GELIFES Seminars - Inge Holtman

Inge Holtman (UMCG)

Data-driven insights into the clinical, pathological, and genetic architecture of neurodegenerative and psychiatric disorders

Neurodegenerative and psychiatric disorders share molecular mechanisms and genetic risk factors, often leading to clinical misdiagnoses. To achieve a data-driven understanding of the heterogeneity underlying these disorders, we established the Netherlands Neurogenomics Database, integrating clinical, neuropathological, and genetic data from over 3,000 brain donors collected by the Netherlands Brain Bank. Using Large Language Models (LLMs), we converted medical record summaries into longitudinal clinical trajectories that captured both known and novel disease-specific symptoms, enabling disease prediction and subtyping. In parallel, analyses of genome-wide variant data and polygenic risk scores (PRS) refined existing GWAS findings and highlighted shared as well as distinct genetic architectures across disorders. Finally, we are employing AI-image analysis models and LLMs to systematically analyze neuropathological images and text data, aiming to disentangle pathological heterogeneity at scale. Together, these integrative approaches reveal converging and diverging biological mechanisms across brain disorders and pave the way toward more precise and personalized diagnostics.

Biosketch:
My fascination with the neurobiological mechanisms underlying brain diseases began during my early encounters with neurology patients as a bachelor student. This interest led me to pursue a PhD on microglial function in health and disease using transcriptomics data, which I obtained with highest honors in 2016. I then completed a postdoctoral fellowship at the University of California, San Diego, focusing on multi-omics analysis, gene regulatory elements, 3D chromatin looping, and GWAS integration in brain and immune cell types.
In 2020, I returned to the Netherlands with a Veni fellowship and established my own research group as a Rosalind Franklin Junior Group Leader at the University Medical Center Groningen (UMCG). That same year, I co-founded the Netherlands Neurogenomics Database (NND) in collaboration with Dr. Huitinga of the Netherlands Brain Bank (NBB). The NND integrates extensive clinical and neuropathological data from the NBB with genetic and multi-omics data to support scientific research.
Building on this foundation, I was awarded an ERC Starting Grant in 2023 to investigate the neurobiology of mental illnesses. In 2024, I became a work package leader at the Institute for Chemical Neuroscience (iCNS), focusing on the biology of neuropsychiatric disorders. I also served as co-applicant on proposals for the Chan Zuckerberg Initiative (2024), centered on AI-based analysis of neuropathological imaging data, and the NWO-Hoofdzaken program (2025), which aims to develop a novel open-access computational infrastructure (NND2:0) for the NBB. My research centers on applying advanced data science methodologies to study psychiatric and neurodegenerative disorders.