Massively parallel functional dissection of schizophrenia-associated noncoding genetic variants.

Area of Science:

• Neurogenetics
• Genomics
• Molecular Psychiatry

Background:

• Schizophrenia (SCZ) is highly heritable, with thousands of genetic variants implicated, primarily in noncoding genomic regions.
• Understanding the pathomechanisms of SCZ is hindered by the unknown causal variants, their functions, and target genes.

Purpose of the Study:

• To map schizophrenia-associated genetic variants to their functions in neural cells at scale.
• To identify causal variants and their target genes contributing to SCZ pathophysiology.

Main Methods:

• Implementation of a massively parallel variant annotation pipeline (MVAP) for variant-to-function mapping.
• Integration of epigenomic data and CRISPR interference (CRISPRi) screening.
• Analysis of variants in disease-relevant neural cell types.

Main Results:

• Identified 620 functional variants (1.7%) associated with SCZ.
• Demonstrated that these variants operate in a developmental and neuronal-activity-dependent manner.
• Linked functional variants to target genes, biological processes, and altered neuronal physiology.

Conclusions:

• Developed a multistage strategy to prioritize functional single-nucleotide polymorphism (SNP)-to-gene-to-endophenotype relationships.
• Provided biological insights into context-dependent molecular processes affected by SCZ-associated genetic variation.
• Advanced understanding of the genetic underpinnings of schizophrenia.