Variant-to-gene mapping for brain related traits and disorders

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Project Summary Since the completion of the Human Genome Project and the HapMap Project, genetic science has identified a wealth of associations between common or rare variants and human complex traits, including diseases. GWAS has arguably been the most successful tool in this so called “post-genomic” era, yielding almost 200,000 robust associations between common SNPs and more than 5,000 human traits. However, because of linkage disequilibrium, GWAS only report genomic “signals” or “loci” tagged by index SNPs and not the underlying true causal variants. Even more crucially, GWAS cannot indicate the effector genes at these loci, which are necessary to translate these findings into development of new therapies for disease. The main challenges to identifying causal variants and effector genes are that 1) the majority of variants identified by GWAS reside in non-coding regions of the genome and are thought to regulate gene expression, often hundreds of kb away in linear distance and 2) gene expression regulation is exquisitely tissue and cell type specific. While consortia such as ENCODE and GTEx have already built high quality, publicly available genome-wide datasets for many epigenetic markers and gene expression in different tissues and cell types, some limitations exist such as the number and heterogeneity of cell and tissue types available, the use of post-mortem samples, and the limited power due to the large sample number needed for QTL studies. As an alternative approach, I propose a variant-to-gene mapping campaign based on genome-wide high-resolution, promoter-focused Capture C, a technique that detects contacts between different regions of the genome in 3D space. Coupled with other genomic techniques, i.e. ATAC-seq, ChIP-seq and RNA-seq, this approach will allow us to identify putative causal variants residing in open chromatin and with enhancer signatures, and their (transcriptionally active) effector genes (including non-coding RNAs). Importantly, this proposal will focus on brain-related traits and disorders, a field where many GWAS signals have been reported, but only a few have been definitely linked to their effector genes, including many neurodegenerative disorders still lacking effective therapies. Using a tractable in vitro model system such as human iPSC-derived neural cell types (neurons, astrocytes and microglia, including co-cultures and brain organoids), I will be able to incorporate a temporal and functional dimension to these studies, which will help us identify mechanisms of disease etiology and progression in neuro-developmental and neurodegenerative disorders. Importantly, the functional genomics studies proposed will be performed in cell lines derived from individuals of different sex and ethnicity, to explore sex and ethnicity -specific differences in gene regulation.