Genome-Wide Copy Number Variant and High-Throughput Transcriptomics Analyses of Placental Tissues Underscore Persisting Child Susceptibility in At-Risk Pregnancies Cleared in Standard Genetic Testing
Abstract
:1. Introduction
2. Results
2.1. Case Mothers Do Not Differ from Controls in Psychological State across Pregnancy following Trisomy Screening Clearance
2.2. Children from Pregnancies Recommended for Follow-Up Prenatal Genetic Testing Carry Higher Likelihood of Negative Developmental and Disease-Related Outcomes
2.2.1. Congenital Malformations
2.2.2. Copy Number Variants
2.3. The Placental Transcriptome in Early Pregnancy Carries Signatures of Case-Control-Associated Negative Developmental Outcomes
3. Discussion
4. Materials and Methods
4.1. Sampling and Phenotypes
4.1.1. Study Samples
4.1.2. Phenotypes
Maternal Characteristics
Child Characteristics
4.2. Biosampling, DNA/RNA Extractions
4.3. Genotyping, Imputation, and MDS Components
4.4. CNV Calling
4.5. RNA Sequencing
4.6. Statistical Analysis
4.6.1. Differences in Congenital Malformations Using Cox Regression
4.6.2. Association of Congenital Malformations with Screening Variables
4.6.3. CNV Associations
4.6.4. Differential Gene Expression
4.6.5. p-Values
4.6.6. Enrichment for Pre-Eclampsia Genes
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Maternal Characteristics | Cases (n = 544) | Controls (n = 399) | p-Value 5 |
---|---|---|---|
Age at delivery, years, mean (SD), CI | 35.54 (5.5) [35.52–35.56] | 33.71 (4.2) [33.69–33.73] | 7.16 × 10−9 |
Antenatal corticosteroid treatment, n (%) | 23 (4.2%) | 9 (2.3%) | 1.41 × 10−1 |
Cesarean section, n (%) | 120 (22.1%) | 79 (19.8%) | 4.48 × 10−1 |
Diabetes Disorders in pregnancy, n (%) | 120 (22.06%) | 77 (19.3%) | 3.43 × 10−1 |
Early pregnancy BMI, median (IQR), CI | 23.43 (5.23) [23.05–23.74] | 22.65 (4.24) [22.27–23.03] | 1.42 × 10−3 |
Hypertensive Disorders in pregnancy, n (%) | 46 (8.5%) | 20 (5.0%) | 5.50 × 10−2 |
Primiparous, n (%) | 221 (40.6%) | 243 (60.9%) | 1.15 × 10−9 |
Smoking during pregnancy 1, n (%) | 36 (6.6%) | 4 (1.0%) | 1.83 × 10−5 |
Thyroid disorders 2, n (%) | 9 (1.7%) | 8 (2.0%) | 8.79 × 10−1 |
Child characteristics | |||
Birth weight, g, median (IQR), CI | 3533 (675) [3470–3585] | 3562 (610) [3508–3620] | 3.83 × 10−1 |
Gestational age at birth, weeks, median (IQR), CI | 40.00 (2.0) [40.00–40.14] | 40.14 (1.7) [40.00–40.29] | 5.17 × 10−1 |
Preterm birth 3 (<37 weeks), n (%) | 33 (6.1%) | 13 (3.3%) | 6.80 × 10−2 |
Sex, girl, (%) | 256 (47.1%) | 204 (51.1%) | 2.42 × 10−1 |
Screening variables | |||
β-hCG level (MoM, ug/L), median (IQR), CI | 1.31 (1.17) [1.30–1.73] | 0.98 (0.74) [0.93–1.08] | 1.20 × 10−11 |
NT, MoM mm, median (IQR), CI | 1.80 (1.15) [1.58–1.88] | 0.84 (0.32) [0.83–0.88] | 1.58 × 10−36 |
PAPP-A level, MoM, mU/L, median (IQR), CI | 0.75 (0.80) [0.75–1.08] | 1.12 (0.73) [1.09–1.20] | 3.45 × 10−18 |
Risk for Down syndrome 4, median (IQR), CI | 0.65 (1.01) [0.63–0.89] | 0.01 (0.2) [0.008–0.11] | 3.06 × 10−101 |
Risk for trisomy 18 4, median (IQR), CI | 0.003 (0.01) [0.003–0.014] | 0.001 (0.00) [0.001–0.001] | 1.15 × 10−64 |
Phenotype | Cases (n = 260) | Controls (n = 353) | p-Value 1 |
---|---|---|---|
CESD 19 gestational weeks, median (IQR), CI | 9 (9) [9–14] | 9 (8) [9–11] | 0.32 |
CESD 26 gestational weeks, median (IQR), CI | 8 (10) [9–12] | 9 (8) [9–11] | 0.35 |
CESD 38 gestational weeks, median (IQR), CI | 8 (9) [8–11] | 9 (9) [9–10] | 0.43 |
Cohen’s perceived stress scale 19 gestational weeks, median (IQR), CI | 5 (4.06) [6–8] | 6 (4) [6–7] | 0.48 |
Cohen’s 26 gestational weeks, median (IQR), CI | 5 (5) [5–7] | 5.5 (3) [6–6] | 0.30 |
Cohen’s perceived stress scale 38 gestational weeks, median (IQR), CI | 5 (4) [5–6] | 5 (4) [4.5–6] | 0.87 |
STAI 19 gestational weeks, median (IQR). CI | 37 (11) [39–42] | 38 (9) [38.95–41] | 0.74 |
STAI 26 gestational weeks, median (IQR), CI | 36 (9) [37–40] | 37 (10) [37–39] | 0.38 |
STAI 38 gestational weeks, median (IQR), CI | 36 (10.42) [36–39] | 37 (10) [36–38] | 0.70 |
Gene 1 | Position (hg19) 2 | Log2 (FC) 3 | p-Value 4 | Adjusted p-Value 5 | Correlation CVS and Placenta 6 |
---|---|---|---|---|---|
LEP | chr7: 127,881,331–127,897,682 | 1.99 | 1.16 × 10−6 | 5.28 × 10−3 | r = 0.27; p = 0.01 |
CRH | chr8: 67,088,612–67,090,846 | 1.69 | 1.99 × 10−8 | 1.81 × 10−4 | r = 0.14; p = 0.17 |
FSTL3 | chr19: 676,389–683,392 | 1.42 | 1.11 × 10−5 | 1.68 × 10−2 | r = 0.26; p = 0.01 |
PAPPA2 | chr1: 176,432,307–176,811,970 | 1.26 | 1.79 × 10−5 | 2.32 × 10−2 | r = 0.30; p < 0.01 |
INHBA | chr7: 41,733,514–41,818,976 | 1.18 | 1.18 × 10−4 | 7.36 × 10−2 | r = 0.23; p = 0.03 |
HTRA1 | chr10: 124,221,041–124,274,424 | 1.16 | 2.38 × 10−6 | 7.22 × 10−3 | r = 0.30; p < 0.01 |
DHRS2 | chr14: 24,105,573–24,114,848 | 1.11 | 4.16 × 10−5 | 4.20 × 10−2 | r < 0.01; p = 0.97 |
HS3ST3B1 | chr17: 14,204,506–14,249,492 | 0.98 | 4.27 × 10−6 | 9.71 × 10−3 | r = 0.13; p = 0.23 |
ANXA4 | chr2: 69,969,127–70,053,596 | 0.78 | 7.15 × 10−5 | 6.47 × 10−2 | r < 0.01; p = 0.97 |
MAN1C1 | chr1: 25,943,959–26,111,258 | 0.78 | 1.15 × 10−4 | 7.36 × 10−2 | r = 0.05; p = 0.60 |
MROH1 | chr8:145,202,919–145,316,843 | 0.70 | 9.64 × 10−5 | 7.30 × 10−2 | r = −0.14; p = 0.17 |
SEMA7A | chr15: 74,701,630-74,726,299 | 0.68 | 1.21 × 10−4 | 7.36 × 10−2 | r = 0.07; p = 0.53 |
FLT1 | chr13: 28,874,483–29,069,265 | 0.56 | 8.27 × 10−6 | 1.50 × 10−2 | r = 0.32; p < 0.01 |
RPS6KA5 | chr14: 91,337,167–91,526,993 | 0.56 | 4.06 × 10−5 | 4.20 × 10−2 | r = 0.30; p < 0.01 |
HEXIM1 | chr17: 43,224,684–43,229,468 | 0.45 | 7.83 × 10−5 | 6.47 × 10−2 | r < 0.01; p = 0.97 |
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Czamara, D.; Cruceanu, C.; Lahti-Pulkkinen, M.; Dieckmann, L.; Ködel, M.; Sauer, S.; Rex-Haffner, M.; Sammallahti, S.; Kajantie, E.; Laivuori, H.; et al. Genome-Wide Copy Number Variant and High-Throughput Transcriptomics Analyses of Placental Tissues Underscore Persisting Child Susceptibility in At-Risk Pregnancies Cleared in Standard Genetic Testing. Int. J. Mol. Sci. 2022, 23, 11448. https://doi.org/10.3390/ijms231911448
Czamara D, Cruceanu C, Lahti-Pulkkinen M, Dieckmann L, Ködel M, Sauer S, Rex-Haffner M, Sammallahti S, Kajantie E, Laivuori H, et al. Genome-Wide Copy Number Variant and High-Throughput Transcriptomics Analyses of Placental Tissues Underscore Persisting Child Susceptibility in At-Risk Pregnancies Cleared in Standard Genetic Testing. International Journal of Molecular Sciences. 2022; 23(19):11448. https://doi.org/10.3390/ijms231911448
Chicago/Turabian StyleCzamara, Darina, Cristiana Cruceanu, Marius Lahti-Pulkkinen, Linda Dieckmann, Maik Ködel, Susann Sauer, Monika Rex-Haffner, Sara Sammallahti, Eero Kajantie, Hannele Laivuori, and et al. 2022. "Genome-Wide Copy Number Variant and High-Throughput Transcriptomics Analyses of Placental Tissues Underscore Persisting Child Susceptibility in At-Risk Pregnancies Cleared in Standard Genetic Testing" International Journal of Molecular Sciences 23, no. 19: 11448. https://doi.org/10.3390/ijms231911448