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When Does A Fetus Get A Genetic Makeup

Written By Thursday, May 12, 2022 Add Comment Edit

Abstruse

Aberrant fetal growth is associated with morbidities and mortality during childhood and adult life. Although genetic and environmental factors are known to influence in utero growth, their relative contributions over pregnancy is unknown. Nosotros estimated, across gestation, the genetic heritability, contribution of shared environment, and genetic correlations of fetal growth measures (abdominal circumference (AC), humerus length (HL), femur length (FL), and estimated fetal weight (EFW)) in a prospective cohort of dichorionic twin gestations recruited through the NICHD Fetal Growth Studies. Structural equation models were fit at the end of showtime trimester, during mid-gestation, tardily second trimester, and third trimester of pregnancy. The contribution of fetal genetics on fetal size increased with gestational age, peaking in late second trimester (Air conditioning = 53%, HL = 57%, FL = 72%, EFW = 71%; p < 0.05). In dissimilarity, shared environment explained nigh of phenotypic variations in fetal growth in the first trimester (AC = 50%, HL = 54%, FL = 47%, EFW = 54%; p < 0.05), suggesting that the first trimester presents an intervention opportunity for a more optimal early fetal growth. Genetic correlations between growth traits (range 0.34–1.00; p < 0.05) were strongest at the finish of first trimester and declined with gestation, suggesting that different fetal growth measures are more likely to be influenced by the same genes in early pregnancy.

Introduction

Fetal growth is an important determinant of health and affliction in kid- and developed-hood. Measures of aberration of fetal growth are associated with perinatal morbidity and bloodshed, and long-term adverse health outcomesi,ii,three,iv,5. Complex interactions between genetic and environmental factors including fetal and parental genetic variations, maternal nutrition, and placental function play important roles in fetal growth6,7. Despite the knowledge that size at nascence does not reverberate the design of fetal growth in utero, previous genetic and non-genetic studies have primarily used birthweight every bit crude measure out of intrauterine growth6,vii,8,9,10,11. Studies that demonstrate genetic and non-genetic contributions to the longitudinal pattern of growth in utero, identifying the timing when genetic and/or environmental factors during pregnancy are about influential, are defective.

To date, a total of threescore loci associated with birthweight take been discovered using genome-wide association studies (GWASs)ix,10,12. About 15% of the variance in birthweight has been explained by single nucleotide polymorphismsten, reinforcing earlier findings on heritability estimates of birthweight that ranged from 25–31%13,14. Information technology has previously been demonstrated that the combined issue of seven candidate genetic loci on birthweight variance was like to those of maternal smoking during pregnancyten, and that of 59 autosomal loci was like to the outcome of maternal body mass index12, suggesting that genetic loci contribute considerably loftier variation in birthweight. Of note, five of the vii fetal loci that were associated with birthweight, equally identified past the previous GWAS study10, were also known to influence type-2 diabetes (ADCY5 and CDKAL1), adult blood pressure level (HMGA2, ADRB1) and adult height (LCORL)ten. These genes encode proteins with diverse functions including transcriptional regulation, adipogenesis, and spermatogenesis. The genes are broadly expressed in several tissues indicating multiple potential downstream effects in tissues (http://www.genecards.org/).

Estimates of heritability (h2), which measure the proportion of total phenotypic variance attributed to additive genetics15, can exist used to measure out the extent to which fetal growth variations in a population can exist explained by genetic effects16. Twin studies are well suited for studying genetic and ecology influences on circuitous traits, because estimating the correlation between monozygotic (MZ) and dizygotic (DZ) twins allows measurement of the relative contributions of fetal additive genetic, shared ecology (c2) and not-shared environmental (due east2) effects on the variance and covariance of fetal growth measures16,17.

Heritability estimates have been used to estimate the relative contributions of genetic and not-genetic factors on parameters of growth measured at birthxviii,19. In addition, several studies accept shown that condiment genetic effects vary at different stages of development during infancytwenty,21,22, childhood23,24,25, adolescence and machismo23,26,27,28. Yet, there is limited understanding of the trends in fetal genetic influences on growth trajectories in utero. Previous studies on heritability of fetal growth found that h2 of fetal growth varies over gestation, but the studies were limited to fetal anthropometry measured in late gestation and evaluated estimated fetal weight merely24,29. Prove suggests that early life interventions can have strong furnishings on the cardiovascular changes that are associated with fetal growth restriction, highlighting the importance of ascertaining sensitive "window of opportunity" for intervention30. A comprehensive understanding of the fetal genetic and environmental influences on variance of a wide array of fetal growth measures will be pivotal to understand the pathobiology of fetal growth, to serve as a benchmark for estimating the missing heritability of previous and future genetic studies, and to inform effective targeting of biomedical interventions. Given that fetal growth is an of import determinant of health and illness in the perinatal menstruum31, understanding etiology of fetal growth will have important clinical implicationsthirty,32.

The goal of this report was to examine the relative contributions of fetal condiment genetic and ecology influences on fetal growth trajectories in a prospective cohort of dichorionic twin gestations recruited through the NICHD Fetal Growth Studies project. Specifically, we estimated hii, cii, and e2 on estimated fetal weight (EFW), intestinal circumference (AC), humerus length (HL), and femur length (FL) at end of first trimester, mid-gestation, late 2nd trimester, and 3rd trimester. We also estimated pair-wise genetic correlations between the fetal growth measures to gain insights on the extent to which the aforementioned genetic factor(s) influence different fetal growth measures during the progression of pregnancy.

Results

Genetic heritability of fetal growth increases throughout pregnancy

Dizygotic twins did not significantly differ from monozygotic twins with regards to their maternal and fetal characteristics and mean EFW, Air-conditioning, HL and FL (Table 1). For all measures of fetal growth, htwo was highest in late 2d trimester and everyman at the stop of start trimester. In contrast, c2 was highest at the end of starting time trimester and lowest in tardily second trimester (Fig. 1, Tabular array S1). Specifically, h2 of EFW increased from end of first trimester (17%) to mid-gestation (41%), peaking in late second trimester (71%), and declining at week 38 (66%). In dissimilarity, cii declined from early through late gestation: 54% at the end of first trimester, 39% at mid-gestation, 11% at late second trimester and 7% at calendar week 38.

Tabular array 1 Study characteristics of participants.

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Figure ane
figure 1

Fetal genetic heritability, shared and unique environmental variance estimates of fetal growth trajectories over gestation. (A) Estimated fetal weight (EFW). (B) Intestinal circumference (AC). (C) Humerus length (HL). (D) Femur length (FL). *Indicate statistically significant estimates (P < 0.05).

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For Air-conditioning, hii increased from finish of first trimester (14%) to mid-gestation (23%), peaking in late second trimester (53%), only declining at week 38 (45%). In contrast, cii for Air-conditioning declined from cease of outset trimester (50%) to mid-gestation (47%), reaching 19% in belatedly 2d trimester and increasing to 26% at week 38. Like contrasting trends in htwo and ctwo were observed for FL and HL. For example, hii for FL slightly increased from first trimester (29%) to mid-gestation (xxx%), peaked in tardily 2nd trimester (72%) and declined at week 38 (39%). c2 for FL declined from 47% at first trimester to 45% at mid-gestation, declining to 0 at belatedly second trimester, and rise to 17% at week 38. htwo for HL continued to increase from 21% at the end of first trimester to 22% in mid-gestation, and 57% in belatedly second trimester, but remained at 56% by calendar week 38. c2 remained at 54% in commencement trimester and mid-gestation, and continued to turn down to 20% at the terminate of 2d trimester and to 18% at week 38. Overall, e2 remained relatively similar at end of first trimester and tardily second trimester, except for HL and FL in which it showed an increment during the third trimester (Table S1). The respective p-values for htwo and c2 estimates are shown in Table S1. Maternal age, fetal sex and race were covariates that were statistically significant and explained six.1–eleven.one% of variance of the fetal growth measures from the end of showtime trimester to end of second trimester (Table S2).

Genetic correlation of fetal growth measures declines over gestation

Pregnant genetic correlations were observed betwixt EFW and measures of skeletal growth (Table 2). The genetic correlation betwixt EFW and FL declined from showtime trimester (ρChiliad = 0.79) reaching to its lowest at week 38 (ρG = 0.67). Similarly, genetic correlation betwixt EFW and HL continually declined from the first trimester (ρG = 0.85) reaching to its everyman at calendar week 38 (ρG = 0.65). Similar declining trend of genetic correlations were found between AC and FL (ρK = 0.57 at first trimester and ρYard = 0.35 at calendar week 38), and Air-conditioning and HL (ρG = 0.67 at first trimester and ρK = 0.39 at week 38).

Table ii Genetic correlation of phenotypes and their trajectories across gestation.

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Discussion

The present study estimated the heritability of fetal growth trajectories using fetal anthropometric data measured throughout gestation. To our noesis, this is the first study that comprehensively assessed fetal genetic and environmental influences on several longitudinal fetal growth indices and identified the timing when genetic and/or environmental factors during pregnancy are virtually influential. Nosotros observed substantial and increasing trends of fetal genetic influences on fetal growth beyond gestation, where htwo increased from beginning trimester to mid-gestation and peaked in belatedly second trimester. In contrast, nosotros observed substantial decline in the contribution of environmental factors on fetal growth variation every bit gestation progresses.

A previous report found that heritability of fetal weight decreased by 23% from week 25 to week 4229. Nosotros observed a similar pattern, where heritability of EFW decreased by 10% from week 27 to week 38. Similar to our ascertainment, the heritability of fetal growth in the Gielen et al. report29 peaked towards late 2nd trimester. As well, in pregnancies complicated by an abnormal glucose tolerance examination, genetic factors (history of a prior large-for-gestational historic period newborn) appeared to predict accelerated fetal growth in the late second and early third trimester (weeks 24–28)33. In dissimilarity, another study reported that heritability of FL and EFW increased from second trimester onwards24. The investigators in that study indicated that their study may exist prone to measurement error, leading to biased heritability estimates. In our report, the correlation betwixt the adept reviewer and site sonographer was >88% for all growth parameters beyond visits, with 21 out of 26 measures having a correlation of ≥95%, suggesting splendid reliability34.

We observed that the contribution of additive fetal genetic factors to fetal growth slightly declined during the tertiary trimester of pregnancy, whereas the variance explained past ecology factors not shared by the twin pairs showed slight increment. The third trimester is a period when the growing fetus's demand for oxygen and nutrients is high29. The placenta is an important unique surround in dichorionic twins, hence a component of non-shared environmental factor with loftier potential to orchestrate higher growth discordance between co-twins in late gestation. Placental weight, a rough marker of placental size, has been plant to exist independently associated with fetal growth in the third trimester35. Placenta-related factors such as differences in umbilical cord insertion sites on the placenta are also known to influence fetal growth36. Together, these data bespeak that differences between dichorionic twins in factors related to placental send functions such as placental volume, placental mass, and site of umbilical cord zipper are likely to accept stronger influence in fetal growth during this period36,37,38, explaining our observed slight increment in the contributions of shared and unshared environmental influences and lower heritability in late gestation.

Shared environmental effects contain maternal factors including age, nutritional status, and adiposity. Several animate being and man studies demonstrated the impact of these factors at dissimilar critical pregnancy fourth dimension periods. Maternal tertiary-trimester cigarette consumption was found to be a strong and independent predictor of nascence weight percentile39. Fetuses of mothers with a higher trunk mass alphabetize had smaller head circumferences at early on gestation (17 weeks)forty. Maternal undernutrition and overnutrition are shown to reduce placental-fetal blood flows and stunt fetal growth in studies of animal models41,42. In humans, maternal undernutrition in the early on stage of gestation has been linked to a number of agin effects on fetal growth and development43. The fauna studies showed that the critical window for programing is different amidst the species41. In our written report, merely maternal age and race as shared environmental factors, and fetal sexual practice as non-shared ecology factor together explained 6.1–xi.1% of variance for each of the fetal growth measures from the end of first trimester to end of 2nd trimester. Our observation that maternal age, race and infant sexual practice together explained the phenotypic variances may suggest that hereafter genome-wide clan studies of fetal growth may attain better power with models that adjusted for these factors.

Our findings for genetic and environmental influences of growth for twins may not exist generalizable to singletons, as studies reported patterns of fetal growth differ in twins and singletons34,44,45. However, previous study by our grouping compared dichorionic twin fetuses to singletons using the current written report population and found that ultrasound measured hateful EFW and AC for the twins was similar to that of singletons until approximately 32 weeks46, consistent with other studies that compared singletons and twins. Get-go at 32 weeks of gestation, dichorionic twins had smaller EFW and AC compared to singletons. This observation for slower growth in twins compared to singletons could be due to lesser capability of sustaining acceptable growth in twin fetuses throughout pregnancy47. In addition, maternal constraint, which involves a gear up of uteroplacental mechanisms by which fetal growth is restricted from reaching its genetic potential, could explicate differences in growth between twins and singletons48.

The stiff genetic correlations we observed betwixt different fetal growth measures peculiarly in early gestation indicates that skeletal growth and adipogenesis may be modulated through a minor set of genetic pathways in early on pregnancy. Interestingly, we observed that genetic correlation was highest during the commencement trimester when the heritability of the fetal growth traits was the lowest. This will be useful in hereafter genomic studies because, if a genetic variant associated with 1 fetal growth trait in early on pregnancy is discovered, there is a high chance that the same genetic variant also influences the other correlated traits. Consistent with our finding, a recent GWAS has demonstrated meaning genetic correlations betwixt birthweight and birth length49. Furthermore, acme and weight during infancy were found to be strongly influenced by the aforementioned additive genetic and shared environmental factors50.

The principal force of our study its longitudinal design and implementation of a standardized ultra-sonology protocol with established quality control. Our written report population included pregnancies with dichorionic twin gestations, which allowed us to assess the influence of private environment on fetal growth (due east.g. placental effects). Chorionicity is associated with agin fetal outcomes51,52,53,54. A prospective study constitute worse outcomes for dichorionic twins47, while another study showed monochorionic twins had college perinatal morbidity and mortality rates compared to discordant twins48. Monochorionic placentation in itself is suggested to accept an changed association with birthweight53. Future studies may benefit from evaluating both di- and mono-chorionic twins. While di-chorionic twins enable usa to study the influence of individual in-utero exposures experience by the co-twins48, mono-chorionic twin studies will be useful to reduce confounders in studying effects of fetal sex and genetic differences in di-zygotic twins.

Our study was underpowered to examine sex-specific genetic and environmental effects. Evaluating the sex-specific associations is important because previous studies take indicated that male and female person offspring reply differently to adverse ecology exposures55,56. Moreover, trans-generational transmission of depression birthweight linking maternal birthweight to offspring birthweight has been found to be sex-specific57. It should exist noted that variations in the relative contribution of genetic and environmental factors on fetal growth may be due to the influence of different genetic loci at different stages of fetal growth, dissimilar levels of influence from the same locus at dissimilar gestational ages, and a combination of the two effects besides equally gene-environment interactions. Lastly, nosotros accept not assessed for maternal genetic effects, and factor-gene and cistron-surroundings interaction effects which may further elucidate mechanisms of fetal growth. Hereafter genetic studies are needed to place the genetic loci and pathways underlying the longitudinal heritability changes found in the nowadays study.

In summary, condiment fetal genetics explained greater proportions of phenotypic variation in fetal growth at the end of gestation. In contrast, shared environs explained most of phenotypic variation in fetal growth in the first trimester, suggesting that early pregnancy presents an intervention opportunity for a more optimal early on fetal growth. Our observation for contrasting trends in genetic heritability and shared environment variance for fetal growth across gestation suggests that environmental factors have stronger influence on growth at early gestation, only are overtaken by genetic influences in late gestation. Our observation for stiff genetic correlations betwixt unlike fetal growth measures advise that the same genes may influence skeletal growth, and fat mass in early gestation.

Methods

Study population, setting and design

The study cohort was designed from the Eunice Kennedy Shriver National Institute of Child Health and Human Evolution (NICHD) Fetal Growth Studies - twins. Briefly, a accomplice of 171 (15 MZ, 133 DZ, eight missing with same sex, and 15 missing neonatal sexual activity and zygosity) women with dichorionic twin pregnancies was recruited from 8 clinical sites in U.S. between 2012 and 201334,58. Twin pregnancies with confirmed zygosity determined using standard unmarried tandem echo identifier kits (Applied Biosystems AmpFLSTR Identifier PCR Amplification Kit; ThermoFisher Scientific, Waltham, MA) (xv MZ and 133 DZ) were included in this study. A standardized ultrasound protocol was implemented, and sonographers underwent extensive training and credentialing. Women underwent up to seven ultrasound examinations at which the fetal anthropometric biometrics HC, AC, HL and FL were measured59. The initial ultrasound imaging was scheduled between xi weeks 0 days and xiii weeks 6 days of gestation. Women were them randomly assigned to receive sonograms co-ordinate to schedule A (16, 20, 24, 28, 32, and 35 weeks) or schedule B (xviii, 22, 26, 30, 34, and 36 weeks)34.EFW was calculated using the Hadlock formula, which incorporated HC, Ac and FL60. Zygosity of same sex twin pairs was determined from collections of placental samples or buccal swabs using standard single tandem echo identifier kits (Applied Biosystems AmpFLSTR Identifiler PCR Amplification Kit; ThermoFisher Scientific, Waltham, MA).

Information on sociodemographic characteristics; medical, reproductive, and pregnancy histories, and health and lifestyle behaviors was obtained through in person interviews conducted at each of the prenatal study visits equally previously described34,58. The study was approved by the Institutional Review Boards of NICHD, participating clinical institutions, and data and imaging analogous centers. Informed consent was obtained from all participants and the report was conducted in accord with relevant standards and guidelines.

Statistical analysis

Linear mixed models with a cubic spline hateful structure and a random effects structure that included linear, quadratic, and cubic random effects, and an intercept term for the private fetus within twin pair61, were used to model growth trajectories for twins and ascertain anthropometric measurements at 13 weeks and 6 days (stop of first trimester), 20th week (mid-gestation), 27 weeks and 6 days (late 2nd trimester), and 38 weeks and half dozen days of gestation (3rd trimester). All models included continuous variables such every bit maternal age, pre-pregnancy body-mass-index (BMI), and categorical variables such equally smoking in the past six months since the fourth dimension of interview, alcohol apply in the past calendar week since the time of interview, race (White/not-Hispanic vs Other), parity (nulliparous vs ≥1 child), gravidity (i, 2 or ≥iii pregnancies), employment status (employed vs other) educational status (≤loftier school vs >high school), and fetal sex (male person vs female) every bit covariates. Fetal growth mensurate were changed normalized to ensure that their residuum kurtosis values were inside normal range.

Twin studies allow us to approximate the contribution of additive fetal genetic, shared environmental and not-shared environmental factors on the variance of fetal growth measures15,xvi. MZ twins share 100% of their genes, whereas DZ twins share 50% of their genes. Both MZ and DZ twins are assumed to be sharing 100% of their shared environmental influences such as in utero experiences. Non-shared ecology influences, including measurement fault and placenta, are assumed to exist unique to the co-twins and contribute to all differences between MZ twins.

For each fetal growth measure out (i.e., EFW, Air-conditioning, HL, and FL), we estimated the: (1) genetic heritability, i.east. the proportion of phenotypic variance attributed to additive fetal genetic variancexv, (2) environmental variances (shared by both twins in a pair and unique to each co-twin), and (3) genetic correlation between fetal growth measures, which measures the proportion of covariance of 2 traits explained by additive fetal genetics using the Sequential Oligogenic Linkage Assay Routines (SOLAR) software version 7.2.v62 (http://solar-eclipse-genetics.org/). SOLAR implements a structural equation modeling approach to estimate additive genetic heritability, shared and unique environmental contributions and the best-fitting variance component models using the maximum-likelihood method63,64,65.

Our report accomplished 80% statistical ability to detect a 25% phenotypic variation due to additive fetal genetics, and a 50% phenotypic variation due to shared environment at α = 0.0566 (https://genepi.qimr.edu.au//general/TwinPowerCalculator/twinpower.cgi). Evidence for shared fetal genetic effects was estimated using ρYard, where pair-wise correlations were estimated using a maximum-likelihood bivariate analysis in SOLAR. Comparing of characteristics of monozygotic and dizygotic twins was washed using SAS 9.iv (SAS Institute, Cary NC).

Data availability

The datasets generated during and/or analyzed during the electric current report are available from the NICHD Fetal Growth Studies squad or the corresponding writer on request, including a brusk protocol with a specific inquiry question, an analysis programme, and a completed Data Apply Agreement. The information, along with a set of guidelines for researchers applying for the data, will also be posted to a information-sharing site, the NICHD/DIPHR Biospecimen Repository Admission and Data Sharing [https://brads.nichd.nih.gov].

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Acknowledgements

This research was supported by the Intramural Inquiry Program of the Eunice Kennedy Shriver National Establish of Child Health and Human Evolution, National Institutes of Health (contract numbers: HHSN275200800013C; HHSN275200800002I; HHSN27500006; HHSN27520 0800003IC; HHSN275200800014C; HHSN275200800 012C; HHSN275200800028C; HHSN275201000009C).

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Affiliations

  1. Epidemiology Branch, Partitioning of Intramural Population Health Research, Eunice Kennedy Shriver National Establish of Child Health and Man Evolution, National Institutes of Health, Bethesda, MD, USA

    Tsegaselassie Workalemahu, Katherine 50. Grantz, Jagteshwar Grewal, Cuilin Zhang & Fasil Tekola-Ayele

  2. Dean's Office, College of Health and Man Services, George Mason University, Fairfax, VA, USA

    Germaine M. Buck Louis

Contributions

F.T.-A. conceived this research idea and designed the assay; J.G., G.B.Fifty., C.Z., and K.L.G. were involved in the accomplice design and data collection; T.W. analyzed the information; T.West. and F.T.-A. wrote the paper; and all authors provided critical intellectual content and approved the concluding manuscript.

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Correspondence to Fasil Tekola-Ayele.

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Workalemahu, T., Grantz, K.L., Grewal, J. et al. Genetic and Ecology Influences on Fetal Growth Vary during Sensitive Periods in Pregnancy. Sci Rep 8, 7274 (2018). https://doi.org/ten.1038/s41598-018-25706-z

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