Massively parallel functional dissection of schizophrenia-associated noncoding genetic variants

• DOI: 10.1016/j.cell.2023.09.015
• Publication Date: 2023-10-17T14:26:50Z
• Authors: Christine K. Rummel; Miriam Gagliardi; Ruhel Ahmad; Alexander Herholt; Laura Jimenez-Barron; Vanessa Murek; Liesa Weigert; Anna Hausruckinger; Susanne Maidl; Barbara Hauger; Florian J. Raabe; Christina Fürle; Lucia Trastulla; Gustavo Turecki; Matthias Eder; Moritz J. Rossner; Michael J. Ziller
• Keywords: Neurons; Mice; Schizophrenia; Humans; Animals; High-Throughput Nucleotide Sequencing; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide; 3. Good health; Genome-Wide Association Study

Schizophrenia (SCZ) is a highly heritable mental disorder with thousands of associated genetic variants located mostly in the noncoding space of the genome. Translating these associations into insights regarding the underlying pathomechanisms has been challenging because the causal variants, their mechanisms of action, and their target genes remain largely unknown. We implemented a massively parallel variant annotation pipeline (MVAP) to perform SCZ variant-to-function mapping at scale in disease-relevant neural cell types. This approach identified 620 functional variants (1.7%) that operate in a highly developmental context and neuronal-activity-dependent manner. Multimodal integration of epigenomic and CRISPRi screening data enabled us to link these functional variants to target genes, biological processes, and ultimately alterations of neuronal physiology. These results provide a multistage prioritization strategy to map functional single-nucleotide polymorphism (SNP)-to-gene-to-endophenotype relations and offer biological insights into the context-dependent molecular processes modulated by SCZ-associated genetic variation.