The high-resolution multi-omic atlas of chromatin accessibility and gene expression during the first-trimester of the developing human brain includes more than 100,000 cell-type- and region-specific developmental accessible chromatin regions, as well as inferred candidate cis-regulatory elements and their predicted regulatory effects. The resource allows for example linking transcription factors to putative enhancers, and enhancers to their target genes. In addition, this resource enables the interpretation of genetic associations with disease.
Marijn Schipper, PhD student at CNCR-CTG, investigated whether the parts of DNA that contain open chromatin in specific types of cells during early embryonic development overlap with genetic variants that have been identified previously in genomewide association studies for psychiatric disorders. We found that the patterns of open chromatin in the DNA in specific types of cells during development coincide with stretches of DNA that are also linked to ADHD, anorexia, autism spectrum disorders, depression, insomnia and schizophrenia. The strongest association was found for depression: genetic variants that have previously been linked to depression occur particularly frequently in stretches of DNA that are mainly active during early embryonic development in the GABAergic neurons in the midbrain. This link with the midbrain is novel, and offers new research directions with a specific focus on the midbrain for understanding the hereditary component of depression.
The paper can be found here: https://www.nature.com/articles/s41586-024-07234-1
This study explains at the molecular level why synapses are stronger and depress faster in the absence of tomosyns. The research was mainly performed by Marieke Meijer (Amsterdam UMC), Miriam Öttl (Vrije Universiteit) and Jie Yang (Yale School of Medicine), among others, who combined synapse physiology on a conditional mouse model of tomosyn deficiency with single-molecule force measurements by the Yongli Zhang lab. Our data reveal that tomosyns produce a new intermediate state in SNARE assembly which drastically reduces the probability that synaptic vesicles fuse.
These findings offer a new explanation for the functional heterogeneity of synaptic vesicles (‘primed’ vs ‘superprimed’). By limiting the amount of synaptic vesicles that reside in a highly fusogenic state, tomosyns equalize neurotransmission during activity. This study also advances our understanding on how synapse function can be regulated by targeting the molecular machinery that releases neurotransmitters.
The paper can be found here: https://rdcu.be/dCvS8
Image credit: ‘fragment of vesicles’ by Rini Brakkee
Pathogenic variants in STXBP1/Munc18-1 cause severe encephalopathies that are among the most common in genetic neurodevelopmental disorders. Different molecular disease mechanisms have been proposed and pathogenicity prediction is limited. The new study led by Annemiek van Berkel (FGA), Timon André and Gurdeep Singh (both University of Heidelberg) aimed to define a generalized disease concept for STXBP1-related disorders and improve prediction.
A cohort of 11 disease-associated and five neutral variants (detected in healthy individuals) was tested in three cell-free assays, and in heterologous cells and primary neurons. A machine learning algorithm (PRESR) that uses both sequence- and 3D structure-based features was developed to improve pathogenicity prediction using 231 known disease-associated variants and comparison to our experimental data.
The researchers found that disease-associated, but none of the neutral variants produced reduced protein levels. Cell-free assays demonstrated directly that disease-associated variants have reduced thermostability, with most variants denaturing around body temperature. In addition, most disease-associated variants impaired SNARE- mediated membrane fusion in a reconstituted assay. Moreover, PRESR outperformed existing tools substantially: Matthews correlation coefficient = 0.71 versus <0.55.
Taken together, this study establishes intrinsic protein instability as the generalizable, primary cause for STXBP1-related disorders and shows that protein-specific ortholog and 3D information improves disease prediction. PRESR is a publicly available diagnostic tool:
The paper is available here.
The prediction tool is available here: PRESR.russelllab.org
One gene can influence multiple characteristics of an organism. This phenomenon is called pleiotropy. Tissink and her colleagues from Vrije Universiteit Amsterdam and the University of Oslo investigated the extent to which pleiotropy occurs for several characteristics of the brain. This concerns, for example, structure, function and tissue composition. Discovering genes that contribute to different aspects of the brain can provide insight into brain diseases. For example, if someone has Alzheimer’s, this is not only reflected in the structure of the brain, but also in the functional connections between the brain areas.
New genes
The researchers found that pleiotropy is common. About half of the genes found influence two or three features of the brain. The structure, function and tissue composition of the brain are measured with three different MRI scans: structural, functional, and diffusion MRI. Pleiotropy is widespread across features measured with these three types of MRI scans. Researchers can use this information intelligently. By combining the MRI scans in one genetic analysis, they discovered a significant number of new genes.
Risk model
One potential application already emerged in the research. The scientists used the results in a genetic risk model for brain diseases. “Unfortunately, the predictive value of these models is currently not good enough to use in practice,” says Tissink. “But we did see that this model becomes better at distinguishing patients with bipolar disorder or ADHD from people who do not.”
Donating DNA
Until a few years ago, it would not have been possible to discover these genes with a combination of three different MRI scans and DNA profiles. But because 40,000 people in the United Kingdom donated their DNA and had MRI scans made, this is now possible. It is expected that 100,000 brain scans and DNA profiles will become available for scientific research in the future.
Elleke Tissink worked at the department of Complex Trait Genetics (CNCR) and received her PhD from Vrije Universiteit Amsterdam in September 2023. The research on which the article in Nature Communications is based forms part of her dissertation.
Their project primarily investigates the contrast of normative brain aging trajectories between humans and macaques. Despite apparent similarities in developmental and aging stages between human and macaques, certain disorders like schizophrenia and Alzheimer’s disease seem to be uniquely human. They will analyze neuroimaging data from over 600 macaques and around 5,000 humans to identify key differences in aging patterns and their relation to brain disorders. Their goal is to uncover the aspects of brain aging that may contribute to human vulnerability to these conditions through a cross-species study approach.
With this grant support, she will explore how to enhance candidate gene targets selection by integrating quantitative trait loci (QTLs) and genome-wide association studies (GWAS) data.
Background: Despite the success of GWAS in identifying thousands of genetic variants associated with complex traits, we are still not closer to the quest of narrowing down the targets for therapeutics design. One issue is that an association at the gene level is not enough evidence for the gene to actually cause disease because transcription and/or translation might not be affected. To help pinpoint candidate genes, QTL mapping is used to narrow down GWAS variants that are associated with expression, methylation, or protein levels. With this grant support, Tanya aims to build a web-platform in order to aggregate available QTLs data and to implement state-of-the-art methods for integrating QTLs and GWAS. While this work focuses on QTLs, it will be a foundation for integrating multiple levels of omics data in the future.
SYT1-associated disorder is a neurodevelopmental disorder characterized by neurodevelopmental delay and autistic features. In a new study published in Molecular Psychiatry (doi: 10.1038/s41380-024-02444-5) Maaike van Boven and Niels Cornelisse from the Functional Genomics department at the Center for Neurogenomics and Cognitive Research and Human Genetics at AmsterdamUMC, in collaboration with Petra Zwijnenburg (Human Genetics, AmsterdamUMC), show that neurotransmitter release is less synchronized in neurons expressing a novel disease mutation associated with the disorder. This sheds new light on the molecular causes of neurodevelopmental disorders and could lead to new therapeutic targets in the future.
Precise timing of neurotransmitter release is essential for information processing in the brain. Children with Syt1-associated disorder carry genetic mutations in Synaptotagmin-1 (SYT1), a gene involved in the regulation of neurotransmitter release in the synaptic connections between nerve cells. Van Boven and colleagues show that a novel mutation in a patient with SYT1-associated disorder impairs the ability of Syt1 to control the precise timing of neurotransmitter release from synapses. Neurotransmission is less synchronized during electrical stimulation, while spontaneous release of neurotransmitter in-between stimulations is drastically increased. Neurons react to this by shortening their dendrites, resulting in fewer synaptic connections. Interestingly, this cellular phenotype is different from the reduced synaptic strength found for patient mutations at other locations in SYT1. This shows that different patient mutations in the same gene can lead to diverse cellular defects, and suggests personalized therapeutic strategies are required for individual patients.
The Cornelisse lab will use stem cell technology to further investigate the link between cellular disease mechanisms and brain activity measured with EEG in patients, in collaboration with the Brainmodel consortium and the N=You Neurodevelopmental Precision Center at Amsterdam UMC. On the long term, this could lead to improved cellular diagnostics and the best possible tailor-made treatment for individual patients.
Their project aims to explore and validate new therapeutic avenues for SCZ by integrating genome-wide association studies (GWAS) with a unique computational and cellular approach.
This research utilizes induced pluripotent stem cell (iPSC) technology to develop a disease model that reflects the complex genetic landscape of SCZ. The team will analyze transcriptomic and proteomic data from iPSC-derived neural cells to identify disease signatures. These signatures will then guide a drug repurposing pipeline, seeking compounds that can mitigate disease-related transcriptomic and proteomics alterations.
Boys who associate with delinquent friends are more likely to display antisocial behavior. A new study by neuroscientists and behavior experts from Vrije Universiteit Amsterdam and Amsterdam UMC, led by CNCR colleague Jorim Tielbeek (dept. of Complex Trait Genetics) shows that this association is stronger in boys with an increased sensitivity to reward.
For the first time, a scientific study on antisocial behavior has demonstrated an interaction effect between a brain mechanism, measured with functional MRI scans, and an environmental factor. The researchers, led by Jorim Tielbeek, specifically focused on at-risk youth (youth who have come into contact with the police before the age of 12), with an average age of 18 during the study period. The results of the research were published today in the prestigious scientific journal Psychological Medicine .
The researchers show that the connection between associating with delinquent peers and antisocial behavior depends on reward sensitivity, measured in the reward center (Ventral Striatum) of the brain. This relationship is stronger in youth with an increased response to reward compared to those with a lower response. The researchers did not observe similar interaction effects for the amygdala and the medial prefrontal cortex, two other brain areas involved in reward processes. Despite functional MRI being a powerful tool, the researchers highlight limitations in reliability, particularly within predetermined areas of interest.
Sensitivity to influences of delinquent peers
With follow-up analyses, the researchers demonstrate that the positive association between associating with delinquent friends and DBD symptoms is only present in male adolescents, and this effect decreases with age. “These findings point to an intriguing biosocial interaction between associating with delinquent friends and the reward sensitivity of the ventral striatum in relation to antisocial behavior. This suggests that individual biological differences may be intertwined with sensitivity to influences of delinquent peers,” says Tielbeek.
Tielbeek continues: “Our research not only sheds new light on the complex factors contributing to antisocial behavior in adolescents but also opens the door to future research focusing on the development of preventive interventions based on these insights. However, our results need to be tested and validated in independent samples first. Replication is essential in fMRI research.”
https://vu.nl/en/news/2023/reward-sensitivity-plays-a-role-in-youth-crime
This work can be found here