Genome-wide association study of offspring birth weight in 86?577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics.
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ABSTRACT:
SUBMITTER: Beaumont RN
PROVIDER: S-EPMC5886200 | biostudies-literature | 2018 Feb
REPOSITORIES: biostudies-literature
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Genome-wide association study of offspring birth weight in 86 577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics.
Beaumont Robin N RN Warrington Nicole M NM Cavadino Alana A Tyrrell Jessica J Nodzenski Michael M Horikoshi Momoko M Geller Frank F Myhre Ronny R Richmond Rebecca C RC Paternoster Lavinia L Bradfield Jonathan P JP Kreiner-Møller Eskil E Huikari Ville V Metrustry Sarah S Lunetta Kathryn L KL Painter Jodie N JN Hottenga Jouke-Jan JJ Allard Catherine C Barton Sheila J SJ Espinosa Ana A Marsh Julie A JA Potter Catherine C Zhang Ge G Ang Wei W Berry Diane J DJ Bouchard Luigi L Das Shikta S Hakonarson Hakon H Heikkinen Jani J Helgeland Øyvind Ø Hocher Berthold B Hofman Albert A Inskip Hazel M HM Jones Samuel E SE Kogevinas Manolis M Lind Penelope A PA Marullo Letizia L Medland Sarah E SE Murray Anna A Murray Jeffrey C JC Njølstad Pål R PR Nohr Ellen A EA Reichetzeder Christoph C Ring Susan M SM Ruth Katherine S KS Santa-Marina Loreto L Scholtens Denise M DM Sebert Sylvain S Sengpiel Verena V Tuke Marcus A MA Vaudel Marc M Weedon Michael N MN Willemsen Gonneke G Wood Andrew R AR Yaghootkar Hanieh H Muglia Louis J LJ Bartels Meike M Relton Caroline L CL Pennell Craig E CE Chatzi Leda L Estivill Xavier X Holloway John W JW Boomsma Dorret I DI Montgomery Grant W GW Murabito Joanne M JM Spector Tim D TD Power Christine C Järvelin Marjo-Ritta MR Bisgaard Hans H Grant Struan F A SFA Sørensen Thorkild I A TIA Jaddoe Vincent W VW Jacobsson Bo B Melbye Mads M McCarthy Mark I MI Hattersley Andrew T AT Hayes M Geoffrey MG Frayling Timothy M TM Hivert Marie-France MF Felix Janine F JF Hyppönen Elina E Lowe William L WL Evans David M DM Lawlor Debbie A DA Feenstra Bjarke B Freathy Rachel M RM
Human molecular genetics 20180201 4
Genome-wide association studies of birth weight have focused on fetal genetics, whereas relatively little is known about the role of maternal genetic variation. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth. We meta-analysed data on up to 8.7 million SNPs in up to 86 577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equat ...[more]
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Project description:BackgroundLow birth weight (LBW) and fetal growth restriction are associated with the development of cardio-metabolic diseases later in life. A recent Mendelian randomization study concluded that the susceptibility of LBW infants to develop hypertension during adulthood is due to the inheritance of hypertension genes from the mother and not to an unfavorable intrauterine environment. Therein, a negative linear association has been assumed between genetically estimated maternal blood pressure (BP) and birth weight, while the observed relationship between maternal BP and birth weight is substantially different from that assumption. As many hypertension genes are likely involved in vasculature development and function, we hypothesized that BP-increasing genetic variants could affect birth weight by reducing the growth of the placenta, a highly vascular organ, without overtly elevating the maternal BP.MethodsUsing a birth cohort in the Japanese population possessing time-series fetal growth velocity data as a target and a GWAS summary statistics of BioBank Japan as a base data, we performed polygenic score (PGS) analyses for systolic BP (SBP), diastolic BP, mean arterial pressure, and pulse pressure. A causal mediation analysis was performed to assess the meditation effect of placental weight on birth weight reduced by maternal BP-increasing PGS. Maternal genetic risk score constituted of only "vasculature-related" BP single nucleotide polymorphisms (SNPs) was constructed to examine the involvement of vascular genes in the mediation effect of placental weight. We identified gestational week in which maternal SBP-increasing PGS significantly decreased fetal growth velocity.ResultsWe observed that maternal SBP-increasing PGS was negatively associated with offspring birth weight. A causal mediation analysis revealed that a large proportion of the total maternal PGS effect on birth weight was mediated by placental weight. The placental mediation effect was remarkable when genetic risk score was constituted of "vasculature-related" BP SNPs. The inverse association between maternal SBP PGS and fetal growth velocity only became apparent in late gestation.ConclusionsOur study suggests that maternal hypertension genes are strongly associated with placental growth and that fetal growth inhibition is induced through the intrauterine environment established by the placenta.
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Project description:It is well-established that both the child's genetic endowments as well as maternal smoking during pregnancy impact offspring birth weight. In this paper we move beyond the nature versus nurture debate by investigating the interaction between genetic endowments and this critical prenatal environmental exposure - maternal smoking - in determining birth weight. We draw on longitudinal data from the Avon Longitudinal Study of Parents and Children (ALSPAC) study and replicate our results using data from the UK Biobank. Genetic endowments of the children are proxied with a polygenic score that is constructed based on the results of the most recent genome-wide association study of birth weight. We instrument the maternal decision to smoke during pregnancy with a genetic variant (rs1051730) located in the nicotine receptor gene CHRNA3. This genetic variant is associated with the number of cigarettes consumed daily, and we present evidence that this is plausibly the only channel through which the maternal genetic variant affects the child's birth weight. Additionally, we deal with the misreporting of maternal smoking by using measures of cotinine, a biomarker of nicotine, collected from the mother's urine during their pregnancy. We confirm earlier findings that genetic endowments as well as maternal smoking during pregnancy significantly affects the child's birth weight. However, we do not find evidence of meaningful interactions between genetic endowments and an adverse fetal environment, suggesting that the child's genetic predisposition cannot cushion the damaging effects of maternal smoking.
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Project description:Background: The association between educational attainment (EA) and offspring birth weight (BW) has been reported by several traditional epidemiological studies. However, evidence for this association tends to be mixed and confounded. This study aimed to investigate the causal association between EA of parents and offspring BW. Methods: Here, we carried out a two-sample bidirectional Mendelian randomization (MR) analysis to examine the causal association between EA of males (n = 131,695) and females (n = 162,028) and offspring BW using genetic instruments. Summary statistics of EA associated single nucleotide polymorphisms (SNPs) were extracted from a GWAS incorporating 293,723 individuals of European descent performed by the Social Science Genetic Association Consortium (SSGAC), and the effects of these SNPs on offspring BW were estimated using a GWAS meta-analysis of 86,577 participants of European descent from 25 studies. Univariable MR analyses were conducted using the inverse-variance weighted (IVW) method and four other methods. Further sensitivity analyses were carried out to test the viability of the results. Multivariable MR was used to examine the confounders between the exposure and outcome. Results: The result shows evidence that the offspring BW is positively causally affected by female EA. Each one standard deviation (SD) increase in female EA was associated with 0.24 SD higher of offspring BW (95% confidence interval [CI], 0.10 to 0.37, p < 0.001 for the IVW method). Similarly, change in offspring BW was 0.21 SD (95% CI: 0.07 to 0.34, p = 2.82 × 10-3) per one SD higher in male EA. No causal effect of BW on EA was found by any of the five methods. The causal association between female EA and offspring BW maintained after adjusting for alcoholic drinks per week and BMI. The effect of male EA on offspring BW was attenuated when we adjusted for BMI and alcoholic drinks per week using multivariable MR analysis. Conclusion: Our study indicated that female EA is positively causally associated with offspring BW. The association between male EA and offspring BW may be confounded by alcoholic drinks per week and BMI.
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Project description:We aimed to gain mechanistic insights into the impact of uteroplacental insufficiency upon hepatic cholestrol metabolism pathways in young adult offspring.Uterine artery ablation-induced low birth weight (LBW) and normal birth weight (NBW) male and female guinea pig offspring were fed a control diet from weaning until postnatal day 150. Analysis of whole hepatic transcriptome results identified that between LBW and NBW offspring livers, 51 (29 up-regulated and 22 down-regulated) and 31 (8 up-regulated and 23 down-regulated) genes were differentially expressed in males and females respectively (fold change| >= 2 and p-value < 0.05). KEGG pathway analysis of these differentially expressed genes revealed that “Cholesterol metabolism” was an enriched pathway in LBW males but not females (p<0.05).
2020-11-10 | GSE161124 | GEO
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