Mapping gene by early life stress interactions on child subcortical brain structures: A genome‐wide prospective study

Abstract

Background: Although it is well-established that both genetics and the environment influence brain development, they are typically examined separately. Here, we aimed to prospectively investigate the interactive effects of genetic variants-from a genome-wide approach-and early life stress (ELS) on child subcortical brain structures, and their association with subsequent mental health problems.Method: Primary analyses were conducted using data from the Generation R Study (N = 2257), including genotype and cumulative prenatal and postnatal ELS scores (encompassing life events, contextual risk, parental risk, interpersonal risk, direct victimisation). Neuroimaging data were collected at age 10 years, including intracranial and subcortical brain volumes (accumbens, amygdala, caudate, hippocampus, pallidum, putamen, thalamus). Genome-wide association and genome-wide-byenvironment interaction analyses (GWEIS, run separately for prenatal/postnatal ELS) were conducted for eight brain outcomes (i.e., 24 genome-wide analyses) in the Generation R Study (discovery). Polygenic scores (PGS) using the resulting weights were calculated in an independent (target) cohort (adolescent brain cognitive development Study; N = 10,751), to validate associations with corresponding subcortical volumes and examine links to later mother-reported internalising and externalising problems.Results: One GWEIS-prenatal stress locus was associated with caudate volume (rs139505895, mapping onto PRSS12 and NDST3) and two GWEIS-postnatal stress loci with the accumbens (rs2397823 and rs3130008, mapping onto CUTA, SYN-GAP1, and TABP). Functional annotation revealed that these genes play a role in neuronal plasticity and synaptic function, and have been implicated in neurodevelopmental phenotypes, for example, intellectual disability, autism, and schizophrenia. None of these associations survived a more stringent correction for multiple testing across all analysis sets. In the validation sample, all PGS genotype were associated with their respective brain volumes, but no PGS GxE associated with any Koen Bolhuis and Rosa H. Mulder shared as first author.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Early-life stress and the gut microbiome: A comprehensive population-based investigation

“…Scores within each domain were adjusted for total amount of risk factors (meaning scores are relative and ranged between 0 and 1) and subsequently averaged into a composite score of overall ELS. Previously, this ELS score and its individual domains have been found to associate with neural, cognitive, and mental health outcomes ( Bolhuis et al, 2022 ; Defina et al, 2023 ; Schuurmans et al, 2022 ). Missing data (maximum set at 50 % of items; item-level range was 0−32 %) on risk factors were imputed with the mice package ( Buuren and Groothuis-Oudshoorn, 2010 ) in R (R Core Team, 2013), using a maximum of 60 iterations, creating 30 datasets ( Defina et al, 2023 ).…”

Positive or negative environmental modulations on human brain development: the morpho-functional outcomes of music training or stress

“…Also, epigenetic changes in some genes associated to child abuse may enhance the risk of child depression 10.3389/fnins.2023.1266766 Frontiers in Neuroscience 07 frontiersin.org (Weder et al, 2014), and regions of low methylation differentiated children receiving less tactile contact (Moore et al, 2017). Lastly, genome-wide mapping fished out some loci linked to postnatal stress and subcortical structures like caudate and accumbens nuclei, which have a role in neuronal plasticity and neurodevelopmental disorders, however causality remains to be ascertained (Bolhuis et al, 2022).…”