Schizophrenia, Schizoaffective, and Bipolar disorders share behavioral and phenomenological traits, intermediate phenotypes, and some associated genetic loci with pleiotropic effects. Volumetric abnormalities in brain structures are among the intermediate phenotypes consistently reported associated with these disorders. In order to examine the genetic underpinnings of these structural brain modifications, we performed genome-wide association analyses (GWAS) on 60 quantitative structural brain MRI phenotypes in a sample of 777 subjects (483 cases and 294 controls pooled together). Genotyping was performed with the Illumina PsychChip microarray, followed by imputation to the 1000 genomes multiethnic reference panel. Enlargement of the Temporal Horns of Lateral Ventricles (THLV) is associated with an intronic SNP of the gene NRXN1 (rs12467877, P = 6.76E–10), which accounts for 4.5% of the variance in size. Enlarged THLV is associated with psychosis in this sample, and with reduction of the hippocampus and enlargement of the choroid plexus and caudate. Eight other suggestively significant associations (P < 5.5E–8) were identified with THLV and 5 other brain structures. Although rare deletions of NRXN1 have been previously associated with psychosis, this is the first report of a common SNP variant of NRXN1 associated with enlargement of the THLV in psychosis.

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Background: Choroid plexus (ChP) enlargement has been described in first-episode psychosis and psychosis spectrum disorders, but whether ChP enlargement occurs before disease onset is unknown. This study investigated whether ChP volume is enlarged in individuals with clinical high-risk (CHR) for psychosis and whether these changes are related to clinical, cortical, and plasma analyte measures. Methods: Clinical and neuroimaging data from the North American Prodrome Longitudinal Study 2 (NAPLS2) was used for analysis. A total of 509 participants (169 controls, 340 CHR) were recruited across 8 sites. Conversion status was determined until 2-years of follow-up, with 36 patients developing psychosis. The lateral ventricle ChP was manually segmented from all available baseline brain scans. A subsample of 84 participants (31 controls, 53 CHR) had plasma analyte and neuroimaging data. Results: Compared to controls, CHR overall (d=0.22, p=0.017) and converters (d=0.21, p=0.041) demonstrated higher ChP volumes, but not nonconverters. In CHR, greater ChP volume correlated with lower cortical (r=-0.22, p<0.001) and subcortical gray matter volume (r=-0.21, p<0.001), total white matter volume (r=-0.28,p<0.001), and larger lateral ventricle volume (r=0.63,p<0.001). In CHR, greater ChP volume, but not lateral ventricle volume, correlated with higher C3 (r=0.39, p=0.005) and TSH (r=0.31, p=0.026), and lower MMP7 (r=-0.30, p=0.032) and UMOD (r=-0.33, p=0.019). Conclusions and Relevance: CHR and converters to psychosis demonstrated significantly larger ChP volumes compared to controls. ChP enlargement was associated with cortical volume reduction and increased peripheral inflammatory markers. These findings suggest that the ChP may be a key biomarker in psychosis disease onset and conversion.