Genome-wide association study of offspring birth weight in 86 577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics.

Genome-wide association studies of birth weight have focused on fetal genetics, whereas relatively little is known about the role of maternal genetic variation. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth. We meta-analysed data on up to 8.7 million SNPs in up to 86 577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother-child pairs to quantify the separate maternal and fetal genetic effects. Maternal SNPs at 10 loci (MTNR1B, HMGA2, SH2B3, KCNAB1, L3MBTL3, GCK, EBF1, TCF7L2, ACTL9, CYP3A7) were associated with offspring birth weight at P < 5 × 10-8. In SEM analyses, at least 7 of the 10 associations were consistent with effects of the maternal genotype acting via the intrauterine environment, rather than via effects of shared alleles with the fetus. Variants, or correlated proxies, at many of the loci had been previously associated with adult traits, including fasting glucose (MTNR1B, GCK and TCF7L2) and sex hormone levels (CYP3A7), and one (EBF1) with gestational duration. The identified associations indicate that genetic effects on maternal glucose, cytochrome P450 activity and gestational duration, and potentially on maternal blood pressure and immune function, are relevant for fetal growth. Further characterization of these associations in mechanistic and causal analyses will enhance understanding of the potentially modifiable maternal determinants of fetal growth, with the goal of reducing the morbidity and mortality associated with low and high birth weights.

Genetic Evidence for Causal Relationships Between Maternal Obesity-Related Traits and Birth Weight.

IMPORTANCE: Neonates born to overweight or obese women are larger and at higher risk of birth complications. Many maternal obesity-related traits are observationally associated with birth weight, but the causal nature of these associations is uncertain. OBJECTIVE: To test for genetic evidence of causal associations of maternal body mass index (BMI) and related traits with birth weight. DESIGN, SETTING, AND PARTICIPANTS: Mendelian randomization to test whether maternal BMI and obesity-related traits are potentially causally related to offspring birth weight. Data from 30,487 women in 18 studies were analyzed. Participants were of European ancestry from population- or community-based studies in Europe, North America, or Australia and were part of the Early Growth Genetics Consortium. Live, term, singleton offspring born between 1929 and 2013 were included. EXPOSURES: Genetic scores for BMI, fasting glucose level, type 2 diabetes, systolic blood pressure (SBP), triglyceride level, high-density lipoprotein cholesterol (HDL-C) level, vitamin D status, and adiponectin level. MAIN OUTCOME AND MEASURE: Offspring birth weight from 18 studies. RESULTS: Among the 30,487 newborns the mean birth weight in the various cohorts ranged from 3325 g to 3679 g. The maternal genetic score for BMI was associated with a 2-g (95% CI, 0 to 3 g) higher offspring birth weight per maternal BMI-raising allele (P = .008). The maternal genetic scores for fasting glucose and SBP were also associated with birth weight with effect sizes of 8 g (95% CI, 6 to 10 g) per glucose-raising allele (P = 7 × 10(-14)) and -4 g (95% CI, -6 to -2 g) per SBP-raising allele (P = 1×10(-5)), respectively. A 1-SD ( ≈ 4 points) genetically higher maternal BMI was associated with a 55-g higher offspring birth weight (95% CI, 17 to 93 g). A 1-SD ( ≈ 7.2 mg/dL) genetically higher maternal fasting glucose concentration was associated with 114-g higher offspring birth weight (95% CI, 80 to 147 g). However, a 1-SD ( ≈ 10 mm Hg) genetically higher maternal SBP was associated with a 208-g lower offspring birth weight (95% CI, -394 to -21 g). For BMI and fasting glucose, genetic associations were consistent with the observational associations, but for systolic blood pressure, the genetic and observational associations were in opposite directions. CONCLUSIONS AND RELEVANCE: In this mendelian randomization study, genetically elevated maternal BMI and blood glucose levels were potentially causally associated with higher offspring birth weight, whereas genetically elevated maternal SBP was potentially causally related to lower birth weight. If replicated, these findings may have implications for counseling and managing pregnancies to avoid adverse weight-related birth outcomes.

Genome-wide association and longitudinal analyses reveal genetic loci linking pubertal height growth, pubertal timing and childhood adiposity.

The pubertal height growth spurt is a distinctive feature of childhood growth reflecting both the central onset of puberty and local growth factors. Although little is known about the underlying genetics, growth variability during puberty correlates with adult risks for hormone-dependent cancer and adverse cardiometabolic health. The only gene so far associated with pubertal height growth, LIN28B, pleiotropically influences childhood growth, puberty and cancer progression, pointing to shared underlying mechanisms. To discover genetic loci influencing pubertal height and growth and to place them in context of overall growth and maturation, we performed genome-wide association meta-analyses in 18 737 European samples utilizing longitudinally collected height measurements. We found significant associations (P < 1.67 × 10(-8)) at 10 loci, including LIN28B. Five loci associated with pubertal timing, all impacting multiple aspects of growth. In particular, a novel variant correlated with expression of MAPK3, and associated both with increased prepubertal growth and earlier menarche. Another variant near ADCY3-POMC associated with increased body mass index, reduced pubertal growth and earlier puberty. Whereas epidemiological correlations suggest that early puberty marks a pathway from rapid prepubertal growth to reduced final height and adult obesity, our study shows that individual loci associating with pubertal growth have variable longitudinal growth patterns that may differ from epidemiological observations. Overall, this study uncovers part of the complex genetic architecture linking pubertal height growth, the timing of puberty and childhood obesity and provides new information to pinpoint processes linking these traits.

Is obesity associated with depression in children? Systematic review and meta-analysis.

OBJECTIVES: To compare the odds of depression in obese and overweight children with that in normal-weight children in the community. DESIGN: Systematic review and random-effect meta-analysis of observational studies. DATA SOURCES: EMBASE, PubMed and PsychINFO electronic databases, published between January 2000 and January 2017. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Cross-sectional or longitudinal observational studies that recruited children (aged <18 years) drawn from the community who had their weight status classified by body mass index, using age-adjusted and sex-adjusted reference charts or the International Obesity Task Force age-sex specific cut-offs, and concurrent or prospective odds of depression were measured. RESULTS: Twenty-two studies representing 143 603 children were included in the meta-analysis. Prevalence of depression among obese children was 10.4%. Compared with normal-weight children, odds of depression were 1.32 higher (95% CI 1.17 to 1.50) in obese children. Among obese female children, odds of depression were 1.44 (95% CI 1.20 to 1.72) higher compared with that of normal-weight female children. No association was found between overweight children and depression (OR 1.04, 95% CI 0.95 to 1.14) or among obese or overweight male subgroups and depression (OR 1.14, 95% CI 0.93 to 1.41% and 1.08, 95% CI 0.85 to 1.37, respectively). Subgroup analysis of cross-sectional and longitudinal studies separately revealed childhood obesity was associated with both concurrent (OR 1.26, 95% CI 1.09 to 1.45) and prospective odds (OR 1.51, 95% CI 1.21 to 1.88) of depression. CONCLUSION: We found strong evidence that obese female children have a significantly higher odds of depression compared with normal-weight female children, and this risk persists into adulthood. Clinicians should consider screening obese female children for symptoms of depression. BACKGROUND: Childhood mental illness is poorly recognised by healthcare providers and parents, despite half of all lifetime cases of diagnosable mental illness beginning by the age of 14 years. 1 Globally, depression is the leading cause of disease burden, as measured by disability-adjusted life years, in children aged 10-19 years. 2 Untreated, it is associated with poor school performance and social functioning, substance misuse, recurring depression in adulthood and increased suicide risk, which is the second leading cause of preventable death among young people. 3-6 The resulting cost to the National Health Service of treating depression is estimated at over £2 billion, and the wider social and economic impact of depression is likely to be considerable. 7.

GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI.

Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the LEPR/LEPROT locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies.

Impact of health behaviours and deprivation on well-being in a national sample of English young people.

OBJECTIVE: To determine the modifiable factors influencing well-being in boys and girls by accounting for deprivation, ethnicity and clustering within local authorities. METHODS: We used data from a very large nationally representative survey, the What About Youth study involving 120 115 adolescents aged 15 years. Our outcome measure of mental well-being was the Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS). Potential explanatory factors included substance abuse, screen time, eating habits, reading, bullying, sleeping pattern, physical activity and area-level deprivation. We ran unadjusted and adjusted multilevel models for each explanatory factor, after adjusting for ethnicity, deprivation and including a random effect for the local authority. RESULTS: Boys had a higher overall mean WEMWBS score than girls (p<0.0001). In the adjusted model, each of multiple risk behaviours, eating habits, sleep, bullying, physical activity, screen-time and reading were independently associated with mental well-being in both boy and girls (p<0.0001 for both). Sleep and eating behaviours had a stronger association in both sexes than bullying, physical activity and screen time. Young people from black ethnic groups had significantly higher well-being in both sexes. Deprivation was not associated with well-being among boys but was among girls. CONCLUSION: The largest contributors to adolescent well-being appear to be sleep, eating behaviours and bullying when considered in a multivariable framework. While adolescents from black ethnic groups had higher overall well-being scores, area deprivation did not affect male well-being but had a small effect on female well-being. Future longitudinal studies and health policies need to consider a range of behavioural factors to drive improvements in adolescent well-being.

Effectiveness of Universal Self-regulation-Based Interventions in Children and Adolescents: A Systematic Review and Meta-analysis.

Importance: Childhood and adolescence self-regulation (SR) is gaining importance as a target of intervention because of mounting evidence of its positive associations with health, social and educational outcomes. Objective: To conduct a systematic review and meta-analysis of rigorously evaluated interventions to improve self-regulation in children and adolescents. Data Sources: Keyword searches of the PsycINFO, PubMed, EMBASE, CINAHL Plus, ERIC, British Education Index, Child Development and Adolescent Studies, and CENTRAL were used to identify all studies published through July 2016. Study Selection: To be eligible for this review, studies had to report cluster randomized trials or randomized clinical trials, evaluate universal interventions designed to improve self-regulation in children and adolescents aged 0 to 19 years, include outcomes associated with self-regulation skills, and be published in a peer-reviewed journal with the full text available in English. Data Extraction and Synthesis: A total of 14 369 published records were screened, of which 147 were identified for full-text review and 49 studies reporting 50 interventions were included in the final review. Results were summarized by narrative review and meta-analysis. Main Outcomes and Measures: Self-regulation outcomes in children and adolescents. Results: This review identified 17 cluster randomized trials and 32 randomized clinical trials evaluating self-regulation interventions, which included a total of 23 098 participants ranging in age from 2 to 17 years (median age, 6.0 years). Consistent improvement in self-regulation was reported in 16 of 21 curriculum-based interventions (76%), 4 of the 8 mindfulness and yoga interventions (50%), 5 of 9 family-based programs (56%), 4 of 6 exercise-based programs (67%), and 4 of 6 social and personal skills interventions (67%), or a total of 33 of 50 interventions (66%). A meta-analysis evaluating associations of interventions with self-regulation task performance scores showed a positive effect of such interventions with pooled effect size of 0.42 (95% CI, 0.32-0.53). Only 24 studies reported data on distal outcomes (29 outcomes). Positive associations were reported in 11 of 13 studies (85%) on academic achievement, 4 of 5 studies on substance abuse (80%), and in all studies reporting on conduct disorders (n = 3), studies on social skills (n = 2), studies on depression (n = 2), studies on behavioral problems (n = 2), and study on school suspensions (n = 1). No effect was seen on 2 studies reporting on academic achievement, 1 study reporting on substance abuse, and 1 additional study reporting on psychological well-being. Conclusions and Relevance: A wide range of interventions were successful in improving self-regulation in children and adolescents. There was improvement in distal academic, health, and behavioral outcomes in most intervention groups compared with controls.

Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation.

We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10(-11) to 5.0 × 10(-21)). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10(-6)). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.

Multiple measures of adiposity are associated with mean leukocyte telomere length in the northern Finland birth cohort 1966.

Studies of leukocyte telomere length (LTL) and adiposity have produced conflicting results, and the relationship between body mass index (BMI) and telomere length throughout life remains unclear. We therefore tested association of adult LTL measured in 5,598 participants with: i) childhood growth measures (BMI and age at adiposity rebound (AR)); ii) change in BMI from childhood to adulthood and iii) adult BMI, waist-to-hip ratio (WHR), body adiposity index (BAI). Childhood BMI at AR was positively associated with LTL at 31 years in women (P = 0.041). Adult BMI and WHR in both men (P = 0.025 and P = 0.049, respectively) and women (P = 0.029 and P = 0.008, respectively), and BAI in women (P = 0.021) were inversely associated with LTL at 31 years. An increase in standardised BMI between early childhood and adulthood was associated with shorter adult LTL in women (P = 0.008). We show that LTL is inversely associated with multiple measures of adiposity in both men and women. Additionally, BMI increase in women from childhood to adulthood is associated with shorter telomeres at age 31, potentially indicating accelerated biological ageing.

Estimation of newborn risk for child or adolescent obesity: lessons from longitudinal birth cohorts.

OBJECTIVES: Prevention of obesity should start as early as possible after birth. We aimed to build clinically useful equations estimating the risk of later obesity in newborns, as a first step towards focused early prevention against the global obesity epidemic. METHODS: We analyzed the lifetime Northern Finland Birth Cohort 1986 (NFBC1986) (N = 4,032) to draw predictive equations for childhood and adolescent obesity from traditional risk factors (parental BMI, birth weight, maternal gestational weight gain, behaviour and social indicators), and a genetic score built from 39 BMI/obesity-associated polymorphisms. We performed validation analyses in a retrospective cohort of 1,503 Italian children and in a prospective cohort of 1,032 U.S. children. RESULTS: In the NFBC1986, the cumulative accuracy of traditional risk factors predicting childhood obesity, adolescent obesity, and childhood obesity persistent into adolescence was good: AUROC = 0·78[0·74-0.82], 0·75[0·71-0·79] and 0·85[0·80-0·90] respectively (all p<0·001). Adding the genetic score produced discrimination improvements ≤1%. The NFBC1986 equation for childhood obesity remained acceptably accurate when applied to the Italian and the U.S. cohort (AUROC = 0·70[0·63-0·77] and 0·73[0·67-0·80] respectively) and the two additional equations for childhood obesity newly drawn from the Italian and the U.S. datasets showed good accuracy in respective cohorts (AUROC = 0·74[0·69-0·79] and 0·79[0·73-0·84]) (all p<0·001). The three equations for childhood obesity were converted into simple Excel risk calculators for potential clinical use. CONCLUSION: This study provides the first example of handy tools for predicting childhood obesity in newborns by means of easily recorded information, while it shows that currently known genetic variants have very little usefulness for such prediction.

Common variants at 12q15 and 12q24 are associated with infant head circumference.

To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association studies (GWAS) (N = 10,768 individuals of European ancestry enrolled in pregnancy and/or birth cohorts) and followed up three lead signals in six replication studies (combined N = 19,089). rs7980687 on chromosome 12q24 (P = 8.1 × 10(-9)) and rs1042725 on chromosome 12q15 (P = 2.8 × 10(-10)) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height, their effects on infant head circumference were largely independent of height (P = 3.8 × 10(-7) for rs7980687 and P = 1.3 × 10(-7) for rs1042725 after adjustment for infant height). A third signal, rs11655470 on chromosome 17q21, showed suggestive evidence of association with head circumference (P = 3.9 × 10(-6)). SNPs correlated to the 17q21 signal have shown genome-wide association with adult intracranial volume, Parkinson's disease and other neurodegenerative diseases, indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life.

A genome-wide association meta-analysis identifies new childhood obesity loci.

Multiple genetic variants have been associated with adult obesity and a few with severe obesity in childhood; however, less progress has been made in establishing genetic influences on common early-onset obesity. We performed a North American, Australian and European collaborative meta-analysis of 14 studies consisting of 5,530 cases (≥95th percentile of body mass index (BMI)) and 8,318 controls (<50th percentile of BMI) of European ancestry. Taking forward the eight newly discovered signals yielding association with P < 5 × 10(-6) in nine independent data sets (2,818 cases and 4,083 controls), we observed two loci that yielded genome-wide significant combined P values near OLFM4 at 13q14 (rs9568856; P = 1.82 × 10(-9); odds ratio (OR) = 1.22) and within HOXB5 at 17q21 (rs9299; P = 3.54 × 10(-9); OR = 1.14). Both loci continued to show association when two extreme childhood obesity cohorts were included (2,214 cases and 2,674 controls). These two loci also yielded directionally consistent associations in a previous meta-analysis of adult BMI(1).