Neonatal genetics of gene expression reveal potential origins of autoimmune and allergic disease risk

Abstract

Chronic immune-mediated diseases of adulthood often originate in early childhood. To investigate genetic associations between neonatal immunity and disease, we map expression quantitative trait loci (eQTLs) in resting myeloid cells and CD4 + T cells from cord blood samples, as well as in response to lipopolysaccharide (LPS) or phytohemagglutinin (PHA) stimulation, respectively. Cis-eQTLs are largely specific to cell type or stimulation, and 31% and 52% of genes with cis-eQTLs have response eQTLs (reQTLs) in myeloid cells and T cells, respectively. We identified cis regulatory factors acting as mediators of trans effects. There is extensive colocalisation between condition-specific neonatal cis-eQTLs and variants associated with immune-mediated diseases, in particular CTSH had widespread colocalisation across diseases. Mendelian randomisation shows causal neonatal gene expression effects on disease risk for BTN3A2, HLA-C and others. Our study elucidates the genetics of gene expression in neonatal immune cells, and aetiological origins of autoimmune and allergic diseases.

Early-life-trauma triggers interferon-β resistance and neurodegeneration in a multiple sclerosis model via downregulated β1-adrenergic signaling

“…Exposure to severe stress and trauma in early life can disrupt various regulatory processes such as the HPA axis 46 , autonomic nervous system 47 , immune system 19 , 48 , 49 , and gut microbiome 48 , 50 across the life span in both animals and humans 51 . A human case study published in 1982 demonstrates that ELT increases MS susceptibility among female patients 52 .…”

“…Animal studies using multiple model of MS in rats and mice also indicate an association between ELT and disease severity 13 – 16 . ELT is proposed to alter immune cell properties in adults and is associated with increased risk of chronic illnesses 17 – 19 . However, the mechanism through which ELT alters MS disease progression remains elusive.…”

MRLocus: Identifying causal genes mediating a trait through Bayesian estimation of allelic heterogeneity

“…Some genes provide evidence for up to 13 independent cis-eQTL signals, detected by conditional analysis in peripheral blood [28]. A recent study integrating neonatal gene expression with GWAS of autoimmune and allergic disease performed MR analysis across 52 genes that had three or more cis-eQTLs [30]. Therefore, while not all genes display allelic heterogeneity at current eQTL study sample sizes, it is common enough to allow for mediation modeling of many candidate genes.…”

Genetic control of the dynamic transcriptional response to immune stimuli and glucocorticoids at single cell resolution

“…These cellular environments can induce expression of genes that are silent in baseline conditions, thus revealing previously-unobserved genetic effects and uncover genotype-specific differences in gene expression response to external stimuli. Previous approaches have successfully mapped the genetic determinants of responses to infection, drugs, and other stimuli [2, 7, 11, 25, 37, 39, 45, 46, 47, 50, 60, 61, 63, 75, 77, 83, 92, 97, 113] using bulk RNA-seq. However, these genotype-by-environment (GxE) effects are also likely to be cell-type-specific [28], especially in the context of highly-specialized immune responses, as investigated in recent studies of response eQTL mapping using single cell technology in immune cells exposed to pathogens, bacteria and yeast [78], and influenza A [87].…”