Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Area of Science:

• Genetics
• Neuroscience
• Psychiatry

Background:

• Schizophrenia (SCZ) is a severe mental disorder with high heritability (60-80%), largely due to common genetic variants.
• Identifying specific genetic loci and causal genes is crucial for understanding SCZ pathophysiology.

Purpose of the Study:

• To conduct a large-scale genome-wide association study (GWAS) to identify common genetic variants associated with schizophrenia.
• To fine-map associated loci and identify candidate genes and biological pathways implicated in SCZ.

Main Methods:

• A two-stage GWAS involving up to 76,755 individuals with SCZ and 243,649 control individuals.
• Utilized fine-mapping and functional genomic data to prioritize genes and variants.
• Integrated findings with rare variant association data for SCZ and neurodevelopmental disorders.

Main Results:

• Identified 287 distinct genomic loci associated with SCZ risk.
• Concentrated associations in genes expressed in central nervous system neurons.
• Prioritized 120 genes, including 16 with likely causal variations, implicating neuronal function, synaptic organization, and transmission.
• Found enrichment for genes associated with rare disruptive variants in SCZ and neurodevelopmental disorders.

Conclusions:

• Common genetic variants play a significant role in SCZ, primarily through genes expressed in neurons.
• Convergence of common and rare variant associations suggests shared biological pathways in SCZ and neurodevelopmental disorders.
• Provides a valuable resource of prioritized genes and variants for future mechanistic research into SCZ.