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Transl Psychiatry. 2014 May 27;4:e392. doi: 10.1038/tp.2014.41.

Schizophrenia-risk variant rs6994992 in the neuregulin-1 gene on brain developmental trajectories in typically developing children.

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Department of Medicine, John A. Burns School of Medicine, University of Hawaii and Queen's Medical Center, Honolulu, HI, USA.
Department of Radiology, University of California, San Diego, La Jolla, CA, USA.
1] Department of Radiology, University of California, San Diego, La Jolla, CA, USA [2] Department of Psychiatry and Department of Cognitive Science, Center for Human Development, University of California, San Diego, La Jolla, CA, USA.
1] Department of Radiology, University of California, San Diego, La Jolla, CA, USA [2] Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA.
Scripps Genomic Medicine and Scripps Translational Science Institute, The Scripps Research Institute, La Jolla, CA, USA.
Department of Psychiatry, University of Massachusetts Medical School, Worcester, MA, USA.
Departments of Psychiatry and Behavioral Sciences, University of California, Davis, CA, USA.
Departments of Pediatrics and Investigative Medicine, Child Health Research Center, Yale University School of Medicine, New Haven, CT, USA.
Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Sackler Institute for Developmental Psychobiology, Weil Cornell Medical College, New York, NY, USA.
Department of Pediatrics, University of Southern California, and Children's Hospital, Los Angeles, CA, USA.


The neuregulin-1 (NRG1) gene is one of the best-validated risk genes for schizophrenia, and psychotic and bipolar disorders. The rs6994992 variant in the NRG1 promoter (SNP8NRG243177) is associated with altered frontal and temporal brain macrostructures and/or altered white matter density and integrity in schizophrenic adults, as well as healthy adults and neonates. However, the ages when these changes begin and whether neuroimaging phenotypes are associated with cognitive performance are not fully understood. Therefore, we investigated the association of the rs6994992 variant on developmental trajectories of brain macro- and microstructures, and their relationship with cognitive performance. A total of 972 healthy children aged 3-20 years had the genotype available for the NRG1-rs6994992 variant, and were evaluated with magnetic resonance imaging (MRI) and neuropsychological tests. Age-by-NRG1-rs6994992 interactions and genotype effects were assessed using a general additive model regression methodology, covaried for scanner type, socioeconomic status, sex and genetic ancestry factors. Compared with the C-carriers, children with the TT-risk-alleles had subtle microscopic and macroscopic changes in brain development that emerge or reverse during adolescence, a period when many psychiatric disorders are manifested. TT-children at late adolescence showed a lower age-dependent forniceal volume and lower fractional anisotropy; however, both measures were associated with better episodic memory performance. To our knowledge, we provide the first multimodal imaging evidence that genetic variation in NRG1 is associated with age-related changes on brain development during typical childhood and adolescence, and delineated the altered patterns of development in multiple brain regions in children with the T-risk allele(s).

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