Social interactions and the overall psychosocial environment have a demonstrated impact on health, particularly for people living in disadvantaged urban areas. Here we investigated the effect of psychosocial experiences on gene expression in peripheral blood immune cells of 251 children with asthma in Metro Detroit. Using RNA-sequencing and a new machine learning approach, we identified transcriptional signatures of 20 variables including psychosocial factors, blood cell composition and asthma symptoms. Importantly, we found 174 genes causally associated with asthma that are regulated by psychosocial factors, and 349 significant gene-environment interactions. These results demonstrate that social environments modulate the causal link between immune gene expression and asthma risk.

Research has demonstrated links between adult romantic attachment and one's own physical health; little is known about links between adult attachment orientations and offspring health. Prior work has shown that parents' greater attachment anxiety and avoidance predicts less warmth toward their children. Extensive work has also shown that lower maternal warmth has negative downstream effects on offspring health. We tested the novel hypothesis that mothers' dispositional romantic attachment would be linked—via maternal warmth—to their children's expression of the glucocorticoid receptor gene NR3C1, higher expression of which is associated with healthier stress-regulation and inflammatory response. In a sample of 132 youth with asthma, we found that mothers' attachment anxiety and avoidance were both negatively associated with children's expression of NR3C1, explained by lower youth-rated maternal warmth. Effects held after adjusting for demographic and psychosocial covariates. Implications for parents' attachment influencing the health of offspring are discussed.

Social interactions and the overall psychosocial environment have a demonstrated impact on health, particularly for people living in disadvantaged urban areas. Here we investigated the effect of psychosocial experiences on gene expression in peripheral blood immune cells of children with asthma in Metro Detroit. Using RNA-sequencing and a new machine learning approach, we identified transcriptional signatures of 19 variables including psychosocial factors, blood cell composition and asthma symptoms. Importantly, we found 169 genes associated with asthma or allergic disease that are regulated by psychosocial factors, and 344 significant gene-environment interactions for gene expression levels. These results demonstrate that immune gene expression mediates the link between negative psychosocial experiences and asthma risk.

Synthetic glucocorticoids, such as dexamethasone, have been used as a treatment for many immune conditions, such as asthma and, more recently, severe COVID-19. Single-cell data can capture more fine-grained details on transcriptional variability and dynamics to gain a better understanding of the molecular underpinnings of inter-individual variation in drug response. Here, we used single-cell RNA-seq to study the dynamics of the transcriptional response to glucocorticoids in activated peripheral blood mononuclear cells from 96 African American children. We used novel statistical approaches to calculate a mean-independent measure of gene expression variability and a measure of transcriptional response pseudotime. Using these approaches, we showed that glucocorticoids reverse the effects of immune stimulation on both gene expression mean and variability. Our novel measure of gene expression response dynamics, based on the diagonal linear discriminant analysis, separated individual cells by response status on the basis of their transcriptional profiles and allowed us to identify different dynamic patterns of gene expression along the response pseudotime. We identified genetic variants regulating gene expression mean and variability, including treatment-specific effects, and showed widespread genetic regulation of the transcriptional dynamics of the gene expression response.

Puberty is an important developmental period marked by hormonal, metabolic and immune changes. Puberty also marks a shift in sex differences in susceptibility to asthma. Yet, little is known about the gene expression changes in immune cells that occur during pubertal development. Here we assess pubertal development and leukocyte gene expression in a longitudinal cohort of 251 children with asthma. We identify substantial gene expression changes associated with age and pubertal development. Gene expression changes between pre- and post-menarcheal females suggest a shift from predominantly innate to adaptive immunity. We show that genetic effects on gene expression change dynamically during pubertal development. Gene expression changes during puberty are correlated with gene expression changes associated with asthma and may explain sex differences in prevalence. Our results show that molecular data used to study the genetics of early onset diseases should consider pubertal development as an important factor that modifies the transcriptome.