Copy number variation in schizophrenia in Sweden.

Area of Science:

• Genetics
• Neuropsychiatry
• Genomics

Background:

• Schizophrenia (SCZ) is a complex, highly heritable neuropsychiatric disorder.
• Previous studies identified rare copy number variations (CNVs) associated with SCZ risk, but more research is needed to find additional CNVs and pathways.

Purpose of the Study:

• To conduct a genome-wide survey for copy number variations (CNVs) associated with schizophrenia (SCZ) in a large Swedish national sample.
• To identify novel recurrent CNVs and biological pathways implicated in SCZ etiology.

Main Methods:

• Genome-wide survey of CNVs using genotyping array intensity data in 4719 SCZ cases and 5917 controls.
• Statistical analysis to measure the effect of CNVs on SCZ risk.
• Gene set association analyses to identify enriched biological pathways.

Main Results:

• Confirmed increased burden of large, rare CNVs in SCZ cases.
• Validated associations for 16p11.2 duplications, 22q11.2 deletions, and 3q29 deletions.
• Reported a novel association for 17q12 duplications (OR=4.16, P=0.018) with SCZ.
• Identified enriched biological pathways including calcium channel signaling and FMRP binding partners.
• Found increased burden of large CNVs (>500kb) in postsynaptic density genes, SCZ GWAS regions, and mitochondrial/cytoplasmic gene products.

Conclusions:

• Genomic inquiry, including CNV, common variation, and exonic variation studies, is converging on similar biological pathways and genes for SCZ.
• The identified novel CNVs and pathways provide new targets for understanding SCZ pathogenesis.
• These findings advance the genetic understanding of schizophrenia and its underlying biological mechanisms.