DESCRIPTION (provided by applicant): The genetics of schizophrenia (SCZ) is advancing at rapid pace. An increasing number of risk-associated polymorphisms and variants are found in intergenic, intronic and other non-coding sequence. However, it has been a major challenge to design testable hypotheses to elucidate the potential function of such types of disease-associated non-coding DNA. Many of these sequences are thought to exert regulatory functions, including long range enhancer and repressor elements physically interacting with transcription start sites (TSS) separated on the linear genome by many kilobases of interspersed DNA. We will first construct high-resolution Expression Quantitative Loci (eQTL) maps by analyzing jointly gene expression, and genotyping and epigenomic profiles from publicly available as well as in-house generated datasets and then integrate the eQTL maps with the most updated dataset from the Psychiatric Genomics Consortium (PGC) that provides with genome-wide SNP coverage for more than 35,000 SCZ cases and 47,000 controls, with replication look-up into 70,000 subjects. We will thereby identify SCZ associated non- coding regions that are positioned within regulatory regions tagged with combinatorial histone modification signatures indicative of poised or active enhancers and statistical (eQTL) evidence for long range TSS interactions. We then will employ innovative approaches in neuroepigenetics, including chromosome conformation capture (3C) to map long range enhancer-promoter interactions in human brain collected postmortem, complemented by functional assays with gene expression reporter systems and activity-induced paradigms in cultured neurons derived from reprogrammed skin cells. The multidimensional approach presented here provides a roadmap to unravel the neurological functions of the vast but in brain largely unexplored non-coding sequences of the human genome.

PUBLIC HEALTH RELEVANCE: In the United States, over a million people have schizophrenia. The costs are staggering in human and financial terms. We will study the genetic risk architecture of schizophrenia, with focus on the vast but in brain largely unexplored portions of the human genome that do not encode protein. We will explore chromosomal loopings and other three-dimensional higher order chromatin at risk-associated DNA variants and polymorphisms in brain and nerve cells grown in the culture dish from reprogrammed skin cells. These data will provide first insights into the role of non-coding DNA for spatial genome architecture in human brain cells, including potential alterations in schizophrenia.