Psychosocial experiences modulate asthma-associated genes through gene-environment interactions

Justyna A Resztak, Allison K Farrell, Henriette Mair-Meijers, Adnan Alazizi, Xiaoquan Wen, Derek E Wildman, Samuele Zilioli, Richard B Slatcher, Roger Pique-Regi, Francesca Luca, Justyna A Resztak, Allison K Farrell, Henriette Mair-Meijers, Adnan Alazizi, Xiaoquan Wen, Derek E Wildman, Samuele Zilioli, Richard B Slatcher, Roger Pique-Regi, Francesca Luca

Abstract

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.

Keywords: GxE; asthma; eQTLs; gene expression; genetics; genomics; human.

Conflict of interest statement

JR, AF, HM, AA, XW, DW, SZ, RS, RP, FL No competing interests declared

© 2021, Resztak et al.

Figures

Figure 1.. Transcriptional signatures of psychosocial experiences…
Figure 1.. Transcriptional signatures of psychosocial experiences and asthma symptoms.
(a) Central hypothesis. (b) Number of genes in elastic net regression models that explain at least 1% of variance. Colors represent different categories of variables. (c) Pearson’s correlations between cross-validated transcriptional signatures and measured variables for elastic net regression models that explain at least 1% of variance. (d) Forced expiratory volume in one second [FEV1] percent predicted transcriptional signature model fit (Pearson’s rho = 0.76, p<0.001). (e) MacArthur socioeconomic status transcriptional signature model fit (Pearson’s rho = 0.67, p<0.001). (f) Longitudinal change in observed neutrophils (x axis) and longitudinal change in transcriptional signature of neutrophils (y axis) (Pearson’s rho = 0.72, p<0.001, gray = identity line).
Figure 1—figure supplement 1.. Clustered heatmap of…
Figure 1—figure supplement 1.. Clustered heatmap of (Pearson) correlations between all variables used in the study.
Color indicates the strength and direction of correlation; white indicates p-value>0.05. Hierarchical clustering is represented on the top and side of the heatmap. Variables are grouped by colors indicating the different categories considered.
Figure 1—figure supplement 2.. Scatterplot of Pearson's…
Figure 1—figure supplement 2.. Scatterplot of Pearson's correlation coefficients between each pair of observed variables (x axis) and metagenes (y axis) for the 19 variables with transcriptional signatures explaining >1% of observed variance.
Color represents significance of the correlation (gray: nonsignificant correlations in observed variables or metagenes; blue: significant correlation between observed variables only; green: significant correlation between transcriptional signatures only; black: correlation significant in both observed variables and metagenes).
Figure 1—figure supplement 3.. Gene set enrichment…
Figure 1—figure supplement 3.. Gene set enrichment analysis results on genes differentially expressed for psychosocial experiences.
(a) Gene Ontology, (b) Kyoto Encyclopedia of Genes and Genomes, and (c) Reactome Pathway Database. Variable symbols: cddstf: self-disclosure; cdmcfl: child-reported conflict with mother; cdres: perceived responsiveness; pincme: parent’s income; ppeqcf: parent-reported conflict with child; psesl: subjective socioeconomic status. Down denotes downregulated genes, up denotes upregulated genes.
Figure 1—figure supplement 4.. Result of identity-by-descent…
Figure 1—figure supplement 4.. Result of identity-by-descent analysis (IBD; maximum likelihood estimation [MLE]) on DNA-derived genotypes for all 251 participants.
k0: probability of sharing zero alleles IBD; k1: probability of sharing one allele IBD.
Figure 1—figure supplement 5.. Self-reported ethnicity (x…
Figure 1—figure supplement 5.. Self-reported ethnicity (x axis) vs. percent global African ancestry (y axis) in 119 participants for whom declared ethnicity is available.
Figure 1—figure supplement 6.. Proportion of reads…
Figure 1—figure supplement 6.. Proportion of reads mapping to the Y chromosome over all mapped reads separately for self-reported females and males.
Each dot is one sample.
Figure 1—figure supplement 7.. Sources of variation…
Figure 1—figure supplement 7.. Sources of variation in gene expression data.
(a) Proportion of global variance in gene expression explained by each covariate tested within a single linear model. (b) Proportion of variance explained by each covariate for each analyzed gene.
Figure 1—figure supplement 8.. Comparison of variance…
Figure 1—figure supplement 8.. Comparison of variance explained by conserved transcriptional response to adversity (CTRA)-based (x axis) and unbiased (y axis) elastic net prediction models; color indicates type of variable (red = identity line).
Figure 2.. Correlation among psychosocial and clinical…
Figure 2.. Correlation among psychosocial and clinical transcriptional signatures.
Heatmap of Pearson’s correlations between transcriptional signatures explaining at least 1% of variance. Heatmap color indicates strength and direction of correlation; white indicates p-value>0.05. Hierarchical clustering of variables is represented above the heatmap, with colors indicating categories for each variable as indicated in the legend.
Figure 2—figure supplement 1.. Network representation of…
Figure 2—figure supplement 1.. Network representation of correlations between transcriptional signatures of psychosocial experiences (edge width reflects absolute value of Pearson's correlation score, edge color reflects positive [red] or negative [blue] correlation).
Figure 2—figure supplement 2.. Network representation of…
Figure 2—figure supplement 2.. Network representation of correlations between all transcriptional signatures (edge width reflects absolute value of Pearson's correlation score, edge color reflects positive [red] or negative [blue] correlation).
Figure 3.. GxE effects on gene expression…
Figure 3.. GxE effects on gene expression and asthma risk.
(a) Interaction expression quantitative trait locus (eQTL) results. GxE genes: number of significant GxE interactions with transcriptional signatures at 10% FDR; OR: odds ratio of enrichment of GxE genes with measured variable (p<0.01) in GxE genes with transcriptional signatures (p<0.01). (b) Network of interactions between environments and eGenes. Each node represents an eGene with an interaction eQTL (black) or a variable that modulates the genetic effect on gene expression. Only nodes with at least two interactions are labeled. Edges represent significant interaction eQTLs (10% FDR). (c, d) Causal gene-complex trait interactions identified through transcriptome-wide association studies (TWAS) are modulated by psychosocial experiences. Psychosocial variables (c) or blood composition (d) are in the left column, eGenes in the central column and complex traits in the right column. A connecting line represents either a causal link between eGene and asthma or allergic disease trait identified through TWAS (middle to right) or a significant interaction eQTL (left to middle). (e, f) Examples of genes causally associated with asthma and with GxE effects that modulate genetic risk. Both genes are causally associated with asthma in TWAS. Each dot is an individual. The same data are presented in the inset and main figure within each panel. In the main figure, the trend lines represent the best model fit between the psychosocial variable and gene expression for each genotype class. The slope of each line and the q-value for the GxE effect are also reported. The boxplot in the inset represents the same normalized gene expression data across the three tertiles of the psychosocial variable.
Figure 3—figure supplement 1.. QQplots of expression…
Figure 3—figure supplement 1.. QQplots of expression quantitative trait locus (eQTL)-transcriptional signature interaction test permutation-corrected p-values, combined for blood composition (top) and psychosocial variables (bottom).
Color indicates whether the equivalent interaction test with observed variable was nominally significant (p-corrected 0.01, black).
Figure 3—figure supplement 2.. Genetic variants interact…
Figure 3—figure supplement 2.. Genetic variants interact with psychosocial environments to alter expression of genes linked to asthma and allergic disease.
Scatterplots depict the following. (a) Self-disclosure interacts with expression quantitative trait locus (eQTL) rs6458333:G:C to alter expression of SRF. (b) Self-disclosure interacts with eQTL rs7203263:C:G to alter expression of NLRC5. (c) Self-disclosure interacts with eQTL rs12922757:G:A to alter expression of GAS8. (d) Self-disclosure interacts with eQTL rs5015567:G:A to alter expression of PFKFB3. (e) Self-disclosure interacts with eQTL rs200494:T:G to alter expression of RP5-874C20.3. (f) Objective maternal responsiveness interacts with eQTL rs17713729:A:C to alter expression of SH3YL1. (g) Objective maternal responsiveness interacts with eQTL rs6458333:G:C to alter expression of SRF. (h) Objective maternal responsiveness interacts with eQTL rs7203263:C:G to alter expression of NLRC5. (i) Objective maternal responsiveness interacts with eQTL rs5015567:G:A to alter expression of PFKFB3. (j) Objective maternal responsiveness interacts with eQTL rs9269774:G:A to alter expression of HLA-DRB9. (k) Socioeconomic status interacts with eQTL rs12424772:A:T to alter expression of SLC6A12. (l) Socioeconomic status interacts with eQTL rs6458333:G:C to alter expression of SRF. (m) Socioeconomic status interacts with eQTL rs7788412:A:G to alter expression of CCM2. (n) Socioeconomic status interacts with eQTL rs36123367:AT:A to alter expression of RNF185. (o) Socioeconomic status interacts with eQTL rs5015567:G:A to alter expression of PFKFB3. (p) Socioeconomic status interacts with eQTL rs12194992:G:A to alter expression of RP3-525N10.2. (q) Percent houses unoccupied interacts with eQTL rs5015567:G:A to alter expression of PFKFB3. Colors signify the genotype class. Green: homozygous reference; purple: heterozygous; orange: homozygous alternate.
Figure 3—figure supplement 3.. Genetic variants interact…
Figure 3—figure supplement 3.. Genetic variants interact with psychosocial environments to alter expression of genes linked to asthma and allergic disease.
Boxplots depict the following. (a) Self-disclosure interacts with expression quantitative trait locus (eQTL) rs6458333:G:C to alter expression of SRF. (b) Self-disclosure interacts with eQTL rs7203263:C:G to alter expression of NLRC5. (c) Self-disclosure interacts with eQTL rs12922757:G:A to alter expression of GAS8. (d) Self-disclosure interacts with eQTL rs5015567:G:A to alter expression of PFKFB3. (e) Self-disclosure interacts with eQTL rs200494:T:G to alter expression of RP5-874C20.3. (f) Objective maternal responsiveness interacts with eQTL rs17713729:A:C to alter expression of SH3YL1. (g) Objective maternal responsiveness interacts with eQTL rs6458333:G:C to alter expression of SRF. (h) Objective maternal responsiveness interacts with eQTL rs7203263:C:G to alter expression of NLRC5. (i) Objective maternal responsiveness interacts with eQTL rs5015567:G:A to alter expression of PFKFB3. (j) Objective maternal responsiveness interacts with eQTL rs9269774:G:A to alter expression of HLA-DRB9. (k) Socioeconomic status interact with eQTL rs12424772:A:T to alter expression of SLC6A12. (l) Socioeconomic status interacts with eQTL rs6458333:G:C to alter expression of SRF. (m) Socioeconomic status interacts with eQTL rs7788412:A:G to alter expression of CCM2. (n) Socioeconomic status interacts with eQTL rs36123367:AT:A to alter expression of RNF185. (o) Socioeconomic status interacts with eQTL rs5015567:G:A to alter expression of PFKFB3. (p) Socioeconomic status interacts with eQTL rs12194992:G:A to alter expression of RP3-525N10.2. (q) Percent houses unoccupied interacts with eQTL rs5015567:G:A to alter expression of PFKFB3. X axis specifies the number of alternate alleles. Colors signify the genotype class. Green: homozygous reference; purple: heterozygous; orange: homozygous alternate.
Figure 3—figure supplement 4.. Causal gene-complex trait…
Figure 3—figure supplement 4.. Causal gene-complex trait interactions identified through transcriptome-wide association studies (TWAS) are modulated by psychosocial experiences.
Psychosocial and biological variables are in the left column, eGenes in the central column, and complex traits in the right column. A connecting line represents either a causal link between eGene and trait identified through TWAS (middle to right) or a significant interaction expression quantitative trait locus (eQTL) (left to middle). Red represents blood composition variables, orange represents asthma variables, and green represents psychosocial variables.
Figure 3—figure supplement 5.. QQplots of interaction…
Figure 3—figure supplement 5.. QQplots of interaction expression quantitative trait locus (eQTL) mapping test p-values (black), permutation p-values (green), and permutation-corrected p-values (pink).

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Source: PubMed

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