OR14-1 Preimplantation embryo development is associated with both birth size and post-natal growth and can predict adult cardiovascular risk

BACKGROUND: The link between birth-size, early childhood growth and later life cardiovascular (CV) risk is well recognised. The contribution to CV risk of growth and cell differentiation during pre-implantation embryo development is unknown. AIMS: Develop a transcriptomic model of developmental trajectory in the pre-implantation embryo and link this model to birthweight, child growth and CV risk in later life. METHODS: Single cell RNA velocity(1) and pseudotime analyses were used to infer developmental trajectory in the preimplantation human embryo(2). Time series clustering was used to identify genes with similar activity patterns. These data were compared with independent genomic data from four further data sets. I) Birthweight genome wide association study (GWAS)(3). II) Genes correlated with gestation(4). III) A previously identified set of 55 genes that classify pre-hypertensive young adults using their blood methylome at age 0, 7 and 17 years(5). IV) A set of genes with differential methylation associated with linear childhood growth(6). Data sets III) and IV) were derived from the Avon Longitudinal Study of Parents and Children (n=6487). Enrichment was assessed using the hypergeometric test and confirmed via random permutation (1×10(5)-fold) and z-score analysis. Random Forest was used to determine the predictive value presented as the area under the curve (AUC) of the receiver operating characteristic. RESULTS: 8256 genes contributed to the velocity of mRNA change in the preimplantation embryo and a temporal wave pattern was revealed with peaks of velocity at 3, 4, and 5-days post-fertilisation. Genes associated with the velocity of the developmental trajectory formed 6 clusters, in which metabolic pathways were over-represented (adj. p<0.02). We found that 16/60 birthweight GWAS (I) and 3096/10521 gestation correlated genes (II) were associated with embryonic developmental trajectory (both 2-fold enrichment, p<5×10-3). Furthermore, 11/55 pre-hypertensive associated genes (III) were linked with embryonic developmental trajectory (>10-fold enrichment, p<1×10-8), these 11 genes predicted adult pre-hypertension in small for gestational age catch-up growth (cuSGA) with an AUC=0.98. Of the 8256 developmental trajectory genes, 307 were differentially methylated in linear childhood growth (IV) (2.3-fold over-enrichment, p<1×10-8). CONCLUSION: Waves of gene expression velocity occur in preimplantation human embryos. These waves mark major developmental transitions and form a transcriptomic developmental trajectory which is associated with both birthweight and gestation. The transcriptomic developmental trajectory genes are over-enriched for genes associated with the linear phase of childhood growth and for genes associated with and predictive for the development of adult pre-hypertension in cuSGA. Pre-implantation gene expression can therefore be linked to the origins of adult disease. 1. LaManno, et al. (2018). Nature. 560(7719): 494-8. 2. Petropoulos, et al. (2016). Cell. 165(4): 1012-26. 3. Horikoshi, et al. (2016). Nature 538(7624): 248-252. 4. Rasmussen, et al. (2022). Nature. https://doi.org/10.1038/s41586-021-04249-w 5. Garner, et al (2021). JES. 5: A654–A655. 6. Garner, et al (2019) ESPE Abstracts 92FC12.6 Presentation: Sunday, June 12, 2022 11:00 a.m. - 11:15 a.m.