A computational tool (H-MAGMA) for improved prediction of brain-disorder risk genes by incorporating brain chromatin interaction profiles.

Abstract

Most risk variants for brain disorders identified by genome-wide association studies (GWAS) reside in non-coding genome, which makes deciphering biological mechanisms difficult. A commonly used tool, MAGMA, addresses this issue by aggregating SNP associations to nearest genes. Here, we developed a platform, Hi-C coupled MAGMA (H-MAGMA), that advances MAGMA by incorporating chromatin interaction profiles from human brain tissue across two developmental epochs and two brain cell types. By employing gene regulatory relationships in the disease-relevant tissue, H-MAGMA identifies neurobiologically-relevant target genes. We applied H-MAGMA to five psychiatric disorders and four neurodegenerative disorders to interrogate biological pathways, developmental windows, and cell types implicated for each disorder. Psychiatric disorder risk genes tended to be expressed during mid-gestation and in excitatory neurons, whereas degenerative disorder risk genes showed increasing expression over time and more diverse cell-type specificities. H-MAGMA adds to existing analytic frameworks to help identify the neurobiological consequences of brain disorder genetics.