Towards a mechanistic understanding of common and rare genetic risk variants for bipolar disorder: studies in iPSC models and extended families

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Bipolar disorder (BD) is a common neuropsychiatric disorder that ranks among the top ten causes of global morbidity. In the past years, we and others identified common genetic risk factors for BD through genome-wide association studies. Recently, we have also initiated next-generation sequencing studies to identify rare risk variants with higher penetrance. Despite considerable progress, many risk genes still await identification. In addition, the functional effects of common and rare risk variants, which show varying degrees of penetrance at the neuronal cellular and clinical outcome level, are largely unclear.The aim of the project is to improve understanding of the molecular basis of BD. To achieve this, research groups at the Universities of Basel (Switzerland) and Bonn (Germany) will apply innovative strategies and complementary expertise. In a functional approach, induced pluripotent stem cell (iPSC)-derived neural cells from selected BD patients and controls will be used to identify disease-associated transcriptomic and cellular signatures that are attributable to combinations of known common risk variants within neurodevelopmental pathways (Gene Ontology (GO)-term informed polygenic risk score analysis (PRS)). We will assess the impact of common variants on the transcriptome (RNA and small RNA) and cellular level using next-generation sequencing and functional assays. The obtained results can then be further validated in patient-specific neural cells.In parallel, we will apply state-of-the-art genetic strategies aiming to identify novel rare BD risk variants in 15 large, multiply affected families with BD that were selected for the possible presence of stronger genetic effects on neurodevelopmental processes (high proportion of patients with the core diagnosis bipolar I disorder, age-at-onset ≤25 years). For the detection of risk variants, SNP microarray (PRS and copy number variants (CNV)) and whole-genome sequencing data (short-read and long-read) will be combined. The inclusion of long-read sequencing will allow the most comprehensive detection of structural risk variants to date.A major strength of the proposed project is that it will combine the complementary expertise of the research groups in Basel and Bonn. We anticipate that the project will reveal cellular alterations associated with BD in iPSC-based model systems. These phenotypic changes will provide insights into disease-related developmental pathways, and thereby improve understanding of BD pathogenesis. Ultimately, this will promote novel strategies for drug-based compensation. For the first time, we will use long-read sequencing technology to investigate the impact of small structural variation, an aspect of BD that has not been studied in previous research. The proposed work will lay the foundation for future projects, in which we plan to model phenotypic effects of the identified rare variants in neural cells generated from iPSCs with high and low PRS backgrounds.