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Multiple Variants within Signaling Pathway Linked to Schizophrenia

NEW YORK (GenomeWeb News) – Together, multiple gene variants located within a single signaling pathway can contribute to schizophrenia, researchers from Johns Hopkins University School of Medicine reported in Molecular Psychiatry today.

Schizophrenia has long been known to run in families, and previous research estimated that it has heritability higher than 80 percent. However, the researchers noted, while genome-wide association studies have unearthed a number of susceptibility loci for the disease, they typically explain a small fraction of genetic risk for the disease.

Researchers at Hopkins, instead, proposed that multiple variants affecting a single signaling pathway could contribute to schizophrenia.

The researchers focused their efforts on the well-characterized neuregulin signaling pathway, as it had been linked previously to the disease. With a combination of linkage analysis and next-generation sequencing, they examined a number of genes involved in the neuregulin signaling pathway in more than 120 multiplex schizophrenia families — those with more than one family member with schizophrenia — and nearly 50 other schizophrenia patients. From this, they found that people with a particular subtype of schizophrenia seem to harbor a number of damaging variants within that pathway.

"These results support the idea that there's no single genetic recipe for schizophrenia, but that a buildup of mutations in a pathway related to the disease — like neuregulin signaling — can be the culprit," said corresponding author Dimitri Avramopoulos, an associate professor at the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins, in a statement. "The results are also evidence for the current theory that schizophrenia isn't a single disease at all, but a suite of related disorders."

To examine the interconnecting relationships between the genes of the neuregulin signaling pathway, the researchers first genotyped 123 multiplex schizophrenia families at more than 6,000 SNPs. They then homed their analysis in on linkages scores for 10 loci — all associated with the neuregulin signaling pathway — and how those linkage scores correlated across families. For a number of loci, they identified evidence for linkage.

Avramopoulos and his team then turned to a cohort of 48 patients, containing 24 pairs of distantly related people with schizophrenia. Using an Illumina platform, they sequenced 120 protein-coding exons involved in the neuregulin signaling pathway — including NRG1, NGR3, ERBB4, beta-secretase, and the gamma-secretase complex components — in this cohort. From this, they identified 13 missense mutations in 15 of the 24 pairs. Seven of those 13 missense mutations were predicted to be deleterious to protein function.

The researchers' model predicted that schizophrenia patients with one deleterious variant in this pathway would likely also have deleterious variants in other genes in the pathway. And indeed, they noted a correlation between deleterious variants in the NRG1 gene with those in the APH1B gene.

Further, schizophrenia patients with deleterious variants in the neuregulin signaling pathway exhibited different symptoms than schizophrenia patients with intact neuregulin signaling pathways. For instance, schizophrenia patients with affected neuregulin signaling pathways were more likely to have hallucinations, though they typically had less impairment than other schizophrenia patients.

"Collectively, our data strongly support the hypothesis that the [neuregulin signaling pathway] is affected by multiple damaging variants in a subset of phenotypically distinct patients," the researchers wrote.

"On the basis of this, we propose a general model of pathway heterogeneity in [schizophrenia], which, in part, may explain its phenotypic variability and genetic complexity," they added.

Indeed, they noted that while they found a link in their study between variants in the neuregulin signaling pathway and schizophrenia, changes to other pathways could be involved in schizophrenia, or even other common, complex genetic diseases like heart disease.