T32. IMPACT OF BIPOLAR DISORDER POLYGENIC RISK ON GENE EXPRESSION IN IPSC-DERIVED NEURAL PROGENITORS FROM GENETICALLY CHARACTERIZED PATIENTS AND CONTROLS

• Published in: European neuropsychopharmacology 2023-10, Vol.75, p.S178-S179
• Main Authors: Hünten, Karola, Krutenko, Tamara, David, Friederike S., Beins, Eva C., Sivalingam, Sugirthan, Stein, Frederike, Herms, Stefan, Kircher, Tilo, Dannlowski, Udo, Witt, Stephanie, Peitz, Michael, Cichon, Sven, Nöthen, Markus M., Brüstle, Oliver, Forstner, Andreas J.
• Format: Article
• Language: English
• ISSN: 0924-977X; 1873-7862
• DOI: 10.1016/j.euroneuro.2023.08.318

Bipolar disorder (BD) is a severe and highly heritable psychiatric disorder, characterized by recurrent episodes of (hypo)mania and depression. Recent genome-wide association studies (GWAS) support a strong polygenic influence. However, its impact on neuronal development and function remains largely unknown. Therefore, we generated induced pluripotent stem cells (iPSCs) from genetically characterized patients with BD type 1 (BD1) and healthy controls (HC) with a high or low polygenic risk score (PRS) for BD1, respectively. Differentiation of these iPSC-lines into neural progenitor cells (NPCs) enables studying the combined effect of common variants in a model of early neurodevelopment. Peripheral blood mononuclear cells for iPSC generation were selected from unrelated male individuals from the German FOR2107 cohort (https://for2107.de/). BD1 patients with the highest and HCs with the lowest PRS for BD1 (Stahl et al., 2019; PRS-CS) were screened for the absence of copy number variants (CNVs) associated with BD or schizophrenia (Green et. al, 2016; Marshall et al, 2017; cnvPartition). From this selection, 10 donors per group were whole genome sequenced using an Illumina NovaSeq 6000. To limit a potential influence of rare deleterious variants on cellular functions, carriers of variants identified in 20 previously published BD sequencing studies were excluded (MAF 20; variant not present in BD1 patients and HCs). iPSC lines were generated and quality controlled for six donors (n = 3 per group) and differentiated into cortical NPCs. Cells were harvested at day 0, 12, 22 and 32 for transcriptome analysis (n = 2 per donor and timepoint). 3’mRNA-sequencing was performed at the NGS Core Facility of the University of Bonn using the Lexogen QuantSeq 3’mRNA-Seq Library Prep Kit. Data was analysed using Partek Flow Genomic Analysis Software. Differentially expressed genes (DEGs) were identified using DESeq2 and used for subsequent gene set enrichment analysis. During the selection process, a total of 13 donors were excluded based on the presence of either CNVs (n = 1) or rare variants (n = 12) associated with BD and/or schizophrenia, highlighting the value of thorough genetic characterization of donors when studying the effect of polygenic risk in iPSC models. The generated iPSC-lines could successfully be differentiated into NPCs without obvious alterations in morphology or neuronal development between BD1 and HC cells. Analysis of transcriptome data revealed that th