Progressive Structural Brain Changes and NRG1 Gene Variants in First-Episode Nonaffective Psychosis

Abstract

Background: Structural brain abnormalities are already present during the early phases of psychosis, but factors underlying brain volume changes are still not well understood. The neuregulin 1 gene (NRG1), influencing neurodevelopment and neuroplasticity, has been associated with schizophrenia. Our aim was to examine whether variations in the NRG1 gene (SNP8NRG221132, SNP8NRG6221533 and SNP8NRG243177 polymorphisms) influence longitudinal changes in the brain during a first episode of psychosis (FEP). Methods: A 3-year follow-up magnetic resonance imaging (MRI) study was performed. Fifty-nine minimally medicated patients who were experiencing FEP and 14 healthy control individuals underwent genotyping and structural brain MRI at baseline and at 1- and 3-year follow-up. A comparison of brain volumes, gray matter, white matter (WM), lateral ventricles (LV), cortical cerebrospinal fluid, and thalamus and caudate was made between the groups according to their genotype. Results: In patients, the SNP8NRG6221533 risk C allele was significantly associated with increased LV volume across time. C allele carriers had significantly less WM compared with subjects homozygous for the T allele after the follow-up. No other significant differences were observed among subgroups. No significant changes according to the genotypes were found in healthy individuals. Conclusion: Our findings suggest that variations of neurodevelopment-related genes, such as the NRG1 gene, can contribute to brain abnormalities described in early phases of schizophrenia and progressive changes during the initial years of the illness. To our knowledge, it is the first time that a relation between NRG1 polymorphisms and longitudinal brain changes is reported.

Neuregulin-1 and schizophrenia in the genome-wide association study era

“…The C 'risk' allele at this locus was associated with lower white matter volume (detected with voxel based morphometry) in the regions of the right uncinate fasciculus, right inferior longitudinal fasciculus and in the overlapping portions of the anterior thalamic radiations and the corticopontine tracts (Cannon et al 2012) compared to TT-genotype carriers. Further, less gross white matter (Suarez-Pinilla et al 2015) and longitudinal changes in lateral ventricular volumes were also noted in those with the C allele at SNP8NRG221533 (Suarez-Pinilla et al 2015). However, one European study has reported negative associations with hippocampus and lateral ventricular volumes (Dutt et al 2009) and the 'non-risk' T-allele was associated with decreased anterior cingulum fractional anisotropy compared to CC genotype carriers in a Han Chinese schizophrenia population (Wang et al 2009), suggesting HAP ICE 'risk' alleles may differ by ancestry.…”

Genetic recovery of ErbB4 in adulthood partially restores brain functions in null mice

“…The following evidence supports the notion that NRG1 and ErbB4 alteration contributes to pathophysiological mechanisms of SZ. First, NRG1 and ErbB4 variants have been shown to be associated with reduced volume and decreased activation of brain regions and cognitive phenotypes (37)(38)(39) and with responses to antipsychotics treatment (40)(41)(42). Second, altered NRG1 or ErbB4 levels were detected in postmortem brain samples and peripheral blood of SZ patients (43)(44)(45).…”

The association between gene variants and longitudinal structural brain changes in psychosis: a systematic review of longitudinal neuroimaging genetics studies

“…Gender distribution ranged from 58 to 79% male, and mean AAO from 10 to 30.6 years old. Eight of the eleven studies included a healthy control (HC) group for genetic, 37 , 42 , 43 structural MRI, or both types of analysis, 34 – 36 , 40 , 41 , 44 and one of these studies also included a sibling comparison group. 41 …”

“…Genes examined were BDNF, 34 , 35 , 42 , 44 COMT, 41 NRG1, 36 , 40 DISC1, 38 CNR1, 37 GAD1, 39 and G72. 43 All studies genotyped individual SNPs, three studies additionally performed haplotype analysis, 39 , 40 , 43 and one study analyzed a microsatellite.…”

“…Five studies compared longitudinal brain changes between genotype or haplotype subgroups of patients with psychosis, 37 – 40 , 42 , 43 while six studies compared longitudinal brain changes between genotype or haplotype groups in both patient and HC groups. 34 – 36 , 40 , 41 , 44 …”