Heritability of DNA methylation in threespine stickleback (Gasterosteus aculeatus)

Epigenetic mechanisms underlying phenotypic change are hypothesized to contribute to population persistence and adaptation in the face of environmental change. To date, few studies have explored the heritability of intergenerationally stable methylation levels in natural populations, and little is known about the relative contribution of cis- and trans-regulatory changes to methylation variation. Here, we explore the heritability of DNA methylation, and conduct methylation quantitative trait loci (meQTLs) analysis to investigate the genetic architecture underlying methylation variation between marine and freshwater ecotypes of threespine stickleback (Gasterosteus aculeatus). We quantitatively measured genome-wide DNA methylation in fin tissue using reduced representation bisulfite sequencing of F1 and F2 crosses, and their marine and freshwater source populations. We identified cytosines (CpG sites) that exhibited stable methylation levels across generations. We found that additive genetic variance explained an average of 24–35% of the methylation variance, with a number of CpG sites possibly autonomous from genetic control. We also detected both cis- and trans-meQTLs, with only trans-meQTLs overlapping with previously identified genomic regions of high differentiation between marine and freshwater ecotypes. Finally, we identified the genetic architecture underlying two key CpG sites that were differentially methylated between ecotypes. These findings demonstrate a potential role for DNA methylation in facilitating adaptation to divergent environments and improve our understanding of the heritable basis of population epigenomic variation.     

Environmentally induced phenotypes and DNA methylation: how to deal with unpredictable conditions until the next generation and after

Organisms often respond to environmental changes by producing alternative phenotypes. Epigenetic processes such as DNA methylation may contribute to environmentally induced phenotypic variation by modifying gene expression. Changes in DNA methylation, unlike DNA mutations, can be influenced by the environment; they are stable at the time scale of an individual and present different levels of heritability. These characteristics make DNA methylation a potentially important molecular process to respond to environmental change. The aim of this review is to present the implications of DNA methylation on phenotypic variations driven by environmental changes. More specifically, we explore epigenetic concepts concerning phenotypic change in response to the environment and heritability of DNA methylation, namely the Baldwin effect and genetic accommodation. Before addressing this point, we report major differences in DNA methylation across taxa and the role of this modification in producing and maintaining environmentally induced phenotypic variation. We also present the different methods allowing the detection of methylation polymorphism. We believe this review will be helpful to molecular ecologists, in that it highlights the importance of epigenetic processes in ecological and evolutionary studies.     

Genetic and environmental influences on self-esteem in a Japanese twin sample.

The purpose of the present study is to clarify the mechanism of Japanese self-esteem (SE) in genetic and environmental influences using twin methodology. Eighty-one pairs of adolescent twins, including 50 pairs of monozygotic (MZ) twins and 31 pairs of dizygotic (DZ) twins, participated in this study. Self-esteem was assessed using the Rosenberg Self-Esteem Scale (RSES), translated into Japanese. As a result of using univariate twin analyses, model comparisons using the Akaike Information Criterion (AIC) indicated that the AE model was the best fit (AIC = -5.35). In the best-fitting AE model, the heritability (a2) of SE was revealed to be moderate, accounting for 49% of the variance; environmental influences (individual-specific environmental factors) explained 51% of the variance. These results are consistent with the findings of some behavioral genetics studies of SE in the West and show that there is no difference between Western and Japanese populations in the mechanism of SE considering genetic and environmental influences. The results also suggest the importance of considering both genetic and environmental factors in studies of Japanese SE.     

Genetic determination of head-size-related anthropometric traits in an ethnically homogeneous sample of 373 Indian pedigrees of West Bengal

The substantial involvement of genetic factors in the determination of head-size and head-shape traits has been firmly established. However, there has been a lack of agreement on a number of specific issues concerning the pattern of inheritance of craniofacial features. In this study we examined some of these issues in a large, ethnically homogeneous sample of Indian pedigrees. The data included 1,263 individuals belonging to 373 nuclear families. Eleven raw head-size traits and two synthetic phenotypes, interpreted as horizontal and vertical head-size components (HOC and VEC, respectively), were used in the analysis. To establish the pattern of inheritance of head traits, we carried out univariate and bivariate analyses. Maximum heritability estimates ranged from 0.41 to 0.83 for the studied head-size phenotypes. The portion of the total residual variance attributable to putative additive genetic factors was 68.3% and 70.3% for HOC and VEC, respectively, and common familial factor effects were found to be nonsignificant. The extent of genetic influences did not differ significantly with respect to sex or between HOC and VEC. The results of bivariate variance decomposition analysis strongly suggest the existence of common genetic factors simultaneously affecting HOC and VEC; 41.8% of the two traits' total residual variance was attributable to the effect of these common genetic factors.     

Narrow-sense heritability and <Emphasis Type="Italic">P</Emphasis><Subscript>ST</Subscript> estimates of DNA methylation in three <Emphasis Type="Italic">Populus nigra</Emphasis> L. populations under contrasting water availability

In a context of climate change and forest decline, a better understanding of the sources of tree flexibility involved in phenotypic plasticity and adaptation is needed. These last years, the role of epigenetics in the response to environmental variations has been established in several model plants at the genotype level but little is known at the level of natural populations grown in pedoclimatic sites. Here, we focused on three French natural populations of black poplar, a key pioneer tree from watersheds, planted in common garden and subjected to controlled variations of water availability. We estimated common genetic parameters such as narrow-sense heritability (h²), phenotypic differentiation index (P_ST), and the overall genetic differentiation index (F_ST) from genome-wide SNPs to evaluate the extent of epigenetic variations. Indeed, global DNA methylation levels from individuals exposed to drought or irrigated in a common garden were used. We found that the three populations were not distinguished by their levels of DNA methylation. However, a moderate drought was associated to a significant decrease in DNA methylation in the populations. Narrow-sense heritability and P_ST estimates of DNA methylation were similar to those found for biomass productivity. Heritability and P_ST were higher when trees were subjected to drought than in control condition. Negative genetic correlations between global DNA methylation and height or biomass were detected in drought condition only. Altogether, our data highlight that global DNA methylation acts as a genetic marker of natural population differentiation under drought stress in a pedoclimatic context.     

A rapid generalized least squares model for a genome-wide quantitative trait association analysis in families

Genome-wide association studies (GWAS) using family data involve association analyses between hundreds of thousands of markers and a trait for a large number of related individuals. The correlations among relatives bring statistical and computational challenges when performing these large-scale association analyses. Recently, several rapid methods accounting for both within- and between-family variation have been proposed. However, these techniques mostly model the phenotypic similarities in terms of genetic relatedness. The familial resemblances in many family-based studies such as twin studies are not only due to the genetic relatedness, but also derive from shared environmental effects and assortative mating. In this paper, we propose 2 generalized least squares (GLS) models for rapid association analysis of family-based GWAS, which accommodate both genetic and environmental contributions to familial resemblance. In our first model, we estimated the joint genetic and environmental variations. In our second model, we estimated the genetic and environmental components separately. Through simulation studies, we demonstrated that our proposed approaches are more powerful and computationally efficient than a number of existing methods are. We show that estimating the residual variance-covariance matrix in the GLS models without SNP effects does not lead to an appreciable bias in the p values as long as the SNP effect is small (i.e. accounting for no more than 1% of trait variance).     

Causes of blood methylomic variation for middle-aged women measured by the HumanMethylation450 array

To address the limitations in current classic twin/family research on the genetic and/or environmental causes of human methylomic variation, we measured blood DNA methylation for 479 women (mean age 56 years) including 66 monozygotic (MZ), 66 dizygotic (DZ) twin pairs and 215 sisters of twins, and 11 random technical duplicates using the HumanMethylation450 array. For each methylation site, we estimated the correlation for pairs of duplicates, MZ twins, DZ twins, and siblings, fitted variance component models by assuming the variation is explained by genetic factors, by shared and individual environmental factors, and by independent measurement error, and assessed the best fitting model. We found that the average (standard deviation) correlations for duplicate, MZ, DZ, and sibling pairs were 0.10 (0.35), 0.07 (0.21), -0.01 (0.14) and -0.04 (0.07). At the genome-wide significance level of 10^?7, 93.3% of sites had no familial correlation, and 5.6%, 0.1%, and 0.2% of sites were correlated for MZ, DZ, and sibling pairs. For 86.4%, 6.9%, and 7.1% of sites, the best fitting model included measurement error only, a genetic component, and at least one environmental component. For the 13.6% of sites influenced by genetic and/or environmental factors, the average proportion of variance explained by environmental factors was greater than that explained by genetic factors (0.41 vs. 0.37, P value <10^?15). Our results are consistent with, for middle-aged woman, blood methylomic variation measured by the HumanMethylation450 array being largely explained by measurement error, and more influenced by environmental factors than by genetic factors.     

Genetic determination of acute phase reactant levels: the strong heart study

OBJECTIVE: C-reactive protein (CRP), fibrinogen and plasminogen activating inhibitor-1 (PAI-1) are acute phase reactants (APRs); and high levels are indicative of physiologic inflammatory responses. Basal (non-stimulated) APR levels have also been shown to predict atherosclerotic complications in a number of populations. We sought to determine the relative contributions of genetic and environmental factors influencing basal serum levels of APRs. METHODS: This study used univariate quantitative genetic analyses to partition the phenotypic variance of these APRs into their additive genetic and environmental components using maximum likelihood variance decomposition methods. Bivariate analyses were done to detect genetic correlation between APRs. The computer program SOLAR was used to perform these analyses. RESULTS: The Strong Heart Study (SHS) includes information on approximately 1,294 American Indian relative pairs. The proportion of variance due to environmental and acquired covariates affecting these APRs was modest, ranging from 16-20%. The proportion of variance due to genetic factors (heritability) ranged from 24-46%. In addition, there were significant genetic correlations between CRP/fibrinogen (rho=0.41 +/- 0.12) and CRP/PAI-1 (rho=0.46 +/- 0.19); but not between fibrinogen/PAI-1. CONCLUSION: In the SHS cohort, the levels of APRs are determined to a substantial degree by genetic influences, and CRP shares common genetic determinants with fibrinogen and PAI-1.     

Characterization of the contribution of shared environmental and genetic factors to metabolic syndrome methylation heritability and familial correlations

Background

Transgenerational epigenetic inheritance has been posited as a possible contributor to the observed heritability of metabolic syndrome (MetS). Yet the extent to which estimates of epigenetic inheritance for DNA methylation sites are inflated by environmental and genetic covariance within families is still unclear. We applied current methods to quantify the environmental and genetic contributors to the observed heritability and familial correlations of four previously associated MetS methylation sites at three genes (CPT1A, SOCS3 and ABCG1) using real data made available through the GAW20.

Results

Our findings support the role of both shared environment and genetic variation in explaining the heritability of MetS and the four MetS cytosine-phosphate-guanine (CpG) sites, although the resulting heritability estimates were indistinguishable from one another. Familial correlations by type of relative pair generally followed our expectation based on relatedness, but in the case of sister and parent pairs we observed nonsignificant trends toward greater correlation than expected, as would be consistent with the role of shared environmental factors in the inflation of our estimated correlations.

Conclusions

Our work provides an interesting and flexible statistical framework for testing models of epigenetic inheritance in the context of human family studies. Future work should endeavor to replicate our findings and advance these methods to more robustly describe epigenetic inheritance patterns in human populations.

     

Role of environment and behaviour in familial resemblances of Plasmodium falciparum infection in a population of Senegalese children

Despite the importance of both environment and behaviour in vector-borne disease epidemiology, these factors are unable to explain alone the distribution of cases in a community and the diversity of clinical presentations, suggesting the involvement of more individual factors such as age, sex, immunity or genetic background. The existence of a genetic factor involved in the susceptibility/resistance to a disease can be suspected by the demonstration of a familial aggregation of cases or by the stability over time of infectious status (infected vs. uninfected; mean level of parasite density (PD), etc.). These familial resemblances can be explained by shared environment, family habits and behaviours (use of bed nets, field activities, etc.). In this preliminary study, we essentially investigated the influence of environment and behaviour on Plasmodium falciparum infection levels and reported the effects of these factors on the existence of familial resemblances. Our results are consistent with the existence of familial resemblances for both the level of P. falciparum infection and the qualitative infection status (QIS) (infected vs. uninfected) that seem to be more related to shared behaviour and environment than to a genetic factor. However, although familial resemblances decreased significantly when adjusted for shared behaviour and environment, this decrease is around 12% for the variability between families, against only 4.5% of that within families. Furthermore, we also demonstrated that the QIS is remarkably stable over time. Both these results are consistent with the hypothesis of the existence of a strong and complex individual factor involved in the control of infection status.     

Familial Resemblance in Eating Behaviors in Men and Women from the Quebec Family Study

Objective: It is commonly recognized that genetic, environmental, behavioral, and social factors are involved in the development of obesity. The family environment may play a key role in shaping children's eating behaviors. The purpose of this study was to estimate the degree of familial resemblance in eating behavioral traits (cognitive dietary restraint, disinhibition, and susceptibility to hunger). Research Methods and Procedures: Eating behavioral traits were assessed with the Three‐Factor Eating Questionnaire in 282 men and 402 women (202 families) from the Quebec Family Study. Familial resemblance for each trait (adjusted for age, sex, and BMI) was investigated using a familial correlation model. Results: The pattern of familial correlation showed significant spouse correlation for the three eating behavior phenotypes, as well as significant parent‐offspring and sibling correlations for disinhibition and susceptibility to hunger. According to the most parsimonious model, generalized heritability estimates (including genetic and shared familial environmental effects) reached 6%, 18%, and 28% for cognitive dietary restraint, disinhibition, and susceptibility to hunger, respectively. Discussion: These results suggest that there is a significant familial component to eating behavioral traits but that the additive genetic component appears to be small, with generalized heritability estimates ranging from 6% to 28%. Thus, non‐familial environmental factors and gene‐gene and gene‐environmental interactions seem to be the major determinants of the eating/behavioral traits.     

Heritability and role for the environment in DNA methylation in AXL receptor tyrosine kinase

DNA methylation in AXL, a receptor tyrosine kinase relevant in cancer and immune function, is reportedly highly heritable. We present evidence to suggest that heritability of DNA methylation in AXL is variable, dependent on population characteristics and cell type studied. Moreover, environmental exposures in utero, particularly exposure to maternal smoking, contributes to variation in DNA methylation of select CpG loci that can affect calculations of heritability. Children exposed to maternal smoking in utero had a 2.3% increase (95 % CI 0.3, 4.2) in DNA methylation in AXL, which was magnified in girls as compared to boys. These results present compelling evidence that environmental exposure to tobacco smoke during pregnancy may alter DNA methylation levels in subtle but potentially important ways, and that these changes are persistent years after birth.     

Genetic and environmental influences on factors associated with cardiovascular disease and the metabolic syndrome

The relative influence of genetics and the environment on factors associated with cardiovascular disease (CVD) and metabolic syndrome (MetS) remains unclear. We performed model-fitting analyses to quantify genetic, common environmental, and unique environmental variance components of factors associated with CVD and MetS [waist circumference, blood pressure, fasting plasma glucose and insulin, homeostatic model assessment of insulin resistance (HOMA-IR), and fasting plasma lipids] in adult male and female monozygotic twins reared apart or together. We also investigated whether MetS components share common influences. Plasma cholesterol and triglyceride concentrations were highly heritable (56–77%, statistically significant). Waist circumference, plasma glucose and insulin, HOMA-IR, and blood pressure were moderately heritable (43–57%, statistically significant). Unique environmental factors contributed to the variance of all variables (20–38%, perforce statistically significant). Common environmental factors contributed 23, 30, and 42% (statistically significant) of the variance of waist circumference, systolic blood pressure, and plasma glucose, respectively. Two shared factors influenced MetS components; one influenced all components except HDL cholesterol, another influenced only lipid (triglyceride and HDL cholesterol) concentrations. These results suggest that genetic variance has a dominant influence on total variance of factors associated with CVD and MetS and support the proposal of one or more underlying pathologies of MetS.     

Epigenetics,heritability and longitudinal analysis

Background

Longitudinal data and repeated measurements in epigenome-wide association studies (EWAS) provide a rich resource for understanding epigenetics. We summarize 7 analytical approaches to the GAW20 data sets that addressed challenges and potential applications of phenotypic and epigenetic data. All contributions used the GAW20 real data set and employed either linear mixed effect (LME) models or marginal models through generalized estimating equations (GEE). These contributions were subdivided into 3 categories: (a) quality control (QC) methods for DNA methylation data; (b) heritability estimates pretreatment and posttreatment with fenofibrate; and (c) impact of drug response pretreatment and posttreatment with fenofibrate on DNA methylation and blood lipids.

Results

Two contributions addressed QC and identified large statistical differences with pretreatment and posttreatment DNA methylation, possibly a result of batch effects. Two contributions compared epigenome-wide heritability estimates pretreatment and posttreatment, with one employing a Bayesian LME and the other using a variance-component LME. Density curves comparing these studies indicated these heritability estimates were similar. Another contribution used a variance-component LME to depict the proportion of heritability resulting from a genetic and shared environment. By including environmental exposures as random effects, the authors found heritability estimates became more stable but not significantly different. Two contributions investigated treatment response. One estimated drug-associated methylation effects on triglyceride levels as the response, and identified 11 significant cytosine-phosphate-guanine (CpG) sites with or without adjusting for high-density lipoprotein. The second contribution performed weighted gene coexpression network analysis and identified 6 significant modules of at least 30 CpG sites, including 3 modules with topological differences pretreatment and posttreatment.

Conclusions

Four conclusions from this GAW20 working group are: (a) QC measures are an important consideration for EWAS studies that are investigating multiple time points or repeated measurements; (b) application of heritability estimates between time points for individual CpG sites is a useful QC measure for DNA methylation studies; (c) drug intervention demonstrated strong epigenome-wide DNA methylation patterns across the 2 time points; and (d) new statistical methods are required to account for the environmental contributions of DNA methylation across time. These contributions demonstrate numerous opportunities exist for the analysis of longitudinal data in future epigenetic studies.

     

Estimating Modifying Effect of Age on Genetic and Environmental Variance Components in Twin Models

Twin studies have been adopted for decades to disentangle the relative genetic and environmental contributions for a wide range of traits. However, heritability estimation based on the classical twin models does not take into account dynamic behavior of the variance components over age. Varying variance of the genetic component over age can imply the existence of gene–environment (G × E) interactions that general genome-wide association studies (GWAS) fail to capture, which may lead to the inconsistency of heritability estimates between twin design and GWAS. Existing parametric G × E interaction models for twin studies are limited by assuming a linear or quadratic form of the variance curves with respect to a moderator that can, however, be overly restricted in reality. Here we propose spline-based approaches to explore the variance curves of the genetic and environmental components. We choose the additive genetic, common, and unique environmental variance components (ACE) model as the starting point. We treat the component variances as variance functions with respect to age modeled by B-splines or P-splines. We develop an empirical Bayes method to estimate the variance curves together with their confidence bands and provide an R package for public use. Our simulations demonstrate that the proposed methods accurately capture dynamic behavior of the component variances in terms of mean square errors with a data set of >10,000 twin pairs. Using the proposed methods as an alternative and major extension to the classical twin models, our analyses with a large-scale Finnish twin data set (19,510 MZ twins and 27,312 DZ same-sex twins) discover that the variances of the A, C, and E components for body mass index (BMI) change substantially across life span in different patterns and the heritability of BMI drops to ∼50% after middle age. The results further indicate that the decline of heritability is due to increasing unique environmental variance, which provides more insights into age-specific heritability of BMI and evidence of G × E interactions. These findings highlight the fundamental importance and implication of the proposed models in facilitating twin studies to investigate the heritability specific to age and other modifying factors.     

Genes and environment

Many quantitative characters depend on the action of a large number of genes and environmental factors. The mode of inheritance of these characters is polygenic. The phenotypic variance of the character is the sum of the components, thus the genetic and the environmental variances (VP = VG + VE). The degree of genetic determination VG/VP and VE/VP are difficult to estimate in man. The heritability a related coefficient to VG/VP can be estimated from the degree of ressemblance between relatives. The heritability is the additive genetique variance as a proportion of the phenotypic variance. Polygenic threshold inheritance can account for the familial non mendelian distribution of multifactorial diseases.     

2型糖尿病环境因素与DNA甲基化的研究进展

2 型糖尿病(Type 2 diabetes mellitus, T2DM)是由于遗传与环境因素共同作用而引起葡萄糖代谢紊乱的疾病。DNA甲基化修饰的研究发现环境因素可以通过影响DNA甲基化修饰, 显著地增加T2DM的患病风险。目前, T2DM环境相关基因的DNA甲基化修饰研究已在人及动物的不同组织中取得进展。此外, T2DM相关基因的甲基化研究主要集中在糖代谢、能量代谢、炎症等。文章系统地综述了目前T2DM致病环境因素与DNA甲基化研究进展。     

Investigation of parent-of-origin effects induced by fenofibrate treatment on triglycerides levels

Background

Genome-wide association studies performed on triglycerides (TGs) have not accounted for epigenetic mechanisms that may partially explain trait heritability.

Results

Parent-of-origin (POO) effect association analyses using an agnostic approach or a candidate approach were performed for pretreatment TG levels, posttreatment TG levels, and pre- and posttreatment TG-level differences in the real GAW20 family data set. We detected 22 genetic variants with suggestive POO effects with at least 1 phenotype (P ≤ 10^− 5). We evaluated the association of these 22 significant genetic variants showing POO effects with close DNA methylation probes associated with TGs. A total of 18 DNA methylation probes located in the vicinity of the 22 SNPs were associated with at least 1 phenotype and 6 SNP-probe pairs were associated with DNA methylation probes at the nominal level of P < 0.05, among which 1 pair presented evidence of POO effect. Our analyses identified a paternal effect of SNP rs301621 on the difference between pre- and posttreatment TG levels (P = 1.2 × 10^− 5). This same SNP showed evidence for a maternal effect on methylation levels of a nearby probe (cg10206250; P = 0.01). Using a causal inference test we established that the observed POO effect of rs301621 was not mediated by DNA methylation at cg10206250.

Conclusions

We performed POO effect association analyses of SNPs with TGs, as well as association analyses of SNPs with DNA methylation probes. These analyses, which were followed by a causal inference test, established that the paternal effect at the SNP rs301621 is induced by treatment and is not mediated by methylation level at cg10206250.

     

Familial Clustering of Abdominal Visceral Fat and Total Fat Mass: The Québec Family Study

The evidence for common familial factors underlying total fat mass (estimated from underwater weighing) and abdominal visceral fat (assessed from CT scan) was examined in families participating in phase 2 of the Québec Family Study (QFS) using a bivariate familial correlation model. Previous QFS investigations suggest that both genetic (major and polygenic) and familial environmental factors influence each phenotype, accounting for between 55% to 71% of the phenotypic variance in fat mass, and between 55% to 72% for abdominal visceral fat The current study suggests that the bivariate familial effect ranges from 29% to 50%. This pattern suggests that there may be common familial determinants for abdominal visceral fat and total fat mass, as well as additional familial factors which are specific to each. The relatively high spouse cross-trait correlations usually suggest that a large percent of the bivariate familial effect may be environmental in origin. However, if mating is not random, then the spouse resemblance may reflect either genetic or environmental causes, depending on the source [i.e., through similar genes or cohabitation (environmental) effects]. Finally, there are significant sex differences in the magnitude of the familial cross-trait correlations involving parents, but not offspring, suggesting complex generation (i.e., age) and sex effects. For example, genes may turn on or off as a function of age and sex, and/or there may be an accumulation over time of effects due to the environment which may vary by sex. Whether the common familial factors are genetic (major and/or polygenic), environmental, or some combination of both, and whether the familial expression depends on sex and/or age warrants further investigation using more complex models.