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Rare Tandem Repeat Expansions May Contribute to Schizophrenia Risk, Genome-Wide Analysis Finds

This article has been updated to reflect that ExpansionHunter Denovo was developed by Illumina, not the researchers.

NEW YORK — Tandem repeat expansions may contribute to someone's risk of developing schizophrenia, a new analysis has found.

Tandem repeat expansions have been linked to more than four dozen conditions, including Huntington's disease and, more recently, autism spectrum disorder, the genetic risk of which overlaps with schizophrenia.

In a new study, researchers from the Hospital for Sick Children and elsewhere examined the burden of tandem repeat expansions within individuals with schizophrenia, as compared to unaffected controls. As they reported on Thursday in the journal Molecular Psychiatry, the researchers found that adults with schizophrenia have a higher burden of rare tandem repeat expansions located near exons than people without. Further, those exons are often in genes associated with schizophrenia and involved in synaptic function.

"This is the first time these rare repeat expansions have been assessed genome-wide in schizophrenia," senior author Ryan Yuen from the Genetics and Genome Biology program at SickKids said in a statement. "Our findings suggest that the tandem repeat expansions are an important class of variants that contribute to schizophrenia risk."

They used a computational approach developed by Illumina called ExpansionHunter Denovo to identify tandem repeat expansions within the genomes of 257 individuals with schizophrenia, which they then compared to the repeats found in the genomes of 225 individuals with no psychiatric conditions and more than 2,500 individuals from the 1000 Genomes Project.

Following that burden analysis, the researchers identified 583 rare tandem repeat expansions in 436 genomic regions in 220 individuals with schizophrenia. Nearly 200 of those regions were genic and involved 193 different genes.

These expansions were particularly present at exon junctions, the researchers noted. They further estimated that the rare tandem repeat expansions near exons account for nearly 4 percent of schizophrenia risk.

These expansions were also often located with genes associated with neurological or nervous system abnormalities or abnormal behavior, as captured by the Mammalian Phenotype Ontology. These genes included ones like DCLK1, ERBB4, GRIK4, GRIN2A, SHANK1, and VIPR2 that have been linked to schizophrenia.

Many of the rare tandem repeat expansion-affected genes are also involved in synaptic functions and signaling, suggesting that the repeats could affect splicing behavior — possibly leading to a loss of function — to alter synaptic function.

The researchers also noted that some individuals in their analysis harbored CNVs or SNVs that were also linked to disease risk, underscoring that schizophrenia is a complex genetic disorder to which multiple genetic factors may contribute risk.

"We found that genes with tandem repeat expansions are overlapping with other discoveries we're seeing in the field," Yuen said. "Our study helps to fill some of the gaps in our knowledge and underlines the important function of the synaptic functions in schizophrenia as well as the complex way in which schizophrenia is affected by different types of genetic variants."

The researchers additionally examined rare tandem repeat expansions in 63 individuals from 14 families with a history of schizophrenia, including 30 individuals who diagnosed themselves with schizophrenia. In two families, the researchers identified rare tandem repeat expansions — near CALCOCO2 and FXN in one family and SHANK1 in another — that they also uncovered in the larger cohort. All the sequenced affected individuals in these families had the expansions, though the researchers noted that some unaffected family members did, as well.

Additional studies with larger cohorts are needed, the researchers noted, to better understand how these expansions may contribute to schizophrenia.