Identification of in vitro model systems capable of capturing the polygenic basis of mental illness

Jiménez Barron, Laura Teresa (2024): Identification of in vitro model systems capable of capturing the polygenic basis of mental illness. Dissertation, LMU München: Medizinische Fakultät

Abstract

Large genome wide association studies have identified thousands of genetic variants associated with psychiatric diseases. These variants are likely to act in a highly condition and cell type specific fashion. However, at this point their cellular context and developmental of action remains poorly understood. Moreover, it remains un- clear to what extent in vivo and in vitro model systems can approximate the human cellular conditions where polygenic psychiatric disease risk is operational. One of the application scenarios of genome wide association studies results, is the calculation of polygenic risk scores to identify subjects at risk of developing disease or to stratify a cohort with a given trait or disease, in this thesis I performed genomic imputation and traditional polygenic risk score calculation of two case/control cohorts for schizophrenia at different P-value thresholds used to subset the GWAS derived SNP associations considered in the scoring. The power of polygenic risk scores in the clinical setting for psychiatric disorders is limited, the fact that the hundreds of loci that contribute to disease liability are likely to act in a cell type specific manner, supports the need to develop cell type specific polygenic risk scores, for this purpose it is crucial to understand how the disease risk affects specific cell types. One of the objectives of this thesis was to identify which cell types are vulnera- ble to psychiatric disease associated polygenic risk, I did this by using stratified LD score regression for partitioning heritability from GWAS summary statistics while accounting for linkage disequilibrium, this allowed me to identify which cell type groups are enriched for psychiatric disorders heritability. I performed this partitioned heritability analysis in the transcriptomic and chromatin accessibility profiles of 10 neuronal and non neuronal cerebral cell types derived from human post-mortem brain tissue of the prefrontal cortex. LD score regression was performed using the identified active elements and GWAS derived summary statistics for various psychiatric disorders as well as control traits. Cell types including excitatory neurons of the cortical layer 2-3, corticothalamic neurons and inhibitory neurons as well as microglial cells and oligodendrocyte progenitor cells were significantly enriched for schizophrenia and bipolar disorder, many more significant positive associations were found between some of these cell types and traits corresponding to psychiatric disorders and Central Nervous System traits. All of this in line with previous research where these cell types had been found to be relevant to susceptibility to variants associated to the above mentioned traits. I performed the same analyses on ATACseq and RNAseq having ATACseq yielding finer and more specific results than RNAseq, which failed to identify some relevant cell types. ATACseq was used in assessing the validity of different model systems to see if they could capture the polygenic architecture of psychiatric diseases, this model systems included iPSC derived neurons, cerebral organoids, post-natal mouse cortical cells and fetal cortical neurons. The results were consistent with the postmortem tissue findings. These results allowed us to benchmark the used in vitro models that maintain the heritability enrichment of postmortem tissues, opening the possibility for a robust use of scATACseq data derived from these models to reliably identify cell type specific elements relevant for disease and leverage this information in building better predictive tools like cell-type specific polygenic risk scores.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 20. Februar 2024
• 1. Bericht­erstatter:in: Koutsouleris, Nikolaos