Variant to function

Variant to function

The human genome's 3 billion basepairs are 99.9% identical between individuals. Yet variations in genetic make-up can cause differences in appearance, disease susceptibility, and medication response. Understanding the function of these variants is key to grasping their role in disease. This thesis of Martijn Vochteloo explores how genetic risk variants for neurological diseases affect gene expression in the brain, aiming to connect genetic variants to biological mechanisms and improve understanding and treatment of brain diseases.

We present two large-scale resources (MetaBrain and scMetaBrain) that can be utilized to disambiguate disease associated genetic variants, point to causal pathways, and prioritize targets for drug discovery. The MetaBrain resource consists of whole-tissue genetic and transcriptome data from diverse brain regions and ancestries, which provides well-powered associations but is mostly agnostic to cellular composition. Conversely, the scMetaBrain resource consists of genetic and single-nucleus transcriptomics data from predominantly prefrontal cortex tissue collected from European individuals, which provides higher cell-type resolution but lower statistical power. Together these resources provide both the statistical power and the tissue- and cellular-specificity required for the interpretation of genetic regulation of gene expression in the brain. We also developed a new statistical method that can help identify additional biological and technical factors affecting genetic regulation of gene expression.

This thesis describes valuable resources that shows how genetic variation regulates gene expression in disease-relevant tissues and cell types. These resources enable new insights into the mechanisms that underlie brain diseases, both as described in the thesis, but also in years to come.

Dissertation: https://hdl.handle.net/11370/3e3dede2-b917-47e8-9f77-119eee9dd44b