic frequencies of 5-HTTVNTR2 polymorphisms associated with smoking behavior in the Turkish Cypriot population. Based on the results of this study, genome-wide association studies should be designed for preventive medicine in this population.

scholarly journals Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Daniel L. McCartney ◽  
Josine L. Min ◽  
Rebecca C. Richmond ◽  
Ake T. Lu ◽  
Maria K. Sobczyk ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Genome Wide Association ◽  
Biological Aging ◽  
Genome Wide Association Studies ◽  
Genetic Loci ◽  
Biomarkers Of Aging ◽  
Genome Wide ◽  
Shared Genetic

Abstract Background Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field. Results Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels. Conclusion This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.

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