Medical studies are rarely easy, and it is especially challenging to understand brain disease. Brains are highly complex organs, and it is, for instance, hard to see the relationships between behavioural change in a person and the changes in the connections among the billions of cells in the brain that cause this behavioural change. Many brain related disorders, such as autism, schizophrenia, and Alzheimer's disease, have some genetic basis. They are influenced by small differences in people's genetic code, which are called variants. Genetic variants can cause differences in the activity or effectiveness of genes. And if genes are involved, knowing which genes these are, and what effect they have can help to find treatments for these diseases. ... Read more

Imaging genetics deals with relationships between genetic variation and imaging variables, often in a disease context. The complex relationships between brain volumes and genetic variants have been explored with both dimension reduction methods and model-based approaches. However, these models usually do not make use of the extensive knowledge of the spatio-anatomical patterns of gene activity. We present a method for integrating genetic markers (single nucleotide polymorphisms) and imaging features, which is based on a causal model and, at the same time, uses the power of dimension reduction. We use structural equation models to find latent variables that explain brain volume changes in a disease context, and which are in turn affected by genetic variants. We make use of publicly available spatial transcriptome data from the Allen Human Brain Atlas to specify the model structure, which reduces noise and improves interpretability. The model is tested in a simulation setting and applied on a case study of the Alzheimer’s Disease Neuroimaging Initiative. ... Read more

This Article contains a typographical error in the spelling of the author Wim Verhaegh, which is incorrectly given as Wim Verheagh. ... Read more

Familial hemiplegic migraine type 1 (FHM1) is a rare monogenic subtype of migraine with aura caused by mutations in CACNA1A that encodes the α1A subunit of voltage-gated CaV2.1 calcium channels. Transgenic knock-in mice that carry the human FHM1 R192Q missense mutation (‘FHM1 R192Q mice’) exhibit an increased susceptibility to cortical spreading depression (CSD), the mechanism underlying migraine aura. Here, we analysed gene expression profiles from isolated cortical tissue of FHM1 R192Q mice 24 h after experimentally induced CSD in order to identify molecular pathways affected by CSD. Gene expression profiles were generated using deep serial analysis of gene expression sequencing. Our data reveal a signature of inflammatory signalling upon CSD in the cortex of both mutant and wild-type mice. However, only in the brains of FHM1 R192Q mice specific genes are up-regulated in response to CSD that are implicated in interferon-related inflammatory signalling. Our findings show that CSD modulates inflammatory processes in both wild-type and mutant brains, but that an additional unique inflammatory signature becomes expressed after CSD in a relevant mouse model of migraine. ... Read more

Spatial and temporal brain transcriptomics has recently emerged as an invaluable data source for molecular neuroscience. The complexity of such data poses considerable challenges for analysis and visualization. We present BrainScope: A web portal for fast, interactive visual exploration of the Allen Atlases of the adult and developing human brain transcriptome. Through a novel methodology to explore high-dimensional data (dual t-SNE), BrainScope enables the linked, all-in-one visualization of genes and samples across the whole brain and genome, and across developmental stages. We show that densities in t-SNE scatter plots of the spatial samples coincide with anatomical regions, and that densities in t-SNE scatter plots of the genes represent gene co-expression modules that are significantly enriched for biological functions. We also show that the topography of the gene t-SNE maps reflect brain region-specific gene functions, enabling hypothesis and data driven research. We demonstrate the discovery potential of BrainScope through three examples: (i) analysis of cell type specific gene sets, (ii) analysis of a set of stable gene co-expression modules across the adult human donors and (iii) analysis of the evolution of co-expression of oligodendrocyte specific genes over developmental stages. Brain- Scope is publicly accessible at www.brainscope.nl. ... Read more

The immense complexity of the mammalian brain is largely reflected in the underlying molecular signatures of its billions of cells. Brain transcriptome atlases provide valuable insights into gene expression patterns across different brain areas throughout the course of development. Such atlases allow researchers to probe the molecular mechanisms which define neuronal identities, neuroanatomy, and patterns of connectivity. Despite the immense effort put into generating such atlases, to answer fundamental questions in neuroscience, an even greater effort is needed to develop methods to probe the resulting high-dimensional multivariate data. We provide a comprehensive overview of the various computational methods used to analyze brain transcriptome atlases. ... Read more

The use of genome-wide data in cancer research, for the identification of groups of patients with similar molecular characteristics, has become a standard approach for applications in therapy-response, prognosis-prediction, and drug-development. To progress in these applications, the trend is to move from single genome-wide measurements in a single cancer-type towards measuring several different molecular characteristics across multiple cancer-types. Although current approaches shed light on molecular characteristics of various cancer-types, detailed relationships between patients within cancer clusters are unclear. We propose a novel multi-omic integration approach that exploits the joint behavior of the different molecular characteristics, supports visual exploration of the data by a two-dimensional landscape, and inspection of the contribution of the different genome-wide data-types. We integrated 4,434 samples across 19 cancer-types, derived from TCGA, containing gene expression, DNA-methylation, copy-number variation and microRNA expression data. Cluster analysis revealed 18 clusters, where three clusters showed a complex collection of cancer-types, squamous-cell-carcinoma, colorectal cancers, and a novel grouping of kidney-cancers. Sixty-four samples were identified outside their tissue-of-origin cluster. Known and novel patient subgroups were detected for Acute Myeloid Leukemia’s, and breast cancers. Quantification of the contributions of the different molecular types showed that substructures are driven by specific (combinations of) molecular characteristics. ... Read more

Migraine is a common brain disorder, with a heritability of 50%. Genome-wide association studies have identified several loci, but interpretation remains challenging. We integrated migraine GWAS data with spatial gene expression data of adult brains from the Allen Human Brain Atlas, to identify specific brain regions and molecular pathways involved in migraine. We used two complementary methods. First, we clustered all genes into co-expression modules and identified those associated with migraine. Second, we constructed local co-expression networks around high-confidence migraine genes. Both approaches converge on functions and anatomy. ... Read more