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

Christopher L Hartl; Gokul Ramaswami; William G Pembroke; Sandrine Muller; Greta Pintacuda; Ashis Saha; Princy Parsana; Alexis Battle; Kasper Lage; Daniel H Geschwind

doi:10.1038/s41593-021-00887-5

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

Nat Neurosci. 2021 Sep;24(9):1313-1323. doi: 10.1038/s41593-021-00887-5. Epub 2021 Jul 22.

Authors

Christopher L Hartl^{1

2}, Gokul Ramaswami², William G Pembroke², Sandrine Muller^{3

4}, Greta Pintacuda^{3

5}, Ashis Saha⁶, Princy Parsana⁶, Alexis Battle^{6

7}, Kasper Lage^{3

4

8}, Daniel H Geschwind^{9

10

11

12}

Affiliations

¹ Interdepartmental Program in Bioinformatics, University of California, Los Angeles, Los Angeles, CA, USA.
² Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
³ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.
⁵ Department of Stem Cell and Regenerative Medicine, Harvard University, Cambridge, MA, USA.
⁶ Department of Computer Science, Johns Hopkins University, Baltimore, MD, USA.
⁷ Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.
⁸ Institute for Biological Psychiatry, Mental Health Center Sct. Hans, University of Copenhagen, Roskilde, Denmark.
⁹ Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. dhg@mednet.ucla.edu.
¹⁰ 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.
¹¹ 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.
¹² Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. dhg@mednet.ucla.edu.

Abstract

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Brain / physiopathology*
Gene Expression Profiling / methods*
Gene Regulatory Networks / physiology*
Genetic Predisposition to Disease / genetics*
Humans
Mental Disorders / genetics*
Mental Disorders / physiopathology
Transcriptome

Abstract

Publication types

MeSH terms

Grants and funding