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Two single-nucleotide polymorphisms (SNPs) (rs4281084 and rs12155594) within the neuregulin-1 (NRG1) gene have been associated with psychosis transition. However, the neurobiological changes associated with these SNPs remain unclear. We aimed to determine what relationship these two SNPs have on lateral ventricular volume and white matter integrity, as abnormalities in these brain structures are some of the most consistent in schizophrenia.
Structural (n = 370) and diffusion (n = 465) magnetic resonance imaging data were obtained from affected and unaffected individuals predominantly of European descent. The SNPs rs4281084, rs12155594, and their combined allelic load were examined for their effects on lateral ventricular volume, fractional anisotropy (FA) as well as axial (AD) and radial (RD) diffusivity. Additional exploratory analyses assessed NRG1 effects on gray matter volume, cortical thickness, and surface area throughout the brain.
Individuals with a schizophrenia age of onset ⩽25 and a combined allelic load ⩾3 NRG1 risk alleles had significantly larger right (up to 50%, padj = 0.01) and left (up to 45%, padj = 0.05) lateral ventricle volumes compared with those with allelic loads of less than three. Furthermore, carriers of three or more risk alleles, regardless of age of onset and case status, had significantly reduced FA and elevated RD but stable AD in the frontal cortex compared with those carrying fewer than three risk alleles.
Our findings build on a growing body of research supporting the functional importance of genetic variation within the NRG1 gene and complement previous findings implicating the rs4281084 and rs12155594 SNPs as markers for psychosis transition.
White matter disruptions in schizophrenia have been widely reported, but it remains unclear whether these abnormalities differ between illness stages. We mapped the connectome in patients with recently diagnosed and chronic schizophrenia and investigated the extent and overlap of white matter connectivity disruptions between these illness stages.
Diffusion-weighted magnetic resonance images were acquired in recent-onset (n = 19) and chronic patients (n = 45) with schizophrenia, as well as age-matched controls (n = 87). Whole-brain fiber tracking was performed to quantify the strength of white matter connections. Connections were tested for significant streamline count reductions in recent-onset and chronic groups, relative to separate age-matched controls. Permutation tests were used to assess whether disrupted connections significantly overlapped between chronic and recent-onset patients. Linear regression was performed to test whether connectivity was strongest in controls, weakest in chronic patients, and midway between these extremities in recent-onset patients (controls > recent-onset > chronic).
Compared with controls, chronic patients displayed a widespread network of connectivity disruptions (p < 0.01). In contrast, connectivity reductions were circumscribed to the anterior fibers of the corpus callosum in recent-onset patients (p < 0.01). A significant proportion of disrupted connections in recent-onset patients (86%) coincided with disrupted connections in chronic patients (p < 0.01). Linear regression revealed that chronic patients displayed reduced connectivity relative to controls, while recent-onset patients showed an intermediate reduction compared with chronic patients (p < 0.01).
Connectome pathology in recent-onset patients with schizophrenia is confined to select tracts within a more extensive network of white matter connectivity disruptions found in chronic illness. These findings may suggest a trajectory of progressive deterioration of connectivity in schizophrenia.