Claire Monnereau

Maternal BMI at the start of pregnancy and offspring epigenome-wide DNA methylation: findings from the pregnancy and childhood epigenetics (PACE) consortium

&NA; Pre‐pregnancy maternal obesity is associated with adverse offspring outcomes at birth and later in life. Individual studies have shown that epigenetic modifications such as DNA methylation could contribute. Within the Pregnancy and Childhood Epigenetics (PACE) Consortium, we meta‐analysed the association between pre‐pregnancy maternal BMI and methylation at over 450,000 sites in newborn blood DNA, across 19 cohorts (9,340 mother‐newborn pairs). We attempted to infer causality by comparing the effects of maternal versus paternal BMI and incorporating genetic variation. In four additional cohorts (1,817 mother‐child pairs), we meta‐analysed the association between maternal BMI at the start of pregnancy and blood methylation in adolescents. In newborns, maternal BMI was associated with small (<0.2% per BMI unit (1 kg/m2), P < 1.06 × 10‐7) methylation variation at 9,044 sites throughout the genome. Adjustment for estimated cell proportions greatly attenuated the number of significant CpGs to 104, including 86 sites common to the unadjusted model. At 72/86 sites, the direction of the association was the same in newborns and adolescents, suggesting persistence of signals. However, we found evidence for acausal intrauterine effect of maternal BMI on newborn methylation at just 8/86 sites. In conclusion, this well‐powered analysis identified robust associations between maternal adiposity and variations in newborn blood DNA methylation, but these small effects may be better explained by genetic or lifestyle factors than a causal intrauterine mechanism. This highlights the need for large‐scale collaborative approaches and the application of causal inference techniques in epigenetic epidemiology.

Adult adiposity susceptibility loci, early growth and general and abdominal fatness in childhood: the Generation R Study

Background:Genome-wide association studies in adults have identified genetic loci associated with adiposity measures. Little is known about the effects of these loci on growth and body fat distribution from early childhood onwards.Methods:In a population-based prospective cohort study among 4144 children, we examined the associations of weighted risk scores combining 29 known genetic markers of adult body mass index (BMI) and 14 known genetic markers of adult waist-hip ratio (WHR) with peak weight velocity, peak height velocity, age at adiposity peak and BMI at adiposity peak in early infancy and additionally with BMI, total fat mass, android/gynoid fat ratio and preperitoneal fat area at the median age of 6.0 years (95% range 5.7, 7.8).Results:A higher adult BMI genetic risk score was associated with a higher age at adiposity peak in infancy and a higher BMI, total fat mass, android/gynoid fat ratio and preperitoneal fat area in childhood (P=0.05, 1.5 × 10−24, 3.6 × 10−18, 4.0 × 10−11 and 1.3 × 10−5, respectively), with the strongest association for childhood BMI with a 0.04 higher s.d. score BMI (95% confidence interval 0.03, 0.05) per additional risk allele. A higher adult WHR genetic risk score was not associated with infant growth measures or childhood BMI and total fat mass, but was associated with childhood android/gynoid fat ratio and preperitoneal fat area (P<0.05).Conclusion:Genetic variants associated with BMI and WHR in adults influence growth patterns and general and abdominal fat development from early childhood onwards.

Influence of genetic variants associated with body mass index on eating behavior in childhood

Childhood eating behaviors are associated with body mass index (BMI). Recent genome‐wide association studies have identified many single‐nucleotide polymorphisms (SNPs) associated with adult and childhood BMI. This study hypothesized that these SNPs also influence eating behavior.

The Influence of Known Genetic Variants on Subclinical Cardiovascular Outcomes in Childhood: Generation R Study.

Background—Genome-wide association studies have identified single-nucleotide polymorphisms (SNPs) for subclinical cardiovascular outcomes in adults. We examined the influence of these variants on the same outcomes in childhood. Methods and Results—In a population-based prospective cohort study among 4137 children, we examined the associations of SNPs, individually and incorporated in genetic risk scores, which were identified in adults for cardiac (2 SNPs for left ventricular end-diastolic diameter and 5 SNPs for aortic root diameter) and blood pressure outcomes (29 SNPs for systolic and diastolic blood pressure, 22 SNPs for mean arterial pressure, and 10 SNPs for pulse pressure) with the same outcomes in children (median age of 6.0 years [95% range, 4.5–8.7]). Weighted and unweighted risk scores for aortic root diameter were associated with childhood aortic root diameter (difference per additional average risk allele 0.09 mm [95% CI: 0.05, 0.13]). Weighted and unweighted risk scores for pulse pressure were associated with childhood pulse pressure (difference per additional average risk allele 0.22 mm Hg [95% CI: 0.08, 0.35] and 0.18 mm Hg [95% CI: 0.05, 0.31], respectively), but not with childhood systolic or diastolic blood pressure or mean arterial pressure. The risk scores for blood pressure and mean arterial pressure were not associated with any of the childhood blood pressure outcomes. Conclusions—Genetic risk scores based on SNPs for aortic root diameter and pulse pressure in adults are associated with the same outcomes in children. SNPs related to cardiovascular outcomes in adulthood at least partly influence cardiovascular development from early life onwards.

Associations of adult genetic risk scores for adiposity with childhood abdominal, liver and pericardial fat assessed by magnetic resonance imaging

Background:Genome-wide association studies (GWASs) identified single-nucleotide polymorphisms (SNPs) involved in adult fat distribution. Whether these SNPs also affect abdominal and organ-specific fat accumulation in children is unknown.Methods:In a population-based prospective cohort study among 1995 children (median age: 9.8 years, 95% range 9.4–10.8), we tested the associations of six genetic risk scores based on previously identified SNPs for childhood body mass index (BMI), adult BMI, liver fat, waist–hip ratio, pericardial fat mass, visceral and subcutaneous adipose tissue ratio (VAT/SAT ratio) and four individual SAT- and VAT-associated SNPs for association with SAT (N=1746), VAT (N=1742), VAT/SAT ratio (N=1738), liver fat fraction (N=1950) and pericardial fat mass (N=1803) measured by magnetic resonance imaging.Results:Per additional risk allele in the childhood BMI genetic risk score, SAT increased 0.020 s.d. scores (SDS) (95% confidence interval (CI): 0.009 to 0.031, P-value: 3.28 × 10−4) and VAT increased 0.021 SDS (95% CI: 0.009 to 0.032, P-value: 4.68 × 10−4). The adult BMI risk score was positively associated with SAT (0.022 SDS increase, CI: 0.015 to 0.029, P-value: 1.33 × 10−9) and VAT (0.017 SDS increase, CI: 0.010 to 0.025, P-value: 7.00 × 10−6) and negatively with VAT/SAT ratio (−0.012 SDS decrease, CI: −0.019 to −0.006, P-value: 2.88 × 10−4). The liver fat risk score was associated with liver fat fraction (0.121 SDS, CI: 0.086 to 0.157, P-value: 2.65 × 10−11). Rs7185735 (SAT) was associated with SAT (0.151 SDS, CI: 0.087 to 0.214, P-value: 3.00 × 10−6) and VAT/SAT ratio (−0.126 SDS, CI: −0.186 to −0.065, P-value: 4.70 × 10−5). After stratification by sex the associations of the adult BMI risk score with SAT and VAT and of the liver fat risk score with liver fat fraction remained in both sexes. Associations of the childhood BMI risk score with SAT, and the adult BMI risk score with VAT/SAT ratio, were present among boys only, whereas the association of the pericardial fat risk score with pericardial fat was present among girls only.Conclusion:Genetic variants associated with BMI, body fat distribution, liver and pericardial fat already affect body fat distribution in childhood.

Maternal body mass index, gestational weight gain, and childhood abdominal, pericardial, and liver fat assessed by magnetic resonance imaging

Background/ObjectivesMaternal obesity and excessive gestational weight gain are associated with an increased risk of obesity in offspring. It remains unclear whether maternal adiposity also affects organ fat, which has important adverse cardiometabolic health consequences and whether the associations reflect intrauterine causal mechanisms. We examined the associations of parental pre-pregnancy body mass index (BMI) and gestational weight gain with general, abdominal, pericardial, and liver fat in 10-year-old children.Subjects/MethodsIn a population-based prospective cohort study among 2354 parents and their children, we obtained pre-pregnancy maternal and paternal BMI and gestational weight gain and offspring BMI, fat mass index (total fat/height4) by dual-energy X-ray absorptiometry, and subcutaneous fat index (subcutaneous fat/height4), visceral fat index (visceral fat/height3), pericardial fat index (pericardial fat/height3), and liver fat fraction by magnetic resonance imaging (MRI) at 10 years.ResultsA 1-standard deviation score (SDS) higher maternal pre-pregnancy BMI was associated with higher childhood BMI (difference 0.32 (95% confidence interval (CI) 0.28, 0.36) SDS), fat mass index (difference 0.28 (95% CI 0.24, 0.31) SDS), subcutaneous fat index (difference 0.26 (95% CI 0.22, 0.30) SDS), visceral fat index (difference 0.24 (95% CI 0.20, 0.28) SDS), pericardial fat index (difference 0.12 (95% CI 0.08, 0.16) SDS), and liver fat fraction (difference 0.15 (95% CI 0.11, 0.19) SDS). After conditioning each MRI adiposity measure on BMI at 10 years, higher maternal pre-pregnancy BMI remained associated with higher childhood subcutaneous and visceral fat indices. Smaller but not statistically different effect estimates were observed for paternal BMI. Gestational weight gain was not consistently associated with organ fat.ConclusionsHigher maternal pre-pregnancy BMI, but not gestational weight gain, was associated with higher general and organ fat. Similar associations of pre-pregnancy maternal and paternal BMI with offspring adiposity suggest a role of family shared lifestyle factors and genetics.

The Influence of Known Genetic Variants on Subclinical Cardiovascular Outcomes in ChildhoodCLINICAL PERSPECTIVE: Generation R Study

Background—Genome-wide association studies have identified single-nucleotide polymorphisms (SNPs) for subclinical cardiovascular outcomes in adults. We examined the influence of these variants on the same outcomes in childhood. Methods and Results—In a population-based prospective cohort study among 4137 children, we examined the associations of SNPs, individually and incorporated in genetic risk scores, which were identified in adults for cardiac (2 SNPs for left ventricular end-diastolic diameter and 5 SNPs for aortic root diameter) and blood pressure outcomes (29 SNPs for systolic and diastolic blood pressure, 22 SNPs for mean arterial pressure, and 10 SNPs for pulse pressure) with the same outcomes in children (median age of 6.0 years [95% range, 4.5–8.7]). Weighted and unweighted risk scores for aortic root diameter were associated with childhood aortic root diameter (difference per additional average risk allele 0.09 mm [95% CI: 0.05, 0.13]). Weighted and unweighted risk scores for pulse pressure were associated with childhood pulse pressure (difference per additional average risk allele 0.22 mm Hg [95% CI: 0.08, 0.35] and 0.18 mm Hg [95% CI: 0.05, 0.31], respectively), but not with childhood systolic or diastolic blood pressure or mean arterial pressure. The risk scores for blood pressure and mean arterial pressure were not associated with any of the childhood blood pressure outcomes. Conclusions—Genetic risk scores based on SNPs for aortic root diameter and pulse pressure in adults are associated with the same outcomes in children. SNPs related to cardiovascular outcomes in adulthood at least partly influence cardiovascular development from early life onwards.

The Influence of Known Genetic Variants on Subclinical Cardiovascular Outcomes in ChildhoodCLINICAL PERSPECTIVE

Background—Genome-wide association studies have identified single-nucleotide polymorphisms (SNPs) for subclinical cardiovascular outcomes in adults. We examined the influence of these variants on the same outcomes in childhood. Methods and Results—In a population-based prospective cohort study among 4137 children, we examined the associations of SNPs, individually and incorporated in genetic risk scores, which were identified in adults for cardiac (2 SNPs for left ventricular end-diastolic diameter and 5 SNPs for aortic root diameter) and blood pressure outcomes (29 SNPs for systolic and diastolic blood pressure, 22 SNPs for mean arterial pressure, and 10 SNPs for pulse pressure) with the same outcomes in children (median age of 6.0 years [95% range, 4.5–8.7]). Weighted and unweighted risk scores for aortic root diameter were associated with childhood aortic root diameter (difference per additional average risk allele 0.09 mm [95% CI: 0.05, 0.13]). Weighted and unweighted risk scores for pulse pressure were associated with childhood pulse pressure (difference per additional average risk allele 0.22 mm Hg [95% CI: 0.08, 0.35] and 0.18 mm Hg [95% CI: 0.05, 0.31], respectively), but not with childhood systolic or diastolic blood pressure or mean arterial pressure. The risk scores for blood pressure and mean arterial pressure were not associated with any of the childhood blood pressure outcomes. Conclusions—Genetic risk scores based on SNPs for aortic root diameter and pulse pressure in adults are associated with the same outcomes in children. SNPs related to cardiovascular outcomes in adulthood at least partly influence cardiovascular development from early life onwards.