Rummel Christine K, Gagliardi Miriam, Herholt Alexander, Ahmad Ruhel, Murek Vanessa, Weigert Liesa, Hausruckinger Anna, Maidl Susanne, Jimenez-Barron Laura, Trastulla Lucia, Eder Mathias, Rossner Moritz, Ziller Michael J
Max Planck Institute of Psychiatry, Munich, Germany.
International Max Planck Research School for Translational Psychiatry (IMPRS-TP), Munich, Germany.
bioRxiv. 2023 Jun 27:2023.06.27.545266. doi: 10.1101/2023.06.27.545266.
Schizophrenia (SCZ) is a highly polygenic disease and genome wide association studies have identified thousands of genetic variants that are statistically associated with this psychiatric disorder. However, our ability to translate these associations into insights on the disease mechanisms has been challenging since the causal genetic variants, their molecular function and their target genes remain largely unknown. In order to address these questions, we established a functional genomics pipeline in combination with induced pluripotent stem cell technology to functionally characterize ~35,000 non-coding genetic variants associated with schizophrenia along with their target genes. This analysis identified a set of 620 (1.7%) single nucleotide polymorphisms as functional on a molecular level in a highly cell type and condition specific fashion. These results provide a high-resolution map of functional variant-gene combinations and offer comprehensive biological insights into the developmental context and stimulation dependent molecular processes modulated by SCZ associated genetic variation.
精神分裂症（SCZ）是一种高度多基因疾病，全基因组关联研究已经鉴定出数千种与这种精神疾病存在统计学关联的基因变异。然而，由于因果基因变异、它们的分子功能及其靶基因在很大程度上仍然未知，我们将这些关联转化为对疾病机制的见解的能力一直具有挑战性。为了解决这些问题，我们建立了一个功能基因组学流程，并结合诱导多能干细胞技术，以功能表征与精神分裂症相关的约35000个非编码基因变异及其靶基因。该分析确定了一组620个（1.7%）单核苷酸多态性在分子水平上以高度细胞类型和条件特异性的方式发挥功能。这些结果提供了一个功能变异-基因组合的高分辨率图谱，并为精神分裂症相关基因变异所调节的发育背景和刺激依赖性分子过程提供了全面的生物学见解。
