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

双相情感障碍（BD）是一种常见的神经精神障碍，是全球十大发病原因之一。在过去的几年中，我们和其他人通过全基因组关联研究确定了双相障碍的常见遗传危险因素。最近，我们也启动了下一代测序研究，以确定具有较高外显率的罕见风险变异。尽管取得了相当大的进展，但许多风险基因仍有待鉴定。此外，在神经细胞和临床结果水平上表现出不同程度外显率的常见和罕见风险变异的功能影响在很大程度上尚不清楚。该项目的目的是提高对BD分子基础的理解。为了实现这一目标，巴塞尔大学（瑞士）和波恩大学（德国）的研究小组将采用创新策略和互补的专业知识。在功能方法中，来自选定的BD患者和对照组的诱导多能干细胞（iPSC）衍生的神经细胞将用于识别与疾病相关的转录组学和细胞特征，这些特征可归因于神经发育途径中已知的常见风险变异的组合(基因本体（GO)-术语知情多基因风险评分分析（PRS））。我们将使用下一代测序和功能分析来评估常见变异对转录组（RNA和小RNA）和细胞水平的影响。获得的结果可以在患者特异性神经细胞中进一步验证。同时，我们将应用最先进的遗传策略，旨在识别15个大的双相障碍家族中新的罕见双相障碍风险变异，这些家族被选中，因为可能存在更强的遗传影响神经发育过程（核心诊断为双相I型障碍的患者比例高，发病年龄≤25岁）。对于风险变异的检测，将结合SNP微阵列（PRS和拷贝数变异（CNV））和全基因组测序数据（短读和长读）。包含长读测序将允许迄今为止最全面的结构风险变异检测。拟议项目的一个主要优势是，它将结合巴塞尔和波恩两个研究小组的互补性专门知识。我们预计该项目将揭示与ipsc为基础的模型系统中BD相关的细胞改变。这些表型变化将提供疾病相关发育途径的见解，从而提高对双相障碍发病机制的理解。最终，这将促进基于药物的补偿的新策略。我们将首次使用长读测序技术来研究小结构变异的影响，这是以往研究中没有研究过的BD的一个方面。这项工作将为未来的项目奠定基础，我们计划在具有高和低PRS背景的iPSCs产生的神经细胞中模拟已确定的罕见变异的表型效应。

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.