Structural covariance networks are coupled to expression of genes enriched in supragranular layers of the human cortex

García, Rogelio Cabo; Whitaker, Kirstie; Váša, František; Seidlitz, Jakob; Shinn, Maxwell; Fonagy, Peter; Dolan, Raymond J.; Jones, Peter B.; Goodyer, Ian; Bullmore, Edward T.; Vértes, Petra E.

doi:10.1101/163758

Cited by 72 publications

(105 citation statements)

References 54 publications

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“…We used the AHBA transcriptomic dataset, with gene expression measurements in 6 postmortem adult brains (45) (http://human.brain-map.org), aged 24-57. Each tissue sample was assigned to an anatomical structure using the AHBA MRI data for each donor (46). Samples were pooled between bilaterally homologous cortical areas.…”

Section: Methodsmentioning

confidence: 99%

Cortical patterning of abnormal morphometric similarity in psychosis is associated with brain expression of schizophrenia related genes

Morgan

Seidlitz

Whitaker

et al. 2018

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105

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Schizophrenia has been conceived as a disorder of brain connectivity but it is unclear how this network phenotype is related to the emerging genetics. We used morphometric similarity analysis of magnetic resonance imaging (MRI) data as a marker of inter-areal cortical connectivity in three prior case-control studies of psychosis: in total, N=185 cases and N=227 controls. Psychosis was associated with globally reduced morphometric similarity (MS) in all 3 studies. There was also a replicable pattern of case-control differences in regional MS which was significantly reduced in patients in frontal and temporal cortical areas, but increased in parietal cortex. Using prior brain-wide gene expression data, we found that the cortical map of casecontrol differences in MS was spatially correlated with cortical expression of a weighted combination of genes enriched for neurobiologically relevant ontology terms and pathways. In addition, genes that were normally over-expressed in cortical areas with reduced MS were significantly up-regulated in a prior post mortem study of schizophrenia. We propose that this combination of neuroimaging and transcriptional data provides new insight into how previously implicated genes and proteins, as well as a number of unreported proteins in their vicinity on the protein interaction network, may interact to drive structural brain network changes in schizophrenia. dysconnectivity | network neuroscience | psychosis | partial least squares | Allen Human Brain AtlasCorrespondence: sem91@cam.ac.uk

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Section: Methodsmentioning

confidence: 99%

Cortical patterning of abnormal morphometric similarity in psychosis is associated with brain expression of schizophrenia related genes

Morgan

Seidlitz

Whitaker

et al. 2018

Preprint

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105

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“…We generated a 308-region (n=152 LH regions) cortical parcellation using a backtracking algorithm to restrict the parcel size to be approximately 500mm 2 , with the Desikan-Killiany atlas boundaries as starting points 50,51 . This parcellation has been used in previous structural 19,52,53 and functional 20 imaging studies of connectomes, and was also used in our first study of MSNs 16 .…”

Section: Cortical Parcellationmentioning

confidence: 99%

“…Methods for the alignment of the microarray gene expression data from 6 adult human donors, provided by the Allen Human Brain Atlas (AHBA), to the left hemisphere (n = 152 regions) of our parcellation has been described in depth elsewhere 8,16,52 , where we have shown that the gene expression data is robust to leaving a given donor out of the analysis. Briefly, we used FreeSurfer's recon-all to reconstruct and parcellate the cerebral cortex of each AHBA donor using the corresponding T1-weighted volume 56 .…”

Section: Transcriptomic Alignment Of Neuroimaging Datamentioning

confidence: 99%

Transcriptomic and Cellular Decoding of Regional Brain Vulnerability to Neurodevelopmental Disorders

Seidlitz¹,

Nadig²,

Liu³

et al. 2019

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Neurodevelopmental disorders are highly heritable and associated with spatially-selective disruptions of brain anatomy. The logic that translates genetic risks into spatially patterned brain vulnerabilities remains unclear but is a fundamental question in disease pathogenesis. Here, we approach this question by integrating (i) in vivo neuroimaging data from patient subgroups with known causal genomic copy number variations (CNVs), and (ii) bulk and single-cell gene expression data from healthy cortex. First, for each of six different CNV disorders, we show that spatial patterns of cortical anatomy change in youth are correlated with spatial patterns of expression for CNV region genes in bulk cortical tissue from typically-developing adults. Next, by transforming normative bulk-tissue cortical expression data into cell-type expression maps, we further link each disorder's anatomical change map to specific cell classes and specific CNV-region genes that these cells express. Finally, we establish convergent validity of this "transcriptional vulnerability model" by inter-relating patient neuroimaging data with measures of altered gene expression in both brain and bloodderived patient tissue. Our work clarifies general biological principles that govern the mapping of genetic risks onto regional brain disruption in neurodevelopmental disorders. We present new methods that can harness these principles to screen for potential cellular and molecular determinants of disease from readily available patient neuroimaging data.

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“…MRI images of the AHBA donors were parcellated using the Desikan-Killiany atlas and each cortical tissue sample was assigned to an anatomical structure. Regional expression levels were compiled to form a (68 × 20,647) regional transcription matrix (38); see SI.…”

Section: Estimation Of Regional Gene Expressionmentioning

confidence: 99%

Schizotypy-related magnetization of cortex in healthy adolescence is co-located with expression of schizophrenia-related genes

Romero-García

Seidlitz

Whitaker

et al. 2018

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= 249 words (max 250 words) Main text = 3997 words (max 4000 words). References = 72 Figures = 4 Table = 1 Intra-cortical magnetization and patterning of schizophrenia-related genes 2 Abstract Background Genetic risk is thought to drive clinical variation on a spectrum of schizophrenia-like traits but the underlying changes in brain structure that mechanistically link genomic variation to schizotypal experience and behaviour are unclear. MethodsWe assessed schizotypy using a self-reported questionnaire, and measured magnetization transfer (MT), as a putative micro-structural MRI marker of intra-cortical myelination, in 68 brain regions, in 248 healthy young people (aged 14-25 years). We used normative adult brain gene expression data, and partial least squares (PLS) analysis, to find the weighted gene expression pattern that was most co-located with the cortical map of schizotypy-related magnetization (SRM). ResultsMagnetization was significantly correlated with schizotypy in bilateral posterior cingulate cortex and precuneus (and for disorganized schizotypy also in medial prefrontal cortex; all FDR-corrected P < 0.05), which are regions of the default mode network specialized for social and memory functions. The genes most positively weighted on the whole genome expression map co-located with SRM were enriched for genes that were significantly downregulated in two prior case-control histological studies of brain gene expression in schizophrenia. Conversely, the most negatively weighted genes were enriched for genes that were transcriptionally up-regulated in schizophrenia. Positively weighted (downregulated) genes were enriched for neuronal, specifically inter-neuronal, affiliations and coded a network of proteins comprising a few highly interactive "hubs" such as parvalbumin and calmodulin. ConclusionsMicrostructural MRI maps of intracortical magnetization can be linked to both the behavioural traits of schizotypy and to prior histological data on dysregulated gene expression in schizophrenia. previous version of this paper was posted on bioRxiv: https://www.biorxiv.org/content/10.1101/487108v1 DATA and CODE SHARING DataRegional magnetisation transfer (MT) for 68 cortical regions, schizotypy scores, age, gender, socio-economic status, scanning site, total brain volume and Euler values, for N=248, are available at: https://github.com/RafaelRomeroGarcia/Schizotypy_MT_geneExp. CodeCortical parcellation of gene expression maps to estimate regional mean gene expression (62): (https://github.com/RafaelRomeroGarcia/geneExpression_Repository) Generate null-models that preserve the spatial contiguity of cortical regions for permutation testing (31): https://github.com/frantisekvasa/rotate_parcellation PLS analysis and bootstrapping to estimate PLS weights (15): https://github.com/KirstieJane/NSPN_WhitakerVertes_PNAS2016/tree/master/SCRIPTS Generate Figure S1 from raw Gandal (5) and Fromer (49) datasets: https://github.com/RafaelRomeroGarcia/Schizotypy_MT_geneExpMapping regional values to the cortical surface for visuali...

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Structural covariance networks are coupled to expression of genes enriched in supragranular layers of the human cortex

Cited by 72 publications

References 54 publications

Cortical patterning of abnormal morphometric similarity in psychosis is associated with brain expression of schizophrenia related genes

Cortical patterning of abnormal morphometric similarity in psychosis is associated with brain expression of schizophrenia related genes

Transcriptomic and Cellular Decoding of Regional Brain Vulnerability to Neurodevelopmental Disorders

Schizotypy-related magnetization of cortex in healthy adolescence is co-located with expression of schizophrenia-related genes

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