Genome-wide profiling of blood pressure in adults and children

Hypertension is an important determinant of cardiovascular morbidity and mortality and has a substantial heritability, which is likely of polygenic origin. The aim of this study was to assess to what extent multiple common genetic variants contribute to blood pressure regulation in both adults and children and to assess overlap in variants between different age groups, using genome-wide profiling. Single nucleotide polymorphism sets were defined based on a meta-analysis of genome-wide association studies on systolic blood pressure and diastolic blood pressure performed by the Cohort for Heart and Aging Research in Genome Epidemiology (n=29 136), using different P value thresholds for selecting single nucleotide polymorphisms. Subsequently, genetic risk scores for systolic blood pressure and diastolic blood pressure were calculated in an independent adult population (n=2072) and a child population (n=1034). The explained variance of the genetic risk scores was evaluated using linear regression models, including sex, age, and body mass index. Genetic risk scores, including also many nongenome-wide significant single nucleotide polymorphisms, explained more of the variance than scores based only on very significant single nucleotide polymorphisms in adults and children. Genetic risk scores significantly explained ≤1.2% (P=9.6*10(-8)) of the variance in adult systolic blood pressure and 0.8% (P=0.004) in children. For diastolic blood pressure, the variance explained was similar in adults and children (1.7% [P=8.9*10(-10)] and 1.4% [P=3.3*10(-5)], respectively). These findings suggest the presence of many genetic loci with small effects on blood pressure regulation both in adults and children, indicating also a (partly) common polygenic regulation of blood pressure throughout different periods of life.     

Functional connectivity between parietal and frontal brain regions and intelligence in young children: The Generation R study

It has been shown in adults that individual differences in intelligence are related to the integrity of the interaction between parietal and frontal brain regions. Since connectivity between distant brain regions strengthens during childhood, it is unclear when in the course of development this relationship emerges. Thus, the goal of this study was to determine whether parietal‐frontal functional connectivity is associated with intelligence in young children. We performed independent component analyses on resting‐state fMRI data of 115 children (6–8 years old) to select seed and target regions for a seed/target region correlation analysis. We found that higher nonverbal intelligence was associated with increased functional connectivity between right parietal and right frontal regions, and between right parietal and dorsal anterior cingulate regions. The association between intelligence and functional connectivity between certain brain regions was stronger in girls than boys. In conclusion, we found that connectivity between the parietal and frontal lobes is critically involved in intelligence in young children. Hum Brain Mapp 34:3299–3307, 2013. © 2012 Wiley Periodicals, Inc.     

Bone Mass and Strength in School‐Age Children Exhibit Sexual Dimorphism Related to Differences in Lean Mass: The Generation R Study

Bone strength, a key determinant of fracture risk, has been shown to display clear sexual dimorphism after puberty. We sought to determine whether sex differences in bone mass and hip bone geometry as an index of strength exist in school‐age prepubertal children and the degree to which the differences are independent of body size and lean mass. We studied 3514 children whose whole‐body and hip scans were measured using the same densitometer (GE‐Lunar iDXA) at a mean age of 6.2 years. Hip dual‐energy X‐ray absorptiometry (DXA) scans underwent hip structural analyses (HSA) with derivation of bone strength indices. Sex differences in these parameters were assessed by regression models adjusted for age, height, ethnicity, weight, and lean mass fraction (LMF). Whole‐body bone mineral density (BMD) and bone mineral content (BMC) levels were 1.3% and 4.3% higher in girls after adjustment by LMF. Independent of LMF, boys had 1.5% shorter femurs, 1.9% and 2.2% narrower shaft and femoral neck with 1.6% to 3.4% thicker cortices than girls. Consequent with this geometry configuration, girls observed 6.6% higher stresses in the medial femoral neck than boys. When considering LMF, the sexual differences on the derived bone strength indices were attenuated, suggesting that differences in muscle loads may reflect an innate disadvantage in bone strength in girls, as consequence of their lower muscular acquisition. In summary, we show that bone sexual dimorphism is already present at 6 years of age, with boys having stronger bones than girls, the relation of which is influenced by body composition and likely attributable to differential adaptation to mechanical loading. Our results support the view that early life interventions (ie, increased physical activity) targeted during the pre‐ and peripubertal stages may be of high importance, particularly in girls, because before puberty onset, muscle mass is strongly associated with bone density and geometry in children. © 2015 American Society for Bone and Mineral Research.     

Fetal and Infant Growth Patterns and Kidney Function at School Age

Low birth weight is associated with ESRD. To identify specific growth patterns in early life that may be related to kidney function in later life, we examined the associations of longitudinally measured fetal and infant growth with kidney function in school-aged children. This study was embedded in a population-based prospective cohort study among 6482 children followed from fetal life onward. Fetal and childhood growth was measured during second and third trimesters of pregnancy, at birth, and at 6, 12, 24, 36, and 48 months postnatally. At the age of 6 years, we measured kidney volume by ultrasound. GFR was estimated using blood creatinine levels. Higher gestational age-adjusted birth weight was associated with higher combined kidney volume and higher eGFR (per 1 SD score increase in birth weight; 1.27 cm³ [95% confidence interval, 0.61 to 1.93] and 0.78 ml/min per 1.73 m² [95% CI, 0.16 to 1.39], respectively). Fetal weight, birth weight, and weight at 6 months were positively associated with childhood kidney volume, whereas higher second trimester fetal weight was positively associated with higher GFR (all P values<0.05). Fetal and childhood lengths were not consistently associated with kidney function. In this cohort, lower fetal and early infant weight growth is associated with smaller kidney volume in childhood, whereas only lower fetal weight growth is associated with lower kidney function in childhood, independent of childhood growth. Whether these associations lead to an increased risk of kidney disease needs to be studied further.Low birth weight is associated with higher risks of ESRD and hypertension in later life.^1–3 Clearly, low birth weight is not the causal factor per se leading to kidney diseases in later life. Birth weight is the result of various exposures and growth patterns in fetal life and the starting point of childhood growth. It has been hypothesized that especially third trimester fetal growth restriction leads to persistently smaller kidneys with a reduced number of nephrons, which may predispose the individual to kidney disease in adulthood.^4–6 This hypothesis is supported by both animal and human studies, showing that kidney volume and nephron number are reduced in fetal growth-restricted subjects and hypertensive subjects.^7–9 Although nephrogenesis is known to continue until 36 weeks of gestation and cease thereafter, not much is known about the specific critical periods and early growth patterns related to kidney function in later life.¹⁰ Also, whether and to what extent the associations of low birth weight with CKD are explained by preterm birth are not known.¹ Longitudinal studies suggested that the associations of low birth weight with hypertension were stronger in subjects with rapid weight gain in childhood, but results are inconclusive.^11,12 A similar growth pattern has not been identified as a risk factor for kidney diseases yet.Prospective studies linking fetal and early childhood growth patterns to kidney outcomes in later life might help to identify early critical periods for developing impaired kidney function in later life.Therefore, we examined, in a population-based prospective cohort study among 6482 children followed from early fetal life onward (Figure 1), the associations of birth weight, gestational age, birth weight for gestational age, and longitudinally measured fetal and early childhood growth patterns with kidney size and function at school age. We used subclinical variations of kidney function in childhood as outcomes, because they relate to kidney disease in later life.¹³Open in a separate windowFigure 1.Flow chart: exclusion criteria and numbers of participants are given. Total numbers of available outcome measurements are given.     

Variation in the IGF1 gene and growth in foetal life and infancy. The Generation R Study

Objective The objective of this study was to examine whether variants of the IGF1 gene are associated with growth patterns from foetal life until infancy. Study design and measurements This study was embedded in the Generation R Study, a population‐based prospective cohort study of foetal life. Foetal growth (head circumference, abdominal circumference, femur length, estimated foetal weight) was assessed by ultrasound in early, mid‐ and late pregnancy. Growth in infancy was assessed at birth (weight) and at the ages of 6 weeks, 6 months and 14 months (head circumference, length, weight). The IGF1 promoter region genotype was determined in 738 children. Results Eight alleles of the IGF1 promoter region were identified. In total, 43% of the subjects were homozygous for the most common 192‐bp allele (wild‐type), 45% were heterozygous, and 12% were noncarriers of the 192‐bp allele. No differences were found in birthweight between the three groups. However, noncarriers had a lower estimated foetal weight in mid‐pregnancy (P = 0·040), followed by an increased growth rate until 6 months (P < 0·005) in comparison to the 192‐bp homozygotes. A similar difference in growth rate was found for length (P < 0·001). Conclusions Variants of the IGF1 promoter region are not associated with birthweight. However, noncarriers of the 192‐bp allele tend to have a smaller foetal size, followed by an increased growth rate from mid‐pregnancy to early infancy. Studies in larger cohorts are necessary to replicate our findings and to examine whether these effects persist throughout childhood.