Schizophrenia brain marker matches genetic risk

By Eleanor McDermid, Senior medwireNews Reporter

Polygenic risk for schizophrenia correlates with neural inefficiency in the left dorsolateral prefrontal cortex (DLPFC), say researchers.

As polygenic risk increased, study participants required more brain activity to complete the same working memory task.

“The finding supports a growing number of reports, which demonstrate a polygenic etiology of schizophrenia and related phenotypes,” say study author Stefan Ehrlich (Dresden University of Technology, Germany) and co-workers.

The team derived a polygenic risk score (PGRS) using data from 3322 schizophrenia patients and 3587 controls in the International Schizophrenia Consortium (ISC). In a further 206 people (including 92 schizophrenia patients), this score was positively associated with neural activity, in an area that included the left DLPFC and left ventrolateral prefrontal cortex, during a working memory task.

An association with brain activity was found only when the score was based on the 608 single nucleotide polymorphisms (SNPs) that were significantly different between ISC patients and controls at the strictest statistical threshold used (p<0.01).

This “supports the idea that DLPFC dysfunction represents a more circumscribed phenotype than clinical phenotypes or diagnostic categories,” write the researchers in Schizophrenia Bulletin.

They add: “Investigating an intermediate phenotype bears the additional advantage of addressing the problem of symptom heterogeneity within a given psychiatric diagnosis and the occurrence of (attenuated) risk markers in healthy controls.”

Furthermore, Ehrlich et al found the same association in a replication cohort of 6458 schizophrenia patients and 8971 controls from the Psychiatric Genomics Consortium.

Although related to neural inefficiency, the risk score was not associated with task performance or diagnosis, suggesting that it “represents unique genetic aspects of dysfunctional neuronal responses related to schizophrenia that are not easy to capture at the level of behavior or symptoms,” they say.

Neural inefficiency rose by a slow but consistent amount with increasing number of SNPs, supporting a model in which many hundreds of polymorphisms have a cumulative effect on schizophrenia risk.

When the researchers mapped these SNPs to known genes, they found them to be predominantly associated with axonogenesis and neuron projection development, ion binding, cell motility and migration, channel activity, and guanosine triphosphatase regulator activity.

Together, the findings show “a robust relationship between the proposed PGRS and schizophrenia,” concludes the team.

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