Abstract
Background Schizophrenia, schizoaffective and bipolar disorder probands share many behavioral and biological traits including brain morphology features, as well as a partially overlapping complex polygenic basis. Ventricular volume enlargement is one of the most enduring anatomical findings in these disorders, representing a quantitative trait associated with severity. Methods We performed GWAS on a multi-ethnic sample from the Bipolar and Schizophrenia Network for Intermediate Phenotypes study (B-SNIP1) containing 1,115 unrelated cases and controls. FreeSurfer-processed volumes from structural MRI were used as quantitative phenotypes in GWAS with PsychChip genotypes imputed to the 1000 Genomes reference panel. Results Genome-wide significance was reached in associations with two regional volumes within the ventricular system: (1) The volume of the Temporal Horn of the Left Lateral Ventricle was associated with a SNP marker of NRXN1 (P= 1.156E-11), and (2) The volume of the Cavum Septum Pellucidum was associated with markers in LRP1B (P=1.661E-11) and RORA (P=1.72E-10). Discussion NRXN1 rare structural variants have been already associated with psychosis and cognition, but this is the first report of common SNP variants associated with increased ventricular volume. Presumably, the observed NRNX1 effect on temporal horn volume reflects shared regulation of morphometric characteristics of the surrounding limbic structures of the medial temporal lobe, not evident when these structures are considered separately. Previous research associated Cavum Septum Pellucidum persistence with schizophrenia, and this is the first report of a common genetic variant associated with its persistence related to neuropsychiatric disease. Co-expression analysis of NRXN1 and LRP1B identified genes involved in cell adhesion and neurotransmission. Our findings represent novel genetic associations implicated in the molecular basis of neuropsychiatric disorders at the stage of brain development.
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