Three-dimensional endovaginal ultrasound assessment using the levator ani deficiency score in primiparas: A replication study.

INTRODUCTION: It is essential to assess the levator ani properly as part of clinical care in patients presenting with pelvic floor dysfunction. The levator ani deficiency scoring system is a previously published method to assess levator ani defects with three-dimensional endovaginal ultrasound. The primary aim of this study was to determine the intra- and interrater reliability of the levator ani deficiency score in a cohort of non-instrumentally delivered primiparas. MATERIAL AND METHODS: Primiparas (n = 141) were examined at least 1 year after vaginal birth. Three-dimensional endovaginal ultrasound volumes were acquired by a single examiner using two different automated ultrasound probes. The volumes were analyzed by two separate raters who were blinded to each other's assessments. Descriptive statistics were calculated for levator ani deficiency score and categorized into three levels (mild, moderate, severe). Kendall's tau-b was calculated for intra- and interrater comparisons. RESULTS: Intrarater comparisons of levator ani deficiency score and levator ani deficiency category were high (Kendall's tau-b ≥0.80 for Rater 1; >0.79 for Rater 2). Interrater comparisons of levator ani deficiency score and levator ani deficiency category were also high (Kendall's tau-b >0.9 for assessment 1 and >0.78 for assessment 2). Varying by rater, probe and assessment, 75.9%-80.1% of the study population had no/mild deficiency, 6.4%-9.2% had moderate deficiency, and 4.3%-6.4% had severe levator ani deficiency. CONCLUSIONS: The levator ani deficiency scoring system is a feasible method to assess defects of the levator ani muscle and can be reproduced with high intra- and interrater correlations. Using the scoring system in clinical practice may facilitate concordant assessment between different examiners. However, the system should be used to support clinical findings and symptomatology and not as a screening tool, as the score is lacking the category of no levator ani deficiency.

One-year follow-up after standardized perineal reconstruction in women with deficient perineum after vaginal delivery.

INTRODUCTION: Perineal tears are common after childbirth and, if not surgically repaired, they may result in a deficient perineum that can cause symptoms of pelvic floor dysfunction. Perineal reconstruction aims to restore the perineal body and increase the support of the pelvic floor. The objective of the present study was to estimate symptom reduction after perineal reconstruction in patients with deficient perineum after vaginal delivery and to compare outcomes between participants with or without concomitant levator ani muscle deficiency. MATERIAL AND METHODS: Participants presenting at the Karolinska Pelvic Floor Center with symptoms of deficient perineum at least 1 year after vaginal birth were invited to the study. Inclusion criteria were a visible perineal scar and confirmed anatomic defect. Levator ani defects were assessed using the Levator Ani Deficiency score. A perineal reconstruction was performed in a standardized way. Subjective symptoms were evaluated using the validated "Karolinska Symptoms After Perineal Tear Inventory" at baseline and 1-year follow-up. A score difference in the symptom of an acquired sensation of a wide vagina was the primary outcome. Results were stratified by the presence or absence of a levator ani deficiency. RESULTS: A perineal reconstruction was performed in 131 patients and 128 patients completed the Karolinska Symptoms After Perineal Tear Inventory at baseline and 119 at follow-up. Median age was 36.1 (interquartile range [IQR] 7.9), median body mass index 22.3 (IQR 5.1) and a median of two vaginal deliveries. Fifty-four women (41.2%) had a levator ani deficiency. The mean score reduction for the item "Do you feel that your vagina is too wide/loose?" was -1.56 (SD 0.96; P < 0.001) from a mean score of 2.75 (maximum 3) at baseline. The mean total score reduction was -9.1 points (SD 5.3; P < 0.001) from a mean score of 18.4 (maximum 33) points at baseline. There were no significant differences between groups when stratifying by levator ani deficiency. CONCLUSIONS: Our results show that perineal reconstructive surgery significantly decreases symptoms of deficient perineum after vaginal delivery. A concomitant levator ani defect does not affect the symptom reduction of an acquired sensation of a wide vagina or the total score reduction after surgery.

Age-of-onset information helps identify 76 genetic variants associated with allergic disease.

Risk factors that contribute to inter-individual differences in the age-of-onset of allergic diseases are poorly understood. The aim of this study was to identify genetic risk variants associated with the age at which symptoms of allergic disease first develop, considering information from asthma, hay fever and eczema. Self-reported age-of-onset information was available for 117,130 genotyped individuals of European ancestry from the UK Biobank study. For each individual, we identified the earliest age at which asthma, hay fever and/or eczema was first diagnosed and performed a genome-wide association study (GWAS) of this combined age-of-onset phenotype. We identified 50 variants with a significant independent association (P<3x10-8) with age-of-onset. Forty-five variants had comparable effects on the onset of the three individual diseases and 38 were also associated with allergic disease case-control status in an independent study (n = 222,484). We observed a strong negative genetic correlation between age-of-onset and case-control status of allergic disease (rg = -0.63, P = 4.5x10-61), indicating that cases with early disease onset have a greater burden of allergy risk alleles than those with late disease onset. Subsequently, a multivariate GWAS of age-of-onset and case-control status identified a further 26 associations that were missed by the univariate analyses of age-of-onset or case-control status only. Collectively, of the 76 variants identified, 18 represent novel associations for allergic disease. We identified 81 likely target genes of the 76 associated variants based on information from expression quantitative trait loci (eQTL) and non-synonymous variants, of which we highlight ADAM15, FOSL2, TRIM8, BMPR2, CD200R1, PRKCQ, NOD2, SMAD4, ABCA7 and UBE2L3. Our results support the notion that early and late onset allergic disease have partly distinct genetic architectures, potentially explaining known differences in pathophysiology between individuals.

Genetic Architectures of Childhood- and Adult-Onset Asthma Are Partly Distinct.

The extent to which genetic risk factors are shared between childhood-onset (COA) and adult-onset (AOA) asthma has not been estimated. On the basis of data from the UK Biobank study (n = 447,628), we found that the variance in disease liability explained by common variants is higher for COA (onset at ages between 0 and 19 years; h2g = 25.6%) than for AOA (onset at ages between 20 and 60 years; h2g = 10.6%). The genetic correlation (rg) between COA and AOA was 0.67. Variation in age of onset among COA-affected individuals had a low heritability (h2g = 5%), which we confirmed in independent studies and also among AOA-affected individuals. To identify subtype-specific genetic associations, we performed a genome-wide association study (GWAS) in the UK Biobank for COA (13,962 affected individuals) and a separate GWAS for AOA (26,582 affected individuals) by using a common set of 300,671 controls for both studies. We identified 123 independent associations for COA and 56 for AOA (37 overlapped); of these, 98 and 34, respectively, were reproducible in an independent study (n = 262,767). Collectively, 28 associations were not previously reported. For 96 COA-associated variants, including five variants that represent COA-specific risk factors, the risk allele was more common in COA- than in AOA-affected individuals. Conversely, we identified three variants that are stronger risk factors for AOA. Variants associated with obesity and smoking had a stronger contribution to the risk of AOA than to the risk of COA. Lastly, we identified 109 likely target genes of the associated variants, primarily on the basis of correlated expression quantitative trait loci (up to n = 31,684). GWAS informed by age of onset can identify subtype-specific risk variants, which can help us understand differences in pathophysiology between COA and AOA and so can be informative for drug development.

Changing genetic architecture of body mass index from infancy to early adulthood: an individual based pooled analysis of 25 twin cohorts.

BACKGROUND: Body mass index (BMI) shows strong continuity over childhood and adolescence and high childhood BMI is the strongest predictor of adult obesity. Genetic factors strongly contribute to this continuity, but it is still poorly known how their contribution changes over childhood and adolescence. Thus, we used the genetic twin design to estimate the genetic correlations of BMI from infancy to adulthood and compared them to the genetic correlations of height. METHODS: We pooled individual level data from 25 longitudinal twin cohorts including 38,530 complete twin pairs and having 283,766 longitudinal height and weight measures. The data were analyzed using Cholesky decomposition offering genetic and environmental correlations of BMI and height between all age combinations from 1 to 19 years of age. RESULTS: The genetic correlations of BMI and height were stronger than the trait correlations. For BMI, we found that genetic correlations decreased as the age between the assessments increased, a trend that was especially visible from early to middle childhood. In contrast, for height, the genetic correlations were strong between all ages. Age-to-age correlations between environmental factors shared by co-twins were found for BMI in early childhood but disappeared altogether by middle childhood. For height, shared environmental correlations persisted from infancy to adulthood. CONCLUSIONS: Our results suggest that the genes affecting BMI change over childhood and adolescence leading to decreasing age-to-age genetic correlations. This change is especially visible from early to middle childhood indicating that new genetic factors start to affect BMI in middle childhood. Identifying mediating pathways of these genetic factors can open possibilities for interventions, especially for those children with high genetic predisposition to adult obesity.

Eleven loci with new reproducible genetic associations with allergic disease risk.

BACKGROUND: A recent genome-wide association study (GWAS) identified 99 loci that contain genetic risk variants shared between asthma, hay fever, and eczema. Many more risk loci shared between these common allergic diseases remain to be discovered, which could point to new therapeutic opportunities. OBJECTIVE: We sought to identify novel risk loci shared between asthma, hay fever, and eczema by applying a gene-based test of association to results from a published GWAS that included data from 360,838 subjects. METHODS: We used approximate conditional analysis to adjust the results from the published GWAS for the effects of the top risk variants identified in that study. We then analyzed the adjusted GWAS results with the EUGENE gene-based approach, which combines evidence for association with disease risk across regulatory variants identified in different tissues. Novel gene-based associations were followed up in an independent sample of 233,898 subjects from the UK Biobank study. RESULTS: Of the 19,432 genes tested, 30 had a significant gene-based association at a Bonferroni-corrected P value of 2.5 × 10-6. Of these, 20 were also significantly associated (P < .05/30 = .0016) with disease risk in the replication sample, including 19 that were located in 11 loci not reported to contain allergy risk variants in previous GWASs. Among these were 9 genes with a known function that is directly relevant to allergic disease: FOSL2, VPRBP, IPCEF1, PRR5L, NCF4, APOBR, IL27, ATXN2L, and LAT. For 4 genes (eg, ATXN2L), a genetically determined decrease in gene expression was associated with decreased allergy risk, and therefore drugs that inhibit gene expression or function are predicted to ameliorate disease symptoms. The opposite directional effect was observed for 14 genes, including IL27, a cytokine known to suppress TH2 responses. CONCLUSION: Using a gene-based approach, we identified 11 risk loci for allergic disease that were not reported in previous GWASs. Functional studies that investigate the contribution of the 19 associated genes to the pathophysiology of allergic disease and assess their therapeutic potential are warranted.

Epigenome-wide meta-analysis of DNA methylation and childhood asthma.

BACKGROUND: Epigenetic mechanisms, including methylation, can contribute to childhood asthma. Identifying DNA methylation profiles in asthmatic patients can inform disease pathogenesis. OBJECTIVE: We sought to identify differential DNA methylation in newborns and children related to childhood asthma. METHODS: Within the Pregnancy And Childhood Epigenetics consortium, we performed epigenome-wide meta-analyses of school-age asthma in relation to CpG methylation (Illumina450K) in blood measured either in newborns, in prospective analyses, or cross-sectionally in school-aged children. We also identified differentially methylated regions. RESULTS: In newborns (8 cohorts, 668 cases), 9 CpGs (and 35 regions) were differentially methylated (epigenome-wide significance, false discovery rate < 0.05) in relation to asthma development. In a cross-sectional meta-analysis of asthma and methylation in children (9 cohorts, 631 cases), we identified 179 CpGs (false discovery rate < 0.05) and 36 differentially methylated regions. In replication studies of methylation in other tissues, most of the 179 CpGs discovered in blood replicated, despite smaller sample sizes, in studies of nasal respiratory epithelium or eosinophils. Pathway analyses highlighted enrichment for asthma-relevant immune processes and overlap in pathways enriched both in newborns and children. Gene expression correlated with methylation at most loci. Functional annotation supports a regulatory effect on gene expression at many asthma-associated CpGs. Several implicated genes are targets for approved or experimental drugs, including IL5RA and KCNH2. CONCLUSION: Novel loci differentially methylated in newborns represent potential biomarkers of risk of asthma by school age. Cross-sectional associations in children can reflect both risk for and effects of disease. Asthma-related differential methylation in blood in children was substantially replicated in eosinophils and respiratory epithelium.

Agreement between asthma questionnaire and health care register data.

PURPOSE: Risk factors and consequences of asthma can be studied by using validated questionnaires. The overall objective of this study was to assess the agreement of parental-reported asthma-related questions regarding their children against Swedish health care registers. METHODS: We linked a population-based twin cohort of 27 055 children aged 9 to 12 years to the Swedish Prescribed Drug Register, National Patient Register, and the primary care register. Parent-reported asthma was obtained from questionnaires, and diagnoses and medication were retrieved from the registers. For the agreement between the questionnaire and the registers, Cohen's kappa was estimated. RESULTS: The kappa of the "reported ever asthma" against a "register-based ever asthma" was 0.69 and 0.57 between the parental-"reported doctor's diagnosis" and "register-based doctor's diagnosis." The highest agreement between "reported current asthma" and "register-based current asthma" with at least 1 dispensed medication or a diagnosis applied to different time windows was seen for an 18-month window (kappa = 0.70). CONCLUSIONS: We found that parent-reported asthma-related questions showed on average good agreement with the Swedish health care registers. This implies that in-depth questionnaires with rich information on phenotypes are suitable proxies for asthma in general and can be used for health care research purposes.

Limited association between markers of stress during pregnancy and fetal growth in 'Born into Life', a new prospective birth cohort.

AIMS: We aimed to investigate the associations between perceived maternal stress or salivary cortisol levels during pregnancy and birthweight. METHODS: In 2010-2012, we recruited 92 women living in Stockholm, Sweden, and followed them from before conception and through pregnancy and childbirth. Their Perceived Stress Scale (PSS) scores and salivary cortisol levels were collected at 26-28 gestational weeks. Birthweight was collected from medical records. Linear regression analyses and Pearson correlations were performed between the PSS scores or cortisol levels and birthweight, respectively, adjusted for gestational age. RESULTS: No significant associations were found between PSS scores or cortisol levels and birthweight. There was a trend towards higher salivary cortisol levels among infants with lower birthweights, and this effect was attenuated after adjusting for gestational age. Morning cortisol levels (r = -0.31, p = 0.01), the decline in cortisol levels (r = -0.26, p = 0.03) and evening cortisol levels (r = -0.21, p = 0.09) were negatively correlated with PSS scores. CONCLUSION: Maternal stress during pregnancy was not associated with birthweight. The inverse correlation between PSS scores and cortisol levels may indicate other mechanisms for maternal stress on child outcomes than the previous explanation of hypothalamic-pituitary-adrenal axis activity.

Impact of childhood asthma on growth trajectories in early adolescence: Findings from the Childhood Asthma Prevention Study (CAPS).

BACKGROUND AND OBJECTIVE: Understanding the associations between childhood asthma and growth in early adolescence by accounting for the heterogeneity of growth during puberty has been largely unexplored. The objective was to identify sex-specific classes of growth trajectories during early adolescence, using a method which takes the heterogeneity of growth into account and to evaluate the association between childhood asthma and different classes of growth trajectories in adolescence. METHODS: Our longitudinal study included participants with a family history of asthma born during 1997-1999 in Sydney, Australia. Hence, all participants were at high risk for asthma. Asthma status was ascertained at 8 years of age using data from questionnaires and lung function tests. Growth trajectories between 11 and 14 years of age were classified using a latent basis growth mixture model. Multinomial regression analyses were used to evaluate the association between asthma and the categorized classes of growth trajectories. RESULTS: In total, 316 participants (51.6% boys), representing 51.3% of the entire cohort, were included. Sex-specific classes of growth trajectories were defined. Among boys, asthma was not associated with the classes of growth trajectories. Girls with asthma were more likely than girls without asthma to belong to a class with later growth (OR: 3.79, 95% CI: 1.33, 10.84). Excluding participants using inhaled corticosteroids or adjusting for confounders did not significantly change the results for either sex. CONCLUSION: We identified sex-specific heterogeneous classes of growth using growth mixture modelling. Associations between childhood asthma and different classes of growth trajectories were found for girls only.

The STOPPA Twin Study Explains the Exhaled Nitric Oxide and Asthma Link by Genetics and Sensitization.

BACKGROUND: The link between asthma and exhaled nitric oxide (FENO) is not completely understood. The aim of this study was to estimate the association between FENO and asthma, taking genetics, sensitization, and inhaled corticosteroids (ICS) into account. METHODS: A total of 681 twins (53% monozygotic [MZ] and 47% dizygotic [DZ]) from the population-based STOPPA study (mean age 12.6 years) were recruited and information on FENO (parts per billion), parental report of current asthma, sensitization to airborne allergens (Phadiatop; IgE ≥0.35 kUA/l), and ICS-treatment was collected. We estimated the association between FENO and asthma, sensitization, and ICS in all twins and within pairs (DZ and MZ) to address shared genetic and environmental factors. Linear regression of log-transformed FENO was used and results presented as exponentiated regression coefficients (exp[ß]), with 95% confidence interval (CI). RESULTS: We found an association between asthma and FENO in all twins, exp(ß) 1.31 [1.11, 1.54]. In within-pairs analysis, the association was stronger within DZ pairs discordant for FENO, exp(ß) 1.50 [1.19, 1.89], compared to MZ pairs, exp(ß) 1.07 [0.84, 1.37], p = .049. There was no difference in FENO in non-sensitized children with asthma, compared to children with neither asthma nor sensitization, exp(ß) 0.89 [0.77, 1.03]. However, increased FENO was associated with sensitization, exp(ß) 1.48 [1.30, 1.69], and with sensitization together with asthma, exp(ß) 1.98 [1.57, 2.51], in all twins and within DZ pairs discordant for FENO, but not in MZ pairs. The FENO asthma association remained in DZ pairs without regular ICS-treatment. CONCLUSIONS: The association between FENO and asthma is explained by genetics and sensitization.

Education in Twins and Their Parents Across Birth Cohorts Over 100 years: An Individual-Level Pooled Analysis of 42-Twin Cohorts.

Whether monozygotic (MZ) and dizygotic (DZ) twins differ from each other in a variety of phenotypes is important for genetic twin modeling and for inferences made from twin studies in general. We analyzed whether there were differences in individual, maternal and paternal education between MZ and DZ twins in a large pooled dataset. Information was gathered on individual education for 218,362 adult twins from 27 twin cohorts (53% females; 39% MZ twins), and on maternal and paternal education for 147,315 and 143,056 twins respectively, from 28 twin cohorts (52% females; 38% MZ twins). Together, we had information on individual or parental education from 42 twin cohorts representing 19 countries. The original education classifications were transformed to education years and analyzed using linear regression models. Overall, MZ males had 0.26 (95% CI [0.21, 0.31]) years and MZ females 0.17 (95% CI [0.12, 0.21]) years longer education than DZ twins. The zygosity difference became smaller in more recent birth cohorts for both males and females. Parental education was somewhat longer for fathers of DZ twins in cohorts born in 1990-1999 (0.16 years, 95% CI [0.08, 0.25]) and 2000 or later (0.11 years, 95% CI [0.00, 0.22]), compared with fathers of MZ twins. The results show that the years of both individual and parental education are largely similar in MZ and DZ twins. We suggest that the socio-economic differences between MZ and DZ twins are so small that inferences based upon genetic modeling of twin data are not affected.

Cohort Profile: Swedish Twin Study on Prediction and Prevention of Asthma (STOPPA).

Asthma is a common childhood disease and several risk factors have been identified; however, the impact of genes and environment is not fully understood. The aim of the Swedish Twin study On Prediction and Prevention of Asthma (STOPPA) is to identify environmental (birth characteristics and early life) and genetic (including epigenetic) factors as determinants for asthmatic disease. Based on the Child and Adolescent Twin Study in Sweden (CATSS) (parental interview at 9 or 12 years, N ~23,900) and an asthma and/or wheezing algorithm, we identified a sample of monozygotic (MZ) and dizygotic (DZ) same-sexed twin pairs. The twin pairs were classified as asthma concordant (ACC), asthma discordant (ADC) and healthy concordant (HCC). A sample of 9- to 14-year-old twins and their parents were invited to participate in a clinical examination. Background characteristics were collected in questionnaires and obtained from the National Health Registers. A clinical examination was performed to test lung function and capacity (spirometry with reversibility test and exhaled nitric oxide) and collect blood (serology and DNA), urine (metabolites), feces (microbiota), and saliva (cortisol). In total, 376 twin pairs (752 individual twins) completed the study, response rate 52%. All participating twins answered the questionnaire and >90% participated in lung function testing, blood-, and saliva sampling. This article describes the design, recruitment, data collection, measures, and background characteristics, as well as ongoing and planned analyses in STOPPA. Potential gains of the study include the identification of biomarkers, the emergence of candidates for drug development, and new leads for prevention of asthma and allergic disease.

Predictors of adolescents' consent to use health records for research and results from data collection in a Swedish twin cohort.

INTRODUCTION: Non-random selection into a study population due to differences between consenters and non-consenters may introduce participation bias. Past investigations of factors predicting consent to collection of medical health records for research imply that age, sex, health status, and education are of importance for participation, but disagree on the direction of effects. Very little is known about influences on consent from adolescents. METHODS: Two cohorts of Swedish 15-year-old twins (total n = 4,611) previously invited to the Child and Adolescent Twin Study in Sweden (CATSS) responded to a questionnaire with information on sex, individual's health, height, weight, and parental factors. The questionnaire included a question for consent to collection of medical health records. Predictors for consent were analyzed using logistic regression. Additionally, regional differences in the collection of health records of consenters were evaluated. RESULTS: Males were significantly less likely to consent compared to females (OR 0.74, 95% CI 0.64-0.85). The twin siblings' decision to consent was strongly associated with consent (OR 10.9, 95% CI 8.76-13.5), and individuals whose parents had responded to the original CATSS study were more likely to consent to record collection at age 15 (OR 2.2, 95% CI 1.81-2.75). Results of the subsequent collection of consenters' medical health records varied between geographical regions of Sweden. CONCLUSION: We identified several predictors for adolescents' consent to collection of their medical health records. Further selection was introduced through the subsequent record collection. Whether this will induce participation bias in future studies depends on the research questions' relationship to the identified predictors.

Genetic and environmental influences on human height from infancy through adulthood at different levels of parental education.

Genetic factors explain a major proportion of human height variation, but differences in mean stature have also been found between socio-economic categories suggesting a possible effect of environment. By utilizing a classical twin design which allows decomposing the variation of height into genetic and environmental components, we tested the hypothesis that environmental variation in height is greater in offspring of lower educated parents. Twin data from 29 cohorts including 65,978 complete twin pairs with information on height at ages 1 to 69 years and on parental education were pooled allowing the analyses at different ages and in three geographic-cultural regions (Europe, North America and Australia, and East Asia). Parental education mostly showed a positive association with offspring height, with significant associations in mid-childhood and from adolescence onwards. In variance decomposition modeling, the genetic and environmental variance components of height did not show a consistent relation to parental education. A random-effects meta-regression analysis of the aggregate-level data showed a trend towards greater shared environmental variation of height in low parental education families. In conclusion, in our very large dataset from twin cohorts around the globe, these results provide only weak evidence for the study hypothesis.

DNA Methylation Trajectories During Pregnancy.

There is emerging evidence on DNA methylation (DNAm) variability over time; however, little is known about dynamics of DNAm patterns during pregnancy. We performed an epigenome-wide longitudinal DNAm study of a well-characterized sample of young women from the Swedish Born into Life study, with repeated blood sampling before, during and after pregnancy (n = 21), using the Illumina Infinium MethylationEPIC array. We conducted a replication in the Isle of Wight third-generation birth cohort (n = 27), using the Infinium HumanMethylation450k BeadChip. We identified 196 CpG sites displaying intra-individual longitudinal change in DNAm with a false discovery rate (FDR) P < .05. Most of these (91%) showed a decrease in average methylation levels over the studied period. We observed several genes represented by ⩾3 differentially methylated CpGs: HOXB3, AVP, LOC100996291, and MicroRNA 10a. Of 36 CpGs available in the replication cohort, 17 were replicated, all but 2 with the same direction of association (replication P < .05). Biological pathway analysis demonstrated that FDR-significant CpGs belong to genes overrepresented in metabolism-related pathways, such as adipose tissue development, regulation of insulin receptor signaling, and mammary gland fat development. These results contribute to a better understanding of the biological mechanisms underlying important physiological alterations and adaptations for pregnancy and lactation.

Parental Education and Genetics of BMI from Infancy to Old Age: A Pooled Analysis of 29 Twin Cohorts.

OBJECTIVE: The objective of this study was to analyze how parental education modifies the genetic and environmental variances of BMI from infancy to old age in three geographic-cultural regions. METHODS: A pooled sample of 29 cohorts including 143,499 twin individuals with information on parental education and BMI from age 1 to 79 years (299,201 BMI measures) was analyzed by genetic twin modeling. RESULTS: Until 4 years of age, parental education was not consistently associated with BMI. Thereafter, higher parental education level was associated with lower BMI in males and females. Total and additive genetic variances of BMI were smaller in the offspring of highly educated parents than in those whose parents had low education levels. Especially in North American and Australian children, environmental factors shared by co-twins also contributed to the higher BMI variation in the low education level category. In Europe and East Asia, the associations of parental education with mean BMI and BMI variance were weaker than in North America and Australia. CONCLUSIONS: Lower parental education level is associated with higher mean BMI and larger genetic variance of BMI after early childhood, especially in the obesogenic macro-environment. The interplay among genetic predisposition, childhood social environment, and macro-social context is important for socioeconomic differences in BMI.

Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight.

Birthweight is associated with health outcomes across the life course, DNA methylation may be an underlying mechanism. In this meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, we find that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from -183 to 178 grams per 10% increase in methylation (PBonferroni < 1.06 x 10-7). In additional analyses in 7,278 participants, <1.3% of birthweight-associated differential methylation is also observed in childhood and adolescence, but not adulthood. Birthweight-related CpGs overlap with some Bonferroni-significant CpGs that were previously reported to be related to maternal smoking (55/914, p = 6.12 x 10-74) and BMI in pregnancy (3/914, p = 1.13x10-3), but not with those related to folate levels in pregnancy. Whether the associations that we observe are causal or explained by confounding or fetal growth influencing DNA methylation (i.e. reverse causality) requires further research.