Recent genome-wide association (GWA) studies have identified dozens of common variants associated with adult height. However, it is unknown how these variants influence height growth during ...childhood. We derived peak height velocity in infancy (PHV1) and puberty (PHV2) and timing of pubertal height growth spurt from parametric growth curves fitted to longitudinal height growth data to test their association with known height variants. The study consisted of N = 3,538 singletons from the prospective Northern Finland Birth Cohort 1966 with genotype data and frequent height measurements (on average 20 measurements per person) from 0-20 years. Twenty-six of the 48 variants tested associated with adult height (p<0.05, adjusted for sex and principal components) in this sample, all in the same direction as in previous GWA scans. Seven SNPs in or near the genes HHIP, DLEU7, UQCC, SF3B4/SV2A, LCORL, and HIST1H1D associated with PHV1 and five SNPs in or near SOCS2, SF3B4/SV2A, C17orf67, CABLES1, and DOT1L with PHV2 (p<0.05). We formally tested variants for interaction with age (infancy versus puberty) and found biologically meaningful evidence for an age-dependent effect for the SNP in SOCS2 (p = 0.0030) and for the SNP in HHIP (p = 0.045). We did not have similar prior evidence for the association between height variants and timing of pubertal height growth spurt as we had for PHVs, and none of the associations were statistically significant after correction for multiple testing. The fact that in this sample, less than half of the variants associated with adult height had a measurable effect on PHV1 or PHV2 is likely to reflect limited power to detect these associations in this dataset. Our study is the first genetic association analysis on longitudinal height growth in a prospective cohort from birth to adulthood and gives grounding for future research on the genetic regulation of human height during different periods of growth.
Many women who experience gestational diabetes (GDM), gestational hypertension (GHT), pre-eclampsia (PE), have a spontaneous preterm birth (sPTB) or have an offspring born small/large for gestational ...age (SGA/LGA) do not meet the criteria for high-risk pregnancies based upon certain maternal risk factors. Tools that better predict these outcomes are needed to tailor antenatal care to risk. Recent studies have suggested that metabolomics may improve the prediction of these pregnancy-related disorders. These have largely been based on targeted platforms or focused on a single pregnancy outcome. The aim of this study was to assess the predictive ability of an untargeted platform of over 700 metabolites to predict the above pregnancy-related disorders in two cohorts. We used data collected from women in the Born in Bradford study (BiB; two sub-samples,
= 2000 and
= 1000) and the Pregnancy Outcome Prediction study (POPs;
= 827) to train, test and validate prediction models for GDM, PE, GHT, SGA, LGA and sPTB. We compared the predictive performance of three models: (1) risk factors (maternal age, pregnancy smoking, BMI, ethnicity and parity) (2) mass spectrometry (MS)-derived metabolites (
= 718 quantified metabolites, collected at 26-28 weeks' gestation) and (3) combined risk factors and metabolites. We used BiB for the training and testing of the models and POPs for independent validation. In both cohorts, discrimination for GDM, PE, LGA and SGA improved with the addition of metabolites to the risk factor model. The models' area under the curve (AUC) were similar for both cohorts, with good discrimination for GDM (AUC (95% CI) BiB 0.76 (0.71, 0.81) and POPs 0.76 (0.72, 0.81)) and LGA (BiB 0.86 (0.80, 0.91) and POPs 0.76 (0.60, 0.92)). Discrimination was improved for the combined models (compared to the risk factors models) for PE and SGA, with modest discrimination in both studies (PE-BiB 0.68 (0.58, 0.78) and POPs 0.66 (0.60, 0.71); SGA-BiB 0.68 (0.63, 0.74) and POPs 0.64 (0.59, 0.69)). Prediction for sPTB was poor in BiB and POPs for all models. In BiB, calibration for the combined models was good for GDM, LGA and SGA. Retained predictors include 4-hydroxyglutamate for GDM, LGA and PE and glycerol for GDM and PE. MS-derived metabolomics combined with maternal risk factors improves the prediction of GDM, PE, LGA and SGA, with good discrimination for GDM and LGA. Validation across two very different cohorts supports further investigation on whether the metabolites reflect novel causal paths to GDM and LGA.
Data on the birth weight-blood pressure relationship are inconsistent. Although an inverse association has been suggested in several large studies, interpretation is complicated by publication and ...other biases. Few data are available on the relationship between other early growth measures and blood pressure. We examined the shape and size of association between determinants of fetal growth, size at birth, growth in infancy, and adult systolic and diastolic blood pressure at 31 years in the prospective northern Finnish 1966 birth cohort of 5960 participants. Birth weight, birth length, gestational age, ponderal index, and birth weight relative to gestational age showed a significant inverse association with blood pressure at age 31. Rapid growth in infancy ("change-up") was positively associated with blood pressure. Adjusted regression coefficients for birth weight indicated systolic/diastolic blood pressure lower by -1.7 (95% confidence interval CI, -2.5, -1.0)/-0.7 (95% CI, -1.4, -0.02) mm Hg for 1 kg higher birth weight. The significant inverse association between birth weight and systolic blood pressure persisted without adjustment for adult body mass index for males. Among females, gestational age showed a stronger association with blood pressure than birth weight: gestational age higher by 7 weeks (equivalent to an average of 1 kg higher birth weight) among singletons associated with -2.9 (95% CI, -4.7, -1.1) mm Hg lower systolic blood pressure. Our results support the concept that birth weight, other birth measures, and infant growth are important determinants of blood pressure and hence cardiovascular disease risk in later life.
Fetal growth restriction, pre-eclampsia, and pre-term birth are major adverse pregnancy outcomes. These complications are considerable contributors to fetal/maternal morbidity and mortality ...worldwide. A significant proportion of these cases are thought to be due to dysfunction of the placenta. However, the underlying mechanisms of placental dysfunction are unclear. The aim of the present study was to investigate whether adverse pregnancy outcomes are associated with evidence of placental eukaryotic infection.
We modified the 18S Illumina Amplicon Protocol of the Earth Microbiome Project and made it capable of detecting just a single spiked-in genome copy of Plasmodium falciparum, Saccharomyces cerevisiae, or Toxoplasma gondii among more than 70,000 human cells. Using this method, we were unable to detect eukaryotic pathogens in placental biopsies in instances of adverse pregnancy outcome (n = 199) or in healthy controls (n = 99).
Eukaryotic infection of the placenta is not an underlying cause of the aforementioned pregnancy complications. Possible clinical applications for this non-targeted, yet extremely sensitive, eukaryotic screening method are manifest.
Aims Low-grade inflammation might mediate associations between size at birth, early life growth, excessive weight gain, and subsequent risk of cardiovascular disease in adult life. Our aim was to ...investigate relationships between fetal growth, weight over the life course, and low-grade inflammation measured by serum high sensitivity C-reactive protein (CRP) levels at 31 years. Methods and results General population-based northern Finland 1966 Birth Cohort study of 5840 participants attending a clinical examination at 31 years, including measurement of CRP. Weight and height were assessed at birth, 12 months, and 14 and 31 years of age. CRP levels at 31 years were 16% 95% confidence interval (CI) 8, 23 higher per 1 kg lower birth weight, 21% (95% CI 2, 37) higher per 10 cm lower birth length, and 24% (95% CI 10, 36) higher per 1 kg/m3 lower ponderal index, after adjustment for potential confounders. Participants with highest tertile body mass index (BMI) at 31 years and lowest tertile birth weight had the highest average CRP levels. Per unit increase in BMI from 14 to 31 years was associated with 16% (95% CI 14, 17) higher CRP levels; the association was larger for those in the top BMI tertile at age 14 years. Conclusion Systemic low-grade inflammation may lie on the causal pathway that relates impaired fetal growth and weight gain from childhood to adulthood to adverse adult cardiovascular health. Lifestyle changes from early life might be an important step in reducing cardiovascular risk in adults.
We have studied the largely unknown genetic underpinnings of height growth by using a unique resource of longitudinal childhood height data available in Finnish population cohorts. After applying ...GWAS mapping of potential genes influencing pubertal height growth followed by further characterization of the genetic effects on complete postnatal growth trajectories, we have identified strong association between variants near LIN28B and pubertal growth (rs7759938; female p = 4.0 × 10−9, male p = 1.5 × 10−4, combined p = 5.0 × 10−11, n = 5038). Analysis of growth during early puberty confirmed an effect on the timing of the growth spurt. Correlated SNPs have previously been implicated as influencing both adult stature and age at menarche, the same alleles associating with taller height and later age of menarche in other studies as with later pubertal growth here. Additionally, a partially correlated LIN28B SNP, rs314277, has been associated previously with final height. Testing both rs7759938 and rs314277 (pairwise r2 = 0.29) for independent effects on postnatal growth in 8903 subjects indicated that the pubertal timing-associated marker rs7759938 affects prepubertal growth in females (p = 7 × 10−5) and final height in males (p = 5 × 10−4), whereas rs314277 has sex-specific effects on growth (p for interaction = 0.005) that were distinct from those observed at rs7759938. In conclusion, partially correlated variants at LIN28B tag distinctive, complex, and sex-specific height-growth-regulating effects, influencing the entire period of postnatal growth. These findings imply a critical role for LIN28B in the regulation of human growth.
Purpose: Previous studies suggest that larger birth size is associated with a higher breast cancer incidence, but studies on birth measures and mortality in breast cancer cases are scarce. This study ...investigates survival of women after breast cancer diagnosis (n = 437) in the Uppsala Birth Cohort born in 1915–1929. Methods: Cox regression was used to analyze mortality from any cause after a breast cancer diagnosis. Birth measures including gestational age (GA), birth weight (BW), BW for GA, birth length, and ponderal index (PI) were converted to standard deviation (SD) scores, and all analyses were adjusted for age and calendar time at diagnosis. Analyses were performed with and without adjustment for other birth measures, reproductive history, and adult socioeconomic position. Results: In fully adjusted analyses, one SD increase in GA was associated with 17 % 95 % confidence interval (CI) 6–26 % lower mortality and one SD increase in BW was associated with 29 % (7–56 %) higher mortality. PI showed a weaker trend in the same direction: hazard ratio = 1.16 (95 % CI 1.03–1.30). Conclusions: Our results bring in new evidence that both high GA and low BW predict a better survival in breast cancer cases. Further studies need to investigate mediation of these associations.
Tooth development is a highly heritable process which relates to other growth and developmental processes, and which interacts with the development of the entire craniofacial complex. Abnormalities ...of tooth development are common, with tooth agenesis being the most common developmental anomaly in humans. We performed a genome-wide association study of time to first tooth eruption and number of teeth at one year in 4,564 individuals from the 1966 Northern Finland Birth Cohort (NFBC1966) and 1,518 individuals from the Avon Longitudinal Study of Parents and Children (ALSPAC). We identified 5 loci at P<5x10(-8), and 5 with suggestive association (P<5x10(-6)). The loci included several genes with links to tooth and other organ development (KCNJ2, EDA, HOXB2, RAD51L1, IGF2BP1, HMGA2, MSRB3). Genes at four of the identified loci are implicated in the development of cancer. A variant within the HOXB gene cluster associated with occlusion defects requiring orthodontic treatment by age 31 years.
To examine whether infant growth rates are influenced by fetal growth characteristics and are associated with the risks of overweight and obesity in early childhood.
This study was embedded in the ...Generation R Study, a population-based prospective cohort study from fetal life onward.
Fetal growth characteristics (femur length (FL) and estimated fetal weight (EFW)) were assessed in the second and third trimesters and at birth (length and weight). Infant peak weight velocity (PWV), peak height velocity (PHV), and body mass index at adiposity peak (BMIAP) were derived for 6267 infants with multiple height and weight measurements.
EFW measured during the second trimester was positively associated with PWV and BMIAP during infancy. Subjects with a smaller weight gain between the third trimester and birth had a higher PWV. FL measured during the second trimester was positively associated with PHV. Gradual length gain between the second and third trimesters and between the third trimester and birth were associated with higher PHV. Compared with infants in the lowest quintile, the infants in the highest quintile of PWV had strongly increased risks of overweight/obesity at the age of 4 years (odds ratio (95% confidence interval): 15.01 (9.63, 23.38)).
Fetal growth characteristics strongly influence infant growth rates. A higher PWV, which generally occurs in the first month after birth, was associated with an increased risk of overweight and obesity at 4 years of age. Longer follow-up studies are necessary to determine how fetal and infant growth patterns affect the risk of disease in later life.
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