Neonatal amygdalae and hippocampi are influenced by genotype and prenatal environment, and reflected in the neonatal DNA methylome

Abstract

The amygdala and hippocampus undergo rapid development in early life. The relative contribution of genetic and environmental factors to the establishment of their developmental trajectories has yet to be examined. We performed imaging on neonates and examined how the observed variation in volume and microstructure of the amygdala and hippocampus varied by genotype, and compared with prenatal maternal mental health and socioeconomic status. Gene × Environment models outcompeted models containing genotype or environment only to best explain the majority of measures but some, especially of the amygdaloid microstructure, were best explained by genotype only. Models including DNA methylation measured in the neonate umbilical cords outcompeted the Gene and Gene × Environment models for the majority of amygdaloid measures and minority of hippocampal measures. This study identified brain region‐specific gene networks associated with individual differences in fetal brain development. In particular, genetic and epigenetic variation within CUX1 was highlighted.

Newborn amygdalar volumes are associated with maternal prenatal psychological distress in a sex-dependent way

“…Genetic influence also deserves consideration. One study that explored genome-wide SNP’s (single nucleotide polymorphisms) interactions with prenatal environments indicated that gene-environment interdependence best explains variation in amygdalar and hippocampal measures: right amygdalar volume in interaction with prenatal maternal depression, and hippocampal white matter asymmetry with prenatal maternal anxiety and household income ( Ong et al, 2019 ). In an Asian population, maternal depressive symptoms were connected with larger right amygdalar volumes among newborns having a high genetic risk profile for depression, whereas, in contrast, the same positive connection was observed in a low risk group in an American population.…”

Infant and Child MRI: A Review of Scanning Procedures

“…Sample sizes and ages at scan are shown in Supplementary Table 1 . Fifty-two studies were completely cross-sectional and performed only one scan per each subject ( Hazlett et al, 2012 ; Deniz Can et al, 2013 ; Deoni et al, 2013 , 2015 ; Gao et al, 2013 ; O’Muircheartaigh et al, 2013 , 2014 ; Qiu et al, 2013a , 2015b ; Broekman et al, 2014 ; Dean et al, 2014b , c , 2017 , 2018a , b ; Grewen et al, 2014 ; Travis et al, 2014 ; Zhang et al, 2014 ; Donald et al, 2015 ; Langer et al, 2015 ; Ou et al, 2015 ; Poh et al, 2015 ; Spann et al, 2015a , b , 2020a , b ; Ferradal et al, 2016 , 2019 ; Li et al, 2016 ; Sethna et al, 2016 ; Adibpour et al, 2018 , 2020 ; Lugo-Candelas et al, 2018 ; Monnelly et al, 2018 ; Chen et al, 2019 ; Hernandez-Castillo et al, 2019 ; Lebenberg et al, 2019 ; Lehtola et al, 2019 ; Ong et al, 2019 ; Tuulari et al, 2019 ; Acosta et al, 2020a , b , 2021 ; Alexander et al, 2020 ; Bruchhage et al, 2020 ; Camacho et al, 2020 ; Dowe et al, 2020 ; Fenchel et al, 2020 ; Gale-Grant et al, 2020 ; Graham et al, 2020 ; Merhar et al, 2020 ; Merz et al, 2020 ). The remaining studies ( n = 34) were longitudinal and conducted serial scans on the same individuals ( Geng et al, 2012 , 2016 ; ...…”

“…A number of different approaches to wrapping the infants were provided, varying from only wrapping them in sheets to placing them into an immobilizer. Several studies ( n = 23) used specific vacuum immobilization mats, bags, or pillows to stabilize the child and reduce natural movement from breathing ( Deoni et al, 2013 ; Zhang et al, 2014 ; Ou et al, 2015 ; Croteau-Chonka et al, 2016 ; Li et al, 2016 ; Dean et al, 2014a , b , c , 2015b , 2017 , 2018a , b ; Dai et al, 2019a , b ; Hernandez-Castillo et al, 2019 ; Lehtola et al, 2019 ; Ong et al, 2019 ; Tuulari et al, 2019 ; Camacho et al, 2020 ; Dowe et al, 2020 ; Graham et al, 2020 ; Merhar et al, 2020 ; Remer et al, 2020 ). Dean et al (2014a) reported placing a mat under the child before the child fell asleep and once asleep the immobilizer was wrapped around the child.…”

“…Sample sizes and ages at scan are shown in Supplementary Table 1. Fifty-two studies were completely cross-sectional and performed only one scan per each subject (Hazlett et al, 2012;Deniz Can et al, 2013;Deoni et al, 2013Deoni et al, , 2015Gao et al, 2013;O'Muircheartaigh et al, , 2014Qiu et al, 2013aQiu et al, , 2015bBroekman et al, 2014;Dean et al, 2014bDean et al, ,c, 2017Dean et al, , 2018aGrewen et al, 2014;Travis et al, 2014;Zhang et al, 2014;Donald et al, 2015;Langer et al, 2015;Ou et al, 2015;Poh et al, 2015;Spann et al, 2015aSpann et al, ,b, 2020aFerradal et al, 2016Ferradal et al, , 2019Li et al, 2016;Sethna et al, 2016;Adibpour et al, 2018Adibpour et al, , 2020Lugo-Candelas et al, 2018;Monnelly et al, 2018;Chen et al, 2019;Hernandez-Castillo et al, 2019; Lebenberg et al, 2019;Lehtola et al, 2019;Ong et al, 2019;Tuulari et al, 2019;Acosta et al, 2020aAcosta et al, ,b, 2021Alexander et al, 2020;Bruchhage et al, 2020;Camacho et al, 2020;…”

Imprinting methylation predicts hippocampal volumes and hyperintensities and the change with age in later life

“…There is some evidence from human 34 and animal studies 35 that epigenetic change in non-imprinted genes may be relevant to the link between early life adversity and hippocampal development but the evidence for imprinted genes has so far been indirect or inferred. Offspring methylation within the imprinted gene MEST has been linked to exposure to maternal stress 36 , which has in turn been linked to www.nature.com/scientificreports/ hippocampal volumes, and there is some genetic evidence that the imprinted gene L3MBTL may work with a subnetwork of genes to influence hippocampal volume, microstructure and asymmetry 37 . White matter hyperintensities in the brain are the consequence of cerebral small vessel disease and are important risk factors for cognitive and functional impairment dementia, stroke, worse outcomes after stroke, gait instability, late-life depression, and death 23,38,39 .…”