Variants in ADCY5 and near CCNL1 are associated with fetal growth and birth weight.
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ABSTRACT:
SUBMITTER: Freathy RM
PROVIDER: S-EPMC2862164 | biostudies-literature | 2010 May
REPOSITORIES: biostudies-literature
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Variants in ADCY5 and near CCNL1 are associated with fetal growth and birth weight.
Freathy Rachel M RM Mook-Kanamori Dennis O DO Sovio Ulla U Prokopenko Inga I Timpson Nicholas J NJ Berry Diane J DJ Warrington Nicole M NM Widen Elisabeth E Hottenga Jouke Jan JJ Kaakinen Marika M Lange Leslie A LA Bradfield Jonathan P JP Kerkhof Marjan M Marsh Julie A JA Mägi Reedik R Chen Chih-Mei CM Lyon Helen N HN Kirin Mirna M Adair Linda S LS Aulchenko Yurii S YS Bennett Amanda J AJ Borja Judith B JB Bouatia-Naji Nabila N Charoen Pimphen P Coin Lachlan J M LJ Cousminer Diana L DL de Geus Eco J C EJ Deloukas Panos P Elliott Paul P Evans David M DM Froguel Philippe P Glaser Beate B Groves Christopher J CJ Hartikainen Anna-Liisa AL Hassanali Neelam N Hirschhorn Joel N JN Hofman Albert A Holly Jeff M P JM Hyppönen Elina E Kanoni Stavroula S Knight Bridget A BA Laitinen Jaana J Lindgren Cecilia M CM McArdle Wendy L WL O'Reilly Paul F PF Pennell Craig E CE Postma Dirkje S DS Pouta Anneli A Ramasamy Adaikalavan A Rayner Nigel W NW Ring Susan M SM Rivadeneira Fernando F Shields Beverley M BM Strachan David P DP Surakka Ida I Taanila Anja A Tiesler Carla C Uitterlinden Andre G AG van Duijn Cornelia M CM Wijga Alet H AH Willemsen Gonneke G Zhang Haitao H Zhao Jianhua J Wilson James F JF Steegers Eric A P EA Hattersley Andrew T AT Eriksson Johan G JG Peltonen Leena L Mohlke Karen L KL Grant Struan F A SF Hakonarson Hakon H Koppelman Gerard H GH Dedoussis George V GV Heinrich Joachim J Gillman Matthew W MW Palmer Lyle J LJ Frayling Timothy M TM Boomsma Dorret I DI Davey Smith George G Power Chris C Jaddoe Vincent W V VW Jarvelin Marjo-Riitta MR McCarthy Mark I MI
Nature genetics 20100406 5
To identify genetic variants associated with birth weight, we meta-analyzed six genome-wide association (GWA) studies (n = 10,623 Europeans from pregnancy/birth cohorts) and followed up two lead signals in 13 replication studies (n = 27,591). rs900400 near LEKR1 and CCNL1 (P = 2 x 10(-35)) and rs9883204 in ADCY5 (P = 7 x 10(-15)) were robustly associated with birth weight. Correlated SNPs in ADCY5 were recently implicated in regulation of glucose levels and susceptibility to type 2 diabetes, pro ...[more]
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Project description:Fetal intrauterine growth is influenced by complex interactions between the maternal genes, environment and fetal genes. The aim of this study was to assess the effect of GWAS-identified genetic variants associated with birth weight on intrauterine fetal growth in 665 children. Fetal growth was estimated by two-dimensional ultrasound scans at 20, 25 and 32 weeks of gestation and growth trajectories were modeled using mixed linear regression. A genetic risk score (GRS) of birth weight-raising variants was associated with intrauterine growth showing an attenuating effect on the unconditional daily reduction in proportional weight gain of 8.92 × 10-6 percentage points/allele/day (p = 2.0 × 10-4), corresponding to a mean difference of 410 g at 40 weeks of gestation between a child with lowest and highest GRS. Eight variants were independently associated with intrauterine growth throughout the pregnancy, while four variants were associated with fetal growth in the periods 20-25 or 25-32 weeks of gestation, indicating that some variants may act in specific time windows during pregnancy. Four of the intrauterine growth variants were associated with type 2 diabetes, hypertension or BMI in the UK Biobank, which may provide basis for further understanding of the link between intrauterine growth and later risk of metabolic disease.
| S-EPMC5976727 | biostudies-literature
Project description:BACKGROUND:We previously identified via a genome wide association study variants near LEKR and CCNL1 and in the ADCY5 genes lead to lower birthweight. Here, we study the impact of these variants and social stress during pregnancy, defined as social adversity and neighborhood disparity, on infant birth size. We aimed to determine whether the addition of genetic variance magnified the observed associations. METHODOLOGY/PRINCIPAL FINDINGS:We analyzed data from the Northern Finland Birth Cohort 1986 (n=5369). Social adversity was defined by young maternal age (<20 years), low maternal education (<11 years), and/or single marital status. Neighborhood social disparity was assessed by discrepancy between neighborhoods relative to personal socio-economic status. These variables are indicative of social and socioeconomic stress, but also of biological risk. The adjusted multiple regression analysis showed smaller birth size in both infants of mothers who experienced social adversity (birthweight by -40.4 g, 95%CI -61.4, -19.5; birth length -0.14 cm, 95%CI -0.23, -0.05; head circumference -0.09 cm 95%CI -0.15, -0.02) and neighborhood disparity (birthweight -28.8 g, 95%CI -47.7, -10.0; birth length -0.12 cm, 95%CI -0.20, -0.05). The birthweight-lowering risk allele (SNP rs900400 near LEKR and CCNL1) magnified this association in an additive manner. However, likely due to sample size restriction, this association was not significant for the SNP rs9883204 in ADCY5. Birth size difference due to social stress was greater in the presence of birthweight-lowering alleles. CONCLUSIONS/SIGNIFICANCE:Social adversity, neighborhood disparity, and genetic variants have independent associations with infant birth size in the mutually adjusted analyses. If the newborn carried a risk allele rs900400 near LEKR/CCNL1, the impact of stress on birth size was stronger. These observations give support to the hypothesis that individuals with genetic or other biological risk are more vulnerable to environmental influences. Our study indicates the need for further research to understand the mechanisms by which genes impact individual vulnerability to environmental insults.
| S-EPMC3369922 | biostudies-literature
Project description:A feature of the Asian Indian phenotype is low birth weight with increased adult type 2 diabetes risk. Most populations show consistent associations between low birth weight and adult type 2 diabetes. Recently, two birth weight-lowering loci on chromosome 3 (near CCNL1 and ADCY5) were identified in a genome-wide association study, the latter of which is also a type 2 diabetes locus. We therefore tested the impact of these genetic variants on birth weight and adult glucose/insulin homeostasis in a large Indian birth cohort.Adults (n?=?2,151) enrolled in a birth cohort (established 1969-73) were genotyped for rs900400 (near CCNL1) and rs9883204 (ADCY5). Associations were tested for birth weight, anthropometry from infancy to adulthood, and type 2 diabetes related glycemic traits. The average birth weight in this population was 2.79±0.47 kg and was not associated with genetic variation in CCNL1 (p?=?0.87) or ADCY5 (p?=?0.54). Allele frequencies for the 'birth weight-lowering' variants were similar compared with Western populations. There were no significant associations with growth or adult weight. However, the 'birth weight-lowering' variant of ADCY5 was associated with modest increase in fasting glucose (? 0.041, p?=?0.027), 2-hours glucose (? 0.127, p?=?0.019), and reduced insulinogenic index (? -0.106, p?=?0.050) and 2-hour insulin (? -0.058, p?=?0.010).The low birth weight in Asian Indians is not even partly explained by genetic variants near CCNL1 and ADCY5 which implies that non-genetic factors may predominate. However, the 'birth-weight-lowering' variant of ADCY5 was associated with elevated glucose and decreased insulin response in early adulthood which argues for a common genetic cause of low birth weight and risk of type 2 diabetes.
| S-EPMC3119677 | biostudies-literature
Project description:BACKGROUND AND AIM:The first genome-wide association study on birth weight was recently published and the most significant associated birth weight lowering variant was the rs900400 C-allele located near LEKR1 and CCNL1. We aimed to replicate the association with birth weight in the Danish Inter99 study and furthermore to evaluate associations between rs900400 and indices of insulin secretion and insulin sensitivity obtained by oral glucose tolerance tests in adults from the Danish Inter99 study and the Finnish, Metabolic Syndrome in Men (METSIM) sample. METHODS:For 4,744 of 6,784 Inter99 participants, midwife journals were traced through the Danish State Archives and association of rs900400 with birth weight was examined. Associations between rs900400 and fasting serum insulin, fasting plasma glucose, insulinogenic index, homeostasis model assessment of insulin resistance (HOMA-IR) and disposition index were studied in 5,484 Danish and 6,915 Finnish non-diabetic individuals and combined in meta-analyses. RESULTS:The C-allele of rs900400 was associated with a 22.1 g lower birth weight ([-41.3;-3.0], P?=?0.024) per allele. Moreover, in combined analyses of the Danish Inter99 study and the Finnish METSIM study we found that the birth weight lowering allele was associated with increased insulin release measured by the insulinogenic index (??=?2.25% [0.59; 3.91], P?=?0.008) and with an increased disposition index (??=?1.76% [0.04; 3.49], P?=?0.05). CONCLUSION:The birth weight lowering effect of the C-allele of rs900400 located near LEKR1 and CCNL1 was replicated in the Danish population. Furthermore the C-allele was associated with increased insulin response following oral glucose stimulation in a meta-analysis based on Danish and Finnish non-diabetic individuals.
| S-EPMC3208566 | biostudies-literature
Project description:ContextThyroid function is known to play an important role in fetal neurological development, but its role in regulating fetal growth is not well established. Overt maternal and fetal thyroid disorders are associated with reduced birth weight. We hypothesized that, even in the absence of overt thyroid dysfunction, maternal and fetal thyroid function influence fetal growth.AimIn normal, healthy pregnancies, we aimed to assess whether fetal thyroid hormone at birth (as measured in cord blood) is associated with fetal growth. We also aimed to study whether fetal thyroid hormone at birth is associated with maternal thyroid hormone in the third trimester.MethodsIn 616 healthy mother-child pairs, TSH, free T(4) (FT4), and free T(3) (FT3) were measured in mothers at 28 wk gestation and in umbilical cord blood at birth. Birth weight, length, head circumference, and tricep and bicep skinfold thicknesses were measured on the babies.ResultsCord FT4 was associated with birth weight (r = 0.25; P < 0.001), length (r = 0.17; P < 0.001), and sum of skinfolds (r = 0.19; P < 0.001). There were no associations between birth measurements and either cord TSH or cord FT3. Maternal FT4 and cord FT4 were correlated (r = 0.14; P = 0.0004), and there were weaker negative associations between maternal TSH and cord FT4 (r = -0.08; P = 0.04) and FT3 (r = -0.10; P = 0.01).ConclusionAssociations between cord FT4 and birth size suggest that fetal thyroid function may be important in regulating fetal growth, both of skeletal size and fat. The correlation between third-trimester maternal FT4 and cord FT4 supports the belief that maternal T(4) crosses the placenta even in late gestation.
| S-EPMC3100744 | biostudies-literature
Project description:The "fetal origins" hypothesis suggests that fetal conditions not only affect birth characteristics such as birth weight and gestational age, but also have lifelong health implications. Despite widespread interest in this hypothesis, few methodological advances have been proposed to improve the measurement and modeling of fetal conditions. A Statistics in Medicine paper by Bollen, Noble, and Adair examined favorable fetal growth conditions (FFGC) as a latent variable. Their study of Filipino children from Cebu provided evidence consistent with treating FFGC as a latent variable that largely mediates the effects of mother's characteristics on birth weight, birth length, and gestational age. This innovative method may have widespread utility, but only if the model applies equally well across diverse settings. Our study assesses whether the FFGC model of Cebu replicates and generalizes to a very different population of children from North Carolina (N=705) and Pennsylvania (N=494). Using a series of structural equation models, we find that key features of the Cebu analysis replicate and generalize while we also highlight differences between these studies. Our results support treating fetal conditions as a latent variable when researchers test the fetal origins hypothesis. In addition to contributing to the substantive literature on measuring fetal conditions, we also discuss the meaning and challenges involved in replicating prior research.
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Project description:BackgroundHigher birthweight is associated with higher adult body mass index (BMI). Alleles that predispose to greater adult adiposity might act in fetal life to increase fetal growth and birthweight. Whether there are fetal effects of recently identified adult metabolically favorable adiposity alleles on birthweight is unknown.AimWe aimed to test the effect on birthweight of fetal genetic predisposition to higher metabolically favorable adult adiposity and compare that with the effect of fetal genetic predisposition to higher adult BMI.MethodsWe used published genome wide association study data (n = upto 406 063) to estimate fetal effects on birthweight (adjusting for maternal genotype) of alleles known to raise metabolically favorable adult adiposity or BMI. We combined summary data across single nucleotide polymorphisms (SNPs) with random effects meta-analyses. We performed weighted linear regression of SNP-birthweight effects against SNP-adult adiposity effects to test for a dose-dependent association.ResultsFetal genetic predisposition to higher metabolically favorable adult adiposity and higher adult BMI were both associated with higher birthweight (3 g per effect allele (95% CI: 1-5) averaged over 14 SNPs; P = 0.002; 0.5 g per effect allele (95% CI: 0-1) averaged over 76 SNPs; P = 0.042, respectively). SNPs with greater effects on metabolically favorable adiposity tended to have greater effects on birthweight (R2 = 0.2912, P = 0.027). There was no dose-dependent association for BMI (R2 = -0.0019, P = 0.602).ConclusionsFetal genetic predisposition to both higher adult metabolically favorable adiposity and BMI is associated with birthweight. Fetal effects of metabolically favorable adiposity-raising alleles on birthweight are modestly proportional to their effects on future adiposity, but those of BMI-raising alleles are not.
| S-EPMC9169452 | biostudies-literature
Project description:The severity of porcine reproductive and respiratory syndrome was compared in pregnant gilts originating from high and low birth weight litters. One-hundred and eleven pregnant gilts experimentally infected with porcine reproductive and respiratory syndrome virus on gestation day 85 (±1) were necropsied along with their fetuses 21 days later. Ovulation rates and litter size did not differ between groups, but fetuses from low birth weight gilts were shorter, lighter and demonstrated evidence of asymmetric growth with large brain:organ weight ratios (i.e. brain sparing). The number of intrauterine growth retarded fetuses, defined by brain:organ weight ratios greater than 1 standard deviation from the mean, was significantly greater in low, compared to high, birth weight gilts. Although ?? T cells significantly decreased over time in high compared to low birth weight gilts, viral load in serum and tissues, gilt serum cytokine levels, and litter outcome, including the percent dead fetuses per litter, did not differ by birth weight group. Thus, this study provided no substantive evidence that the severity of porcine reproductive and respiratory syndrome is affected by dam birth weight. However, intrauterine growth retarded fetuses had lower viral loads in both fetal thymus and in endometrium adjacent to the umbilical stump. Crown rump length did not significantly differ between fetuses that survived and those that died at least one week prior to termination. Taken together, this study clearly demonstrates that birth weight is a transgenerational trait in pigs, and provides evidence that larger fetuses are more susceptible to transplacental PRRSv infection.
| S-EPMC4183575 | biostudies-literature
Project description:The associations between maternal pre-pregnancy obesity and low birth weight (LBW, <2500 g) remain inconclusive. Therefore, birth weight in a Polish prospective cohort of 912 mothers was investigated depending on the pre-pregnancy body mass index (BMI). The whole cohort and the subgroup of gestational weight gain (GWG) in the range of the Institute of Medicine (IOM) recommendations, as well as 'healthy' women (who did not develop diabetes or hypertension in this pregnancy) were investigated. Adjusted odds ratios (AOR) of the newborn outcomes (with 95% confidence intervals, CI) for obesity (BMI ≥ 30 kg/m2) vs. normal BMI (18.5-24.9 kg/m2) were calculated using multiple logistic regression. Risk profiles (in the Lowess method) were presented for BMI values (kg/m2) and threshold BMI values were calculated. (1) In the cohort, LBW affected 6.6% of pregnancies, fetal growth restriction (FGR) 2.3%, and macrosomia 10.6%. (2) The adjusted risk of macrosomia was more than three-fold higher for obesity compared to normal BMI in the whole cohort (AOR = 3.21 (1.69-6.1), p < 0.001) and the result was maintained in the subgroups. A 17-fold higher adjusted LBW risk for obesity was found (AOR = 17.42 (1.5-202.6), p = 0.022), but only in the normal GWG subgroup. The FGR risk profile was U-shaped: in the entire cohort, the risk was more than three times higher for obesity (AOR = 3.12 (1.02-9.54), p = 0.045) and underweight (AOR = 3.84 (1.13-13.0), p = 0.031). (3) The risk profiles showed that the highest BMI values were found to be associated with a higher risk of these three newborn outcomes and the threshold BMI was 23.7 kg/m2 for macrosomia, 26.2 kg/m2 for LBW, and 31.8 kg/m2 for FGR. These results confirm the multidirectional effects of obesity on fetal growth (low birth weight, fetal growth restriction, and macrosomia). The results for LBW were heavily masked by the effects of abnormal gestational weight gain.
| S-EPMC8067544 | biostudies-literature
Project description:ObjectiveTo examine the importance of timing of gestational weight gain during three time periods: 1: ≤ 20 weeks gestation), 2: 21-29 weeks) and 3: ≥ 30 weeks) on fetal growth and infant birth size.MethodsStudy uses secondary data from the PRECONCEPT randomized controlled trial in Thai Nguyen province, Vietnam (n = 1436). Prospective data were collected on women starting pre-pregnancy through delivery. Maternal conditional weight gain (CWG) was defined as window-specific weight gains, uncorrelated with pre-pregnancy body mass index and all prior body weights. Fetal biometry, was assessed by ultrasound measurements of head and abdomen circumferences, biparietal diameter, and femoral length throughout pregnancy. Birth size outcomes included weight and length, and head, abdomen and mid upper arm circumferences as well as small for gestational age (SGA). Adjusted generalized linear and logistic models were used to examine associations.ResultsOverall, three-quarters of women gained below the Institute of Medicine guidelines, and these women were 2.5 times more likely to give birth to a SGA infant. Maternal CWG in the first window (≤ 20 weeks), followed by 21-29 weeks, had the greatest association on all parameters of fetal growth (except abdomen circumference) and infant size at birth. For birth weight, a 1 SD increase CWG in the first 20 weeks had 3 times the influence compared to later CWG (≥ 30 weeks) (111 g vs. 39 g) and was associated with a 43% reduction in SGA risk (OR (95% CI): 0.57 (0.46-0.70).ConclusionThere is a need to target women before or early in pregnancy to ensure adequate nutrition to maximize impact on fetal growth and birth size.Trial registrationClinicalTrials.gov, NCT01665378.
| S-EPMC5256875 | biostudies-literature