NRN1 Gene as a Potential Marker of Early-Onset Schizophrenia: Evidence from Genetic and Neuroimaging Approaches

Abstract

Included in the neurotrophins family, the Neuritin 1 gene (NRN1) has emerged as an attractive candidate gene for schizophrenia (SZ) since it has been associated with the risk for the disorder and general cognitive performance. In this work, we aimed to further investigate the association of NRN1 with SZ by exploring its role on age at onset and its brain activity correlates. First, we developed two genetic association analyses using a family-based sample (80 early-onset (EO) trios (offspring onset ≤ 18 years) and 71 adult-onset (AO) trios) and an independent case-control sample (120 healthy subjects (HS), 87 EO and 138 AO patients). Second, we explored the effect of NRN1 on brain activity during a working memory task (N-back task; 39 HS, 39 EO and 39 AO; matched by age, sex and estimated IQ). Different haplotypes encompassing the same three Single Nucleotide Polymorphisms(SNPs, rs3763180-rs10484320-rs4960155) were associated with EO in the two samples (GCT, TCC and GTT). Besides, the GTT haplotype was associated with worse N-back task performance in EO and was linked to an inefficient dorsolateral prefrontal cortex activity in subjects with EO compared to HS. Our results show convergent evidence on the NRN1 association with EO both from genetic and neuroimaging approaches, highlighting the role of neurotrophins in the pathophysiology of SZ.

Keywords: NRN1; age at onset; functional magnetic resonance imaging (fMRI); schizophrenia-spectrum disorders; working memory.

Figure 1

(A) Axial view of the brain showing the significant cluster derived from the diagnosis x NRN1 HAP678 GTT analysis in the 2-back vs. 1-back contrast. A sagittal view with the marks of the cross slices is also included. The right side of the image represents the right side of the brain. The MNI coordinates are given for the shown slices. Units of the bar correspond to the β values of the regression, standardised to Z scores. (B) Bar plots with the cluster mean activity (estimated marginal means and ±2 standard errors (se)) for healthy subjects (HS; left, non-carriers: n = 27, carriers: n = 10) and subjects with early-onset schizophrenia (EO; right, non-carriers: n = 19, carriers: n = 20).

Figure 2

Bar plots with mean performance (estimated marginal means and ±2 standard errors(se)) for healthy subjects (HS; left, non-carriers: n = 27, carriers: n = 10) and subjects with early-onset schizophrenia (EO; right, non-carriers: n = 19, carriers: n = 20) by NRN1 HAP678 GTT.