Impact of Neuritin 1 (NRN1) polymorphisms on fluid intelligence in schizophrenia

Abstract

Neuritin 1 (NRN1), an activity-regulated gene with multiple roles in neurodevelopment and synaptic plasticity, is located within the 6p24-p25 interval on chromosome 6, previously identified as linked to a subtype of schizophrenia (SZ) characterized by pervasive cognitive deficit (CD). We have tested the effect of NRN1 sequence variation on susceptibility to SZ and on general cognitive ability in patients and non-psychiatric control subjects by re-sequencing the coding regions of NRN1 and its flanking sequences, and genotyping 19 single-nucleotide polymorphisms (SNPs) in 336 SZ patients and 172 healthy control individuals. All participants completed comprehensive neurocognitive assessment, including tests estimating premorbid/prior IQ and current IQ. Logistic regression analyses found no significant association for any of the 19 SNPs with SZ or its CD subtype. However, linear regression analysis gave significant association (P = 0.024 and P = 0.027 after correction for multiple testing) for polymorphisms rs1475157 and rs9405890 with current IQ in the patient group. In SZ, the rs1475157-rs9405890 haplotypes revealed a highly significant association with the abstraction component of current ("fluid") intelligence (P = 0.0014), and with percentage loss of IQ points between premorbid and current intelligence (P = 0.0041). Results in the control group were not significant after correction. This is the first analysis of association between variation in NRN1 and SZ. The findings suggest a role of NRN1 as a modifier of cognitive functioning in SZ, with implications for future research into the impact of the environment on the development and maintenance of "fluid" intelligence.

Involvement of NRN1 gene in schizophrenia-spectrum and bipolar disorders and its impact on age at onset and cognitive functioning

“…This selective impact of NRN1 on intelligence may suggest its involvement in processes underlying cognitive functioning, which are described to be more quantitatively impaired in SSD (Hill et al 2013). Again, although results did not reach significance after permutation, it is of interest that the haplotypes identified in the present study contain the same haplotype that Chandler et al (2010) described to be associated with better fluid intelligence in schizophrenia patients and not in healthy subjects (SNP10-SNP11: C-A).…”

“…Lastly, although the permutation procedures have been applied, if multiple testing is addressed for the overall analyses not all the findings would remain significant. Then, although results cannot be dismissed completely, since they come from a directed hypothesis and they are partially in line with a previous study (Chandler et al 2010), their interpretation should be conducted with caution and replication studies are needed.…”

“…This case-control based approach adds to the only one previous Neuritin 1 gene association study developed by Chandler et al (2010) in a sample of 336 patients with schizophrenia and 172 controls. Unlike Chandler and collaborators, in our sample of 954 patients and 668 healthy subjects we report that NRN1 sequence variability accounts for a modest proportion of the risk for these disorders.…”

“…The optimal set of SNPs that contained maximum information about surrounding variants was selected by using SYSNPs (http://www.sysnps.org/) with a minor allele frequency (MAF)45%, using pairwise option tagger (threshold of r 2 ¼0.8). The SNPs included in the study by Chandler et al (2010) study were also considered. The SNP rs6265 (Val66Met) at BDNF gene was also genotyped.…”

“…According to all the above mentioned, NRN1 was already defined as a candidate gene for neurodevelopment disorders by Chandler et al (2010), who reported the effect of NRN1 polymorphic variation on general intelligence impairments in patients with schizophrenia. We considered the interest of investigating the implication of NRN1 in the aetiology not only of schizophrenia, but also across the SSD and BD continuum.…”