Characterizing Functional Genetic Variants Linking Immunity and Schizophrenia
Immunology
Final Report Abstract
Many GWAS loci occur close to immune-related genes suggesting an important role of the immune system in the biological mechanism underlying genetic risk to various diseases including schizophrenia (SCZ). Moreover, increasing attention has been paid to the role of inflammation in SCZ, and new data suggests a key role for monocytes and microglia in the pathogenesis of SCZ. Despite these intriguing observations, little is known about the role of these functional genetic variants in the relation between the immune system and SCZ. Aim of this research fellowship was to elucidate the molecular mechanisms of functional genetic variants that link immune function with psychiatric disorders such as schizophrenia. For this purpose, I first characterized genetic effects on gene expression in human monocytes activated with diverse pattern recognition receptor (PPR) ligands. I isolated monocytes of 134 individuals and stimulated them with lipopolysaccharide (LPS), muramyldipeptide (MDP) and 5’-triphosphate dsRNA (ppp-dsRNA) to trigger Toll-like receptor 4 (TLR4), Nod-like receptor 2 (NOD2) and retinoic acid–inducible protein I (RIG-I), respectively. I performed transcriptome profiling at three time points (0 min/90 min/6 h) and genome-wide SNP-genotyping. Comparing expression quantitative trait loci (eQTLs) under baseline and upon immune stimulation revealed hundreds of immune response specific eQTLs (reQTLs). I showed that SNPs conferring risk to schizophrenia and other diseases are immune response eQTLs for novel candidate genes, bringing new insights into the pathophysiology of these disorders in the context of PRR-activation. Functional follow up experiments were conducted for the SNP rs13107325, a highly pleiotropic SNP with the strongest effect seen in SCZ. For this purpose, 293T cells were edited using CRISPR/Cas technology. Preliminary results of RNA-seq experiments of stimulated edited cell lines gave first insights into the physiological role of rs13107325 in altering the immune response, which could ultimately represent the mechanistic link between rs13107325 and schizophrenia. This work demonstrates the importance of studying genetic variation under pathophysiologically relevant conditions to resolve functional genetic variants and the transcriptional responses associated with disease.
Publications
- Concerted genetic function in blood traits. Cell 2016
Kim-Hellmuth S, Lappalainen T
(See online at https://doi.org/10.1016/j.cell.2016.10.055) - Genetic regulatory effects modified by immune activation contribute to autoimmune disease associations. Nature Communications 2017
Kim-Hellmuth S, Bechheim M, Pütz B, et al.
(See online at https://doi.org/10.1038/s41467-017-00366-1)
