Coexpression network architecture reveals the brain-wide and multiregional basis of disease susceptibility.

Autor: Hartl CL; Interdepartmental Program in Bioinformatics, University of California, Los Angeles, Los Angeles, CA, USA.; Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA., Ramaswami G; Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA., Pembroke WG; Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA., Muller S; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Surgery, Massachusetts General Hospital, Boston, MA, USA., Pintacuda G; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Stem Cell and Regenerative Medicine, Harvard University, Cambridge, MA, USA., Saha A; Department of Computer Science, Johns Hopkins University, Baltimore, MD, USA., Parsana P; Department of Computer Science, Johns Hopkins University, Baltimore, MD, USA., Battle A; Department of Computer Science, Johns Hopkins University, Baltimore, MD, USA.; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA., Lage K; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.; Institute for Biological Psychiatry, Mental Health Center Sct. Hans, University of Copenhagen, Roskilde, Denmark., Geschwind DH; Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. dhg@mednet.ucla.edu.; Department of Psychiatry and Biobehavioral Sciences, Semel Institue, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. dhg@mednet.ucla.edu.; Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. dhg@mednet.ucla.edu.; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. dhg@mednet.ucla.edu.
Jazyk: angličtina
Zdroj: Nature neuroscience [Nat Neurosci] 2021 Sep; Vol. 24 (9), pp. 1313-1323. Date of Electronic Publication: 2021 Jul 22.
DOI: 10.1038/s41593-021-00887-5
Abstrakt: Gene networks have yielded numerous neurobiological insights, yet an integrated view across brain regions is lacking. We leverage RNA sequencing in 864 samples representing 12 brain regions to robustly identify 12 brain-wide, 50 cross-regional and 114 region-specific coexpression modules. Nearly 40% of genes fall into brain-wide modules, while 25% comprise region-specific modules reflecting regional biology, such as oxytocin signaling in the hypothalamus, or addiction pathways in the nucleus accumbens. Schizophrenia and autism genetic risk are enriched in brain-wide and multiregional modules, indicative of broad impact; these modules implicate neuronal proliferation and activity-dependent processes, including endocytosis and splicing, in disease pathophysiology. We find that cell-type-specific long noncoding RNA and gene isoforms contribute substantially to regional synaptic diversity and that constrained, mutation-intolerant genes are primarily enriched in neurons. We leverage these data using an omnigenic-inspired network framework to characterize how coexpression and gene regulatory networks reflect neuropsychiatric disease risk, supporting polygenic models.
(© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze: MEDLINE
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