Systematic investigation of allelic regulatory activity of schizophrenia-associated common variants

Cell Genom. 2023 Sep 15;3(10):100404. doi: 10.1016/j.xgen.2023.100404. eCollection 2023 Oct 11.ABSTRACTGenome-wide association studies (GWASs) have successfully identified 145 genomic regions that contribute to schizophrenia risk, but linkage disequilibrium makes it challenging to discern causal variants. We performed a massively parallel reporter assay (MPRA) on 5,173 fine-mapped schizophrenia GWAS variants in primary human neural progenitors and identified 439 variants with allelic regulatory effects (MPRA-positive variants). Transcription factor binding had modest predictive power, while fine-map posterior probability, enhancer overlap, and evolutionary conservation failed to predict MPRA-positive variants. Furthermore, 64% of MPRA-positive variants did not exhibit expressive quantitative trait loci signature, suggesting that MPRA could identify yet unexplored variants with regulatory potentials. To predict the combinatorial effect of MPRA-positive variants on gene regulation, we propose an accessibility-by-contact model that combines MPRA-measured allelic activity with neuronal chromatin architecture.PMID:37868037 | PMC:PMC10589626 | DOI:10.1016/j.xgen.2023.100404
Source: Genomics Proteomics ... - Category: Genetics & Stem Cells Authors: Source Type: research