Three components of human brain gene expression reflect normative developmental programmes with specific links to neurodevelopmental disorders

Dear, Richard; Seidlitz, Jakob; Markello, Ross D.; Arnatkevičiūtė, Aurina; Anderson, Kevin; Bethlehem, Richard A. I.; Wagstyl, Konrad; Bullmore, Edward T.; Raznahan, Armin; Vértes, Petra E.

doi:10.1101/2022.10.05.510582

Cited by 6 publications

(5 citation statements)

References 181 publications

(489 reference statements)

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“…We next consider how each connectivity mode is intrinsically organized, both in terms of axes of variation (i.e. “gradients”) and network modules [37, 55, 85, 103]. We show the first principal component of each connectivity mode in Fig.…”

Section: Resultsmentioning

confidence: 99%

Multimodal, multiscale connectivity blueprints of the cerebral cortex

Hansen

Shafiei

Voigt

et al. 2022

Preprint

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The brain is composed of disparate neural populations that communicate and interact with one another. Although fiber bundles, similarities in molecular architecture, and synchronized neural activity all represent brain connectivity, a comprehensive study of how these connectivity modes jointly reflect brain structure and function remains missing. Here we systematically integrate seven multimodal, multiscale brain connectivity profiles derived from gene expression, neurotransmitter receptor density, cellular morphology, glucose metabolism, haemodynamic activity, and electrophysiology. We uncover a compact set of universal organizational principles through which brain geometry and neuroanatomy shape emergent connectivity modes. Connectivity modes also exhibit unique and diverse connection patterns, hub profiles, dominant gradients, and modular organization. Throughout, we observe a consistent primacy of molecular connectivity modes---namely correlated gene expression and receptor similarity---that map well onto multiple phenomena including the rich club and patterns of cortical abnormalities across 13 neurological, psychiatric, and neurodevelopmental disorders. Finally, we fuse all seven connectivity modes into a single multimodal network and show that it maps onto major organizational features of the brain including structural conenctivity, intrinsic functional networks, and cytoarchitectonic classes. Altogether, this work contributes to next-generation connectomics and the integrative study of inter-regional relationships.

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Section: Resultsmentioning

confidence: 99%

Multimodal, multiscale connectivity blueprints of the cerebral cortex

Hansen

Shafiei

Voigt

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…We next consider how each connectivity mode is intrinsically organized, both in terms of axes of variation (i.e., spatial gradients) and network modules [14,22,[84][85][86]. The principal gradient, quantified as the first principal component of a connectivity mode, is a regional quantification of how feature similarity varies across the cerebral cortex.…”

Section: Gradients and Modules Of Connectivity Modesmentioning

confidence: 99%

Integrating multimodal and multiscale connectivity blueprints of the human cerebral cortex in health and disease

Hansen,

Shafiei,

Voigt

et al. 2023

PLoS Biol

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The brain is composed of disparate neural populations that communicate and interact with one another. Although fiber bundles, similarities in molecular architecture, and synchronized neural activity all reflect how brain regions potentially interact with one another, a comprehensive study of how all these interregional relationships jointly reflect brain structure and function remains missing. Here, we systematically integrate 7 multimodal, multiscale types of interregional similarity (“connectivity modes”) derived from gene expression, neurotransmitter receptor density, cellular morphology, glucose metabolism, haemodynamic activity, and electrophysiology in humans. We first show that for all connectivity modes, feature similarity decreases with distance and increases when regions are structurally connected. Next, we show that connectivity modes exhibit unique and diverse connection patterns, hub profiles, spatial gradients, and modular organization. Throughout, we observe a consistent primacy of molecular connectivity modes—namely correlated gene expression and receptor similarity—that map onto multiple phenomena, including the rich club and patterns of abnormal cortical thickness across 13 neurological, psychiatric, and neurodevelopmental disorders. Finally, to construct a single multimodal wiring map of the human cortex, we fuse all 7 connectivity modes and show that the fused network maps onto major organizational features of the cortex including structural connectivity, intrinsic functional networks, and cytoarchitectonic classes. Altogether, this work contributes to the integrative study of interregional relationships in the human cerebral cortex.

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“…Prior studies of brain size have primarily relied on in vivo neuroimaging, which have been only indirectly linked with brain gene expression because of the relative inaccessibility of in vivo human brain tissue. The burgeoning field of "imaging-transcriptomics" [68][69][70] has demonstrated a high degree of spatial alignment between neuroimaging "gradients" -representing topographical variation of brain morphology, function, or connectivity typically derived from magnetic resonance imaging (MRI) data [71][72][73] -and the spatial topography of gene expression identified in highresolution transcriptomic resources such as the Allen Human Brain Atlas (AHBA) 25,[74][75][76][77] . However, only one previous study has directly examined brain size and brain gene expression using the comprehensive Allen Mouse Brain Atlas 78 , finding a robust power-law scaling relationship between spatial gene expression gradients and brain size across mouse development -a model which accurately predicted human brain size 79 .…”

Section: Discussionmentioning

confidence: 99%

The molecular genetic landscape of human brain size variation

Seidlitz

Mallard

Vogel

et al. 2022

Preprint

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Human brain size increases dynamically through early development, peaks in adolescence, and varies up to two-fold among adults. Although previous studies have elucidated changes in brain size across evolution, development, traits, and diseases, the molecular underpinnings of interindividual variation in brain size remain unknown. Here, we leverage postmortem brain RNA sequencing and estimates of brain weight (BW) in 2,531 individuals across three independent datasets, to identify 928 genes that show genome-wide significant associations with either higher or lower BW (BW+, BW-, respectively). These BW gene sets showed distinct neurodevelopmental trajectories and spatial patterns that mapped onto developmental, functional and cellular axes of brain organization. Expression differences among evolutionarily conserved BW genes were predictive of interspecies differences in brain size, and functional annotation of BW genes revealed enrichment for neurogenesis and cell-cell communication. Genome-wide, transcriptome-wide, and phenome-wide association analyses of in vivo neuroimaging phenotypes confirmed that the genetic regulation of BW- transcripts influences cortical surface area and volume, as well as behavioral traits related to brain function and disease. Cumulatively, our study represents a major step towards the goal of delineating the causal mechanisms of human brain size variation in health and disease.

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Three components of human brain gene expression reflect normative developmental programmes with specific links to neurodevelopmental disorders

Cited by 6 publications

References 181 publications

Multimodal, multiscale connectivity blueprints of the cerebral cortex

Multimodal, multiscale connectivity blueprints of the cerebral cortex

Integrating multimodal and multiscale connectivity blueprints of the human cerebral cortex in health and disease

The molecular genetic landscape of human brain size variation

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