Despite its importance, little is known about early-life genetic regulation of gene expression and how it impacts diseases in adulthood. By identifying genes that appear to drive disease risk at birth, targeted interventions could prevent these diseases before symptoms ever occur.

Expression quantitative trait loci (eQTL) are genomic loci that explain variations in the expression levels of messenger RNA (mRNA). Studies exploring eQTLs are able to provide insight into the effects of genetic variants on complex diseases.

In addition to genetic variation, disease development is influenced by individual and cell type-specific responses to external stimuli. Therefore, understanding the interaction between eQTLs and stimuli (called response eOTLs; reOTLs) can provide further understanding into various disease conditions. eQTLs located near the gene-of-origin are referred to as cis-eQTLs whereas those located distant from the gene-of-origin, often on different chromosomes, are referred to as trans-eQTLs.

Researchers from the Cambridge Baker Systems Genomics Initiative characterized the genetics of gene expression in innate and adaptive neonatal immune systems using purified cord blood samples from 152 newborn children. They identified cis- and trans-eOTLs of myeloid cells (white blood cells) and CD4+ T cells.

The neonatal immune cells were exposed to stimuli to see how the cells responded and to identify genetic variants that changed these responses. reOTLs for myeloid cells were stimulated with lipopolysaccharide (LPS) and CD4+ T cells were stimulated with phytohemagglutinin (PHA).

"We looked for overlap between these genetic signals and those that are known to be associated with diseases where we know the immune system plays a role," said Michael Inouye, PhD, Munz Chair of Cardiovascular Prediction and Prevention at the Baker Institute and principal researcher at Cambridge University, in a statement. "We then used statistical analysis to search for possible links between the cell response in newborns and immune diseases in adulthood."

In the study, the researchers identified eQTLs that are specific to neonates. Interestingly, distant gene variations had effects on mediation of gene expression of local (cis-eQTLs) genes. Some of the genetic variations drove gene expression across different immune and inflammatory conditions, some with widespread impacts. For example, altered neonatal BTN3A2 expression, and presumed subsequent immunomodulation dysfunction, plays a role in multiple inflammatory conditions.

The researchers provided evidence for shared genetic basis of neonatal eQTLs and reQTLs with common autoimmune and allergic diseases where many colocalizations are cell type- or stimulation-specific. The extensive overlap of genetic variants can be associated with diseases and gene expression in neonatal immune cells.

Direction of response to changes in gene expression in neonatal immune cells can also impact disease. For example, T cells were colocalized to both up- and down-regulation of CCL20 expression for childhood-onset asthma. This suggests that the disease is associated with T-cell response to changes in expression.

Overall, the study showed that genetic regulation of gene expression is highly complex in innate and adaptive immune systems at birth and has the potential to drive pathogenesis of autoimmune and allergic diseases.

"Our study showed the potential roles of gene expression in disease development, which has helped us to better understand the link between DNA variation and disease risk," said lead author Qinqin Huang, PhD, a researcher at the Wellcome Sanger Institute. "To date, similar studies have only been conducted in adult immune cells. Given the huge difference between neonatal and adult immunity, it is not surprising to see many signals that were unique to newborns."

"With so many diseases sharing a root in the immune system and inflammation we can leverage this information to better understand where each disease has a molecular weak spot and to what extent these are shared among different diseases," explained Inouye. "We've shown this can be dissected using genetics and polygenic risk, hopefully leading to targeted preventative interventions for those who need them most, with the aim of keeping people living healthier for longer."

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