Understanding genetic risk is one of the major goals in human genetics. Genome-wide association studies (GWAS) have identified thousands of genetic variants associated with complex human diseases. The identification of functional regulatory variants underlying such GWAS associations and understanding their pattern of activity is the key for understanding biological processes behind each genetic association to disease. Expression quantitative trait loci (eQTL) studies map genetic variants contributing to variation in gene expression. They have been partially helpful to pinpoint specific genes underlying the predisposition to disease, but often eQTL studies do not capture context-specificity of the disease (e.g. tissue or cell type specificity, gene-environment interaction, etc.). Furthermore, both in GWAS and eQTL studies biological validation to understand the underlying mechanism of how these genetic loci exert their effects is often missing.
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. For example, the link of the immune system and schizophrenia (SCZ) was supported by results of the latest SCZ GWAS, which has identified 108 loci that influence SCZ risk with enrichment among genes that are important in immunity. 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.
This challenge was addressed by the research of the fellow, Dr. Kim-Hellmuth, supervised by Dr. Lappalainen at the New York Genome Center (NYGC) during the outgoing phase and Dr. Müller-Myhsok at the Max Planck Institute of Psychiatry (MPI-P; return phase). The overarching aim was to elucidate the molecular mechanisms of functional genetic variants that link immune function with psychiatric disorders such as schizophrenia. For this purpose, the fellow first characterized genetic effects on gene expression in human monocytes activated with diverse bacterial and viral ligands. The fellow 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 immune activation. The fellow further investigated how cell type specificity of eQTLs can be studied in bulk tissue by mapping interactions between computational estimates of neuron abundance and genotype in 13 brain tissues to identify neuron interaction eQTLs (ieQTLs). She showed that colocalization analysis of these neuron ieQTLs and SCZ GWAS improve resolution and help to pinpoint the cellular origin of disease susceptibility loci. The fellow expanded this method to 6 additional cell types in 20 additional tissues and was able to provide the biggest catalogue of cell type specificity of eQTLs and their role in disease associations.
This work demonstrates the importance of studying genetic variation in the right cell type and under pathophysiologically relevant conditions to resolve functional genetic variants and the transcriptional responses associated with schizophrenia and common diseases in general.
