HORNET: tools to find genes with causal evidence and their regulatory networks using eQTLs.

Motivation: Nearly two decades of genome-wide association studies (GWAS) have identify thousands of disease-associated genetic variants, but very few genes with evidence of causality. Recent methodological advances demonstrate that Mendelian randomization (MR) using expression quantitative loci (eQTLs) as instrumental variables can detect potential causal genes. However, existing MR approaches are not well suited to handle the complexity of eQTL GWAS data structure and so they are subject to bias, inflation, and incorrect inference. Results: We present a whole-genome regulatory network analysis tool (HORNET), which is a comprehensive set of statistical and computational tools to perform genome-wide searches for causal genes using summary level GWAS data, i.e. robust to biases from multiple sources. Applying HORNET to schizophrenia, eQTL effects in the cerebellum were spread throughout the genome, and in the cortex were more localized to select loci. Availability and implementation: Freely available at https://github.com/noahlorinczcomi/HORNET or Mac, Windows, and Linux users.