Supplementary Material for: Publicly Available hiPSC Lines with Extreme Polygenic Risk Scores for Modeling Schizophrenia

Schizophrenia (SZ) is a common and debilitating psychiatric disorder with limited effective treatment options. Although highly heritable, risk for this polygenic disorder depends on the complex interplay of hundreds of common and rare variants. Translating the growing list of genetic loci significantly associated with disease into medically actionable information remains an important challenge. Thus, establishing platforms with which to validate the impact of risk variants in cell-type-specific and donor-dependent contexts is critical. Towards this, we selected and characterized a collection of 12 human induced pluripotent stem cell (hiPSC) lines derived from control donors with extremely low and high SZ polygenic risk scores (PRS). These hiPSC lines are publicly available at the California Institute for Regenerative Medicine (CIRM). The suitability of these extreme PRS hiPSCs for CRISPR-based isogenic comparisons of neurons and glia was evaluated across 3 independent laboratories, identifying 9 out of 12 meeting our criteria. We report a standardized resource of publicly available hiPSCs on which we hope to perform genome engineering and generate diverse kinds of functional data, with comparisons across studies facilitated by the use of a common set of genetic backgrounds.

精神分裂症（Schizophrenia，SZ）是一种常见且致残性的精神疾病，目前有效治疗方案十分有限。尽管该多基因疾病具有高度遗传性，但其发病风险取决于数百种常见与罕见变异的复杂相互作用。将不断涌现的、与疾病显著相关的遗传位点转化为可指导临床实践的信息，仍是一项重要挑战。因此，搭建可在细胞类型特异性及供体依赖的背景下验证风险变异影响的研究平台，至关重要。为此，我们筛选并表征了12株源自对照供体的人类诱导多能干细胞（human induced pluripotent stem cell，hiPSC）系，这些供体分别携带极高和极低的精神分裂症多基因风险评分（polygenic risk scores，PRS）。上述hiPSC系可通过加州再生医学研究所（California Institute for Regenerative Medicine，CIRM）公开获取。本研究在3个独立实验室中评估了这些极端PRS hiPSC系用于基于成簇规律间隔短回文重复序列（CRISPR）的神经元与神经胶质细胞同基因比对的适用性，最终12株细胞系中有9株符合我们的筛选标准。我们在此报道一套可公开获取的标准化hiPSC资源，后续计划在此基础上开展基因组工程操作并生成多种功能数据；通过使用统一的遗传背景，可有效促进不同研究间的结果比对。