Objectives Neuritin 1 gene (NRN1) is involved in neurodevelopment processes and synaptic plasticity and its expression is regulated by brain-derived neurotrophic factor (BDNF). We aimed to investigate the association of NRN1 with schizophrenia-spectrum disorders (SSD) and bipolar disorders (BPD), to explore its role in age at onset and cognitive functioning, and to test the epistasis between NRN1 and BDNF. Methods The study was developed in a sample of 954 SSD/BPD patients and 668 healthy subjects. Genotyping analyses included 11 SNPs in NRN1 and one functional SNP in BDNF. Results The frequency of the haplotype C-C (rs645649–rs582262) was significantly increased in patients compared to controls (P = 0.0043), while the haplotype T-C-C-T-C-A (rs3763180–rs10484320–rs4960155–rs9379002–rs9405890–rs1475157) was more frequent in controls (P = 3.1 × 10−5). The variability at NRN1 was nominally related to changes in age at onset and to differences in intelligence quotient, in SSD patients. Epistasis between NRN1 and BDNF was significantly associated with the risk for SSD/BPD (P = 0.005). Conclusions Results suggest that: (i) NRN1 variability is a shared risk factor for both SSD and BPD, (ii) NRN1 may have a selective impact on age at onset and intelligence in SSD, and (iii) the role of NRN1 seems to be not independent of BDNF. We are grateful to all the participants, whose willingness to take part made this work possible. We also thank Anna Valldeperas for her participation in molecular laboratory tasks. Funding for this study was provided by: i) Centro de Investigación en Red de Salud Mental (CIBERSAM), ii) Fundación Alicia Koplowitz; iii) Ministry of Science and Innovation (PIM2010ERN-00642)-ERA-NET NEURON; iv) P1·1B2010-40 and P1·1B2011-47 from the Fundació Bancaixa-UJI; v) Miguel Servet Research Contracts (CP10/00596) from the Plan Nacional de I + D+i and co-funded by the Instituto de Salud Carlos III-Subdirección General de Evaluación y Fomento de la Investigación and the European Regional Development Fund (FEDER); vi) Health research funds from the Spanish Government (PI11/01977); vii) METSY project of the 7th Framework Programme of the European Commission (FP7-HEALTH-602478) and Ministry of Economy and Competitiveness (PI10/01920, PI14/02096); Claudia Prats was supported by APIF-IBUB grant 2014. Thanks to the Comissionat per a Universitats i Recerca del DIUE (2014SGR1636, 2014SGR1573, 2014SGR489).