Massively parallel functional dissection of schizophrenia- associated noncoding 
genetic variants

Rummel, Christine; Gagliardi, Miriam; Ahmad, Ruhel; Herholt, Alexander; Jiménez-Barrón, Laura; Murek, Vanessa; Weigert, Liesa; Hausruckinger, Anna; Maidl, Susanne; Hauger, Barbara; Raabe, Florian J.; Fuerle, Christina; Trastulla, Lucia; Turecki, Gustavo; Eder, Matthias; Rossner, Moritz J.; Ziller, Michael J.

doi:10.1016/j.cell.2023.09.015

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Massively parallel functional dissection of schizophrenia- associated noncoding genetic variants

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Rummel, Christine
RG Genomics of Complex Diseases, Max Planck Institute of Psychiatry, Max Planck Society;
IMPRS Translational Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

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Ahmad, Ruhel
RG Genomics of Complex Diseases, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons262308

Jiménez-Barrón, Laura
RG Genomics of Complex Diseases, Max Planck Institute of Psychiatry, Max Planck Society;
IMPRS Translational Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons276883

Murek, Vanessa
RG Genomics of Complex Diseases, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons294334

Weigert, Liesa
RG Genomics of Complex Diseases, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons294332

Hausruckinger, Anna
RG Genomics of Complex Diseases, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons294336

Maidl, Susanne
RG Genomics of Complex Diseases, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80355

Hauger, Barbara
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons263179

Trastulla, Lucia
RG Genomics of Complex Diseases, Max Planck Institute of Psychiatry, Max Planck Society;
IMPRS Translational Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80315

Eder, Matthias
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons203557

Ziller, Michael J.
RG Genomics of Complex Diseases, Max Planck Institute of Psychiatry, Max Planck Society;

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Citation

Rummel, C., Gagliardi, M., Ahmad, R., Herholt, A., Jiménez-Barrón, L., Murek, V., et al. (2023). Massively parallel functional dissection of schizophrenia- associated noncoding genetic variants. CELL, 186(23), 5165-5182.e33. doi:10.1016/j.cell.2023.09.015.

Cite as: https://hdl.handle.net/21.11116/0000-000E-0DE5-2

Abstract

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 ac-tion, 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.