C9orf72gene networks in the human brain correlate with cortical thickness in C9-FTD and implicate vulnerable cell types

Author:

Broce Iris J.,Sirkis Daniel W.,Nillo Ryan M.,Bonham Luke W.,Lee Suzee E.,Miller Bruce,Castruita Patricia,Sturm Virginia E.,Sugrue Leo S.,Desikan Rahul S.,Yokoyama Jennifer S.ORCID

Abstract

AbstractIntroductionA hexanucleotide repeat expansion (HRE) intronic to chromosome 9 open reading frame 72 (C9orf72) is recognized as the most common genetic cause of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and ALS-FTD. Identifying genes that show similar regional co-expression patterns toC9orf72may help identify novel gene targets and biological mechanisms that mediate selective vulnerability to ALS and FTD pathogenesis.MethodsWe leveraged mRNA expression data in healthy brain from the Allen Human Brain Atlas to evaluateC9orf72co-expression patterns. To do this, we correlated averageC9orf72expression values in 51 regions across different anatomical divisions (cortex, subcortex, cerebellum) with average gene expression values for 15,633 protein-coding genes, including 50 genes known to be associated with ALS, FTD, or ALS-FTD. We then evaluated whether the identifiedC9orf72co-expressed genes correlated with patterns of cortical thickness in symptomaticC9orf72pathogenic HRE carriers (n=19). Lastly, we explored whether genes with significantC9orf72radiogenomic correlations (i.e., ‘C9orf72gene network’) were enriched in specific cell populations in the brain and enriched for specific biological and molecular pathways.ResultsA total of 1,748 genes showed an anatomical distribution of gene expression in the brain similar toC9orf72and significantly correlated with patterns of cortical thickness inC9orf72HRE carriers. ThisC9orf72gene network was differentially expressed in cell populations previously implicated in ALS and FTD, including layer 5b cells, cholinergic motor neurons in the spinal cord, and medium spiny neurons of the striatum, and was enriched for biological and molecular pathways associated with multiple neurotransmitter systems, protein ubiquitination, autophagy, and MAPK signaling, among others.ConclusionsConsidered together, we identified a network ofC9orf72-associated genes that may influence selective regional and cell-type-specific vulnerabilities in ALS/FTD.

Publisher

Cold Spring Harbor Laboratory

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