Dissecting Autism and Schizophrenia Through Neuroimaging Genomics

Clara A. Moreau; Armin Raznahan; Pierre Bellec; Mallar Chakravarty; Paul M. Thompson; Sebastien Jacquemont;


Brain. 2021;144(7):1943-1957. 

In This Article

Future Directions: Linking Microscale and Macroscale Observations

Gene expression data from the brain at the developmental, spatial and cell type levels provides highly granular information to annotate the brain function genetic variants at the micro- and macroscale levels (Figure 5). A major hypothesis is that patterns of gene expression will allow us to understand the relationship between mutations and their effects on brain architecture and behaviour. Work from the Allen Institute suggests that a set of genes constitutes the core transcriptional machinery of the human brain.[146] Thirty-two modules of co-expressed genes were identified—based on their spatial patterns of expression—highlighting a genome-wide redundancy. They were enriched for specific cell types, intracellular components, and associated with neurodevelopmental and degenerative conditions.[146] These modules recapitulate large-scale gradients of brain organization.[98] This canonical transcriptional organization of the genome (the default gene network[146]) is also highly correlated with the brain's functional network architecture, such as with the default mode network and the principal gradient of macroscale cortical organization.[65,143]

Genomic variants in genes with a similar cortical organization or temporal pattern may lead to a shared set of brain alterations at the structural and functional levels. In other words, patterns of gene expression may predict patterns of neuroimaging alterations in carriers of CNVs and other genomic variants. Recently spatial patterns of cortical anatomy changes in individuals with 22q11.2 deletions, as well as aneuploidies (sex chromosomes and Down syndrome), were found to be correlated with cortical spatial expression of genes within the 22q11.2, X and Y chromosomes.[147] The same observations have been reported at the functional connectivity level, by testing the association between connectivity-signatures of 22q11.2 and 16p11.2 deletion profiles and the brain expression patterns of genes encompassed in these genomic loci.[44] However, it appears that these relationships are not specific. For example, the spatial brain expression pattern of 1834 genes (genome-wide false discovery rate) were correlated with the 22q11.2 functional brain connectivity profile. Indeed, many genes share similar spatial and temporal expression patterns, which may potentially explain the polygenic architecture of brain organization and psychiatric condition as well as the shared variance of cortical alterations across psychiatric disorders.[148]

The cytoarchitecture of the human brain may also help understand the link between genomic variants, their associated brain alterations and psychiatric conditions. For example, genes preferentially expressed in oligodendrocytes show a cortical distribution in their expression that is positively correlated with intracortical myelination measured by magnetization transfer.[149] Brain alterations caused by CNVs and sex chromosome aneuploidies have also been associated with gene expression distributed along gradients of cell types.[147] A similar approach has also linked cell types to patterns of brain alterations associated with ASD, ADHD, bipolar disorder, schizophrenia, OCD, and major depression. This 'virtual histology' approach reveals that the cortical expression patterns of pyramidal, microglia, astrocyte genes were correlated with cortical thickness alteration maps of eight psychiatric conditions.[148]

Although temporal expression during brain development is a dimension that is likely to impact brain architecture, it has not yet been associated with MRI alteration observed in carriers of CNVs and genomic variants. These exciting attempts to bridge macro- and micro-scale observations are initiating fruitful collaborations between genomics, neurobiology, computational and evolutionary neuroscience.

Functional dimensions disturbed across psychiatric conditions may also be distributed through these modules of co-expression and functional gradients.[150] Such properties might be related to emerging properties of the genome and the recent evolution of the human brain.[151,152]