Our pre-print titled “Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights” is now available here. The aim of this work is to move beyond GWAS associations - which implicate wide regions of genome in disease - to identify specific molecular mechanisms that may be driving the association. This involves analysis of expression from multiple tissues (including brain) to identify susceptibility genes for schizophrenia using the TWAS approach, and subsequent analysis of ChIP-seq data measuring chromatin activity to identify specific regulatory mediators for those genes. Some punchlines:
- We find a substantial contribution to sczhiophrenia risk from alternative splice variants identified in brain.
- We connect many susceptibility genes to specific nearby chromatin regulators using a relatively small ChIP-seq reference panel, and speculate that this is an important and detectable disease mechanism.
- We present a general methodological framework for integrating gene expression with other regulatory data and disease GWAS to hone in on specific mechanisms.
See software/data for downloadable genome-wide results from this study.