Impact of Neuritin 1 (NRN1) Polymorphisms on Fluid Intelligence in Schizophrenia

Neuritin I (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 rsl475157- 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. (C) 2009 Wiley-Liss, Inc.