A point mutation in the zinc-transporter gene SLC39A8 may increase the risk of schizophrenia in adulthood by altering development of putamen volume in the adolescent brain, new research suggests.
It's possible, therefore, that testing for this mutation coupled with brain scans "could predict whether or not someone will develop" schizophrenia, first author Qiang Luo, PhD, of the Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, China, told Medscape Medical News by email.
In addition, because the major function of the SLC39A8 gene is accessible to pharmacologic manipulation, the results may help in discovering novel treatments for schizophrenia, the study team says.
The study was published online January 16 in JAMA Psychiatry.
Strongest Link to Date
Although the SLC39A8 gene has been associated with risk for schizophrenia, "it remains largely unknown how this genetic risk leads to a higher risk of schizophrenia by affecting the brain," Luo explained.
To investigate, the researchers combined voxel-wise brain imaging with genome-wide association studies (GWAS) in a discovery cohort that included 1721 healthy adolescents (mean age, 14 years; 50.7% girls) from the IMAGEN cohort and replication samples that included 8690 healthy adults (51.8% women) across the lifespan from four other cohorts.
In the discovery cohort, a genetic variant (minor T allele of rs13107325 in SLC39A8) was associated with larger gray matter volumes in the bilateral putamen and with lower gene expression of SLC39A8 specifically in the putamen.
"This association is among the strongest genetic associations with the brain to date, which explains more than 4% of the variance in putamen volume by this single nucleotide polymorphism," Luo told Medscape Medical News. The rs13107325-putamen association was validated in the replication samples across the lifespan.
These results, said Luo, point to a "new pathway of genetic risk disrupting the development of the adolescent brain and thereby further increasing the risk of mental illness, which will hopefully help reveal the pathogenesis of schizophrenia and provide new possibilities for the theoretical study of prior intervention before the emergence of clinical symptoms."
Commenting on the findings for Medscape Medical News, Javier Costas, PhD, from the Health Research Institute of Santiago de Compostela, Spain, who studies genetic susceptibility factors in schizophrenia but wasn't involved in the current study, said this is "an important" finding.
"Association of SLC39A8 with gray matter volume is not a novel finding. The relevant finding of the JAMA Psychiatry paper is the identification of this association between SLC39A8 and gray matter volume in adolescent brains," Costas explained.
"Bearing in mind that schizophrenia usually appears in early adulthood and that a neurodevelopmental component in schizophrenia susceptibility is generally accepted, the paper strongly suggests that the association of SLC39A8 and schizophrenia may be due to impairment in typical neurodevelopment manifested in alterations in gray matter volume," he added.
What's "astonishing," said Costas, is the direction of the relationship, with larger putamen volumes associated with the variant.
"According to the paper, the allele associated with risk for schizophrenia is the same associated with larger gray matter volume, while it is well-known that brain volume reduction is present in schizophrenia patients. Although some of this reduction may be due to medication, antipsychotic-naive patients also present brain volume reduction. Because of this, the work leaves me with mixed feelings," said Costas.
"GWAS is the first step in the identification of genes associated with risk for complex disorders. Advancing from GWAS significant findings to understanding of the underlying biology is a difficult task. Results such as this one help to progress toward this goal," said Costas.
The research was funded by grants from several organizations. Several authors have disclosed relationships with the pharmaceutical industry. A complete list of funders and author disclosures are listed with the original article. Costas has reported no relevant financial relationships.
Medscape Medical News © 2019 WebMD, LLC
Send comments and news tips to firstname.lastname@example.org.
Cite this: Schizophrenia: Genetic Mutation Alters Teen Brain, Raises Risk - Medscape - Jan 18, 2019.