A computational tool (H-MAGMA) for improved prediction of brain-disorder risk genes by incorporating brain chromatin interaction profiles
- 9 March 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Neuroscience
- Vol. 23 (4), 583-593
- https://doi.org/10.1038/s41593-020-0603-0
Abstract
Most risk variants for brain disorders identified by genome-wide association studies reside in the noncoding genome, which makes deciphering biological mechanisms difficult. A commonly used tool, multimarker analysis of genomic annotation (MAGMA), addresses this issue by aggregating single nucleotide polymorphism 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 analyzing gene regulatory relationships in the disease-relevant tissue, H-MAGMA identified 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 neurodegenerative-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 principles of brain disorders.Funding Information
- U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (5T32NS007431, 5T32NS007431)
- UNC | University of North Carolina at Chapel Hill (Helen Lyng White Fellowship)
- U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (R56MH101454, R0MH106056, R0MH106056, R00MH113823, DP2MH122403)
- Brain and Behavior Research Foundation (NARSAD Young Investigator)
- Simons Foundation (605259)
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