Integrating the genotype with epigenetic marks holds the promise of better understanding the biology that underlies the complex interactions of inherited and environmental components that define the developmental origins of a range of disorders. The quality of the in utero environment significantly influences health over the lifecourse. Epigenetics, and in particular DNA methylation marks, have been postulated as a mechanism for the enduring effects of the prenatal environment. Accordingly, neonate methylomes contain molecular memory of the individual in utero experience. However, interindividual variation in methylation can also be a consequence of DNA sequence polymorphisms that result in methylation quantitative trait loci (methQTLs) and, potentially, the interaction between fixed genetic variation and environmental influences. We surveyed the genotypes and DNA methylomes of 237 neonates and found 1423 punctuate regions of the methylome that were highly variable across individuals, termed variably methylated regions (VMRs), against a backdrop of homogeneity. MethQTLs were readily detected in neonatal methylomes, and genotype alone best explained~25% of the VMRs. We found that the best explanation for 75% of VMRs was the interaction of genotype with different in utero environments, including maternal smoking, maternal depression, maternal BMI, infant birth weight, gestational age, and birth order. Our study sheds new light on the complex relationship between biological inheritance as represented by genotype and individual prenatal experience and suggests the importance of considering both fixed genetic variation and environmental factors in interpreting epigenetic variation.

We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10−11 to 5.0 × 10−21). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10−6). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.

Prenatal maternal depression is associated with alterations in the neonatal amygdala microstructure, shedding light on the timing for the influence of prenatal maternal depression on the brain structure of the offspring. This study aimed to examine the association between prenatal maternal depressive symptomatology and infant amygdala functional connectivity and to thus establish the neural functional basis for the transgenerational transmission of vulnerability for affective disorders during prenatal development. Twenty-four infants were included in this study with both structural magnetic resonance imaging (MRI) and resting-state functional MRI (fMRI) at 6 months of age. Maternal depression was assessed at 26 weeks of gestation and 3 months after delivery using the Edinburgh Postnatal Depression Scale. Linear regression was used to identify the amygdala functional networks and to examine the associations between prenatal maternal depressive symptoms and amygdala functional connectivity. Our results showed that at 6 months of age, the amygdala is functionally connected to widespread brain regions, forming the emotional regulation, sensory and perceptual, and emotional memory networks. After controlling for postnatal maternal depressive symptoms, infants born to mothers with higher prenatal maternal depressive symptoms showed greater functional connectivity of the amygdala with the left temporal cortex and insula, as well as the bilateral anterior cingulate, medial orbitofrontal and ventromedial prefrontal cortices, which are largely consistent with patterns of connectivity observed in adolescents and adults with major depressive disorder. Our study provides novel evidence that prenatal maternal depressive symptomatology alters the amygdala's functional connectivity in early postnatal life, which reveals that the neuroimaging correlates of the familial transmission of phenotypes associated with maternal mood are apparent in infants at 6 months of age.

Exposure to maternal anxiety predicts offspring brain development. However, because children's brains are commonly assessed years after birth, the timing of such maternal influences in humans is unclear. This study aimed to examine the consequences of antenatal and postnatal exposure to maternal anxiety upon early infant development of the hippocampus, a key structure for stress regulation. A total of 175 neonates underwent magnetic resonance imaging (MRI) at birth and among them 35 had repeated scans at 6 months of age. Maternal anxiety was assessed using the State-Trait Anxiety Inventory (STAI) at week 26 of pregnancy and 3 months after delivery. Regression analyses showed that antenatal maternal anxiety did not influence bilateral hippocampal volume at birth. However, children of mothers reporting increased anxiety during pregnancy showed slower growth of both the left and right hippocampus over the first 6 months of life. This effect of antenatal maternal anxiety upon right hippocampal growth became statistically stronger when controlling for postnatal maternal anxiety. Furthermore, a strong positive association between postnatal maternal anxiety and right hippocampal growth was detected, whereas a strong negative association between postnatal maternal anxiety and the left hippocampal volume at 6 months of life was found. Hence, the postnatal growth of bilateral hippocampi shows distinct responses to postnatal maternal anxiety. The size of the left hippocampus during early development is likely to reflect the influence of the exposure to perinatal maternal anxiety, whereas right hippocampal growth is constrained by antenatal maternal anxiety, but enhanced in response to increased postnatal maternal anxiety.