1 THE WORLD JOURNAL OF BIOLOGICAL PSYCHIATRY, 2015 55 http://dx.doi.org/10.3109/15622975.2015.1093658 2 56 3 RESEARCH ARTICLE 57 4 58 5 Involvement of NRN1 gene in schizophrenia-spectrum and bipolar disorders 59 6 and its impact on age at onset and cognitive functioning 60 7 61 8 62 Mar Fatjo´-Vilas1,2*, Claudia Prats1,2*, Edith Pomarol-Clotet2,3, Luisa La´zaro2,4,5, Carmen Moreno2,6, 9 63 Itxaso Gonza´lez-Ortega2,7, Sara Lera-Miguel4, Salvador Miret2,8, Ma Jose´ Mun˜oz9, Ignacio Iba´n˜ez2,10, 10 Sı´lvia Campanera8, Maria Giralt-Lo´pez9, Manuel J. Cuesta11, Victor Peralta11, Genero´s Ortet2,10, 64 11 Mara Parellada2,6, Ana Gonza´lez-Pinto2,7, Peter J. Mckenna2,3 and Lourdes Fan˜ana´s1,2 65 12 66 1 2 13 Departament de Biologia Animal, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain; Instituto De Salud Carlos III, Centro De 67 Investigacio´n Biome´dica En Red De Salud Mental (CIBERSAM), Madrid, Spain; 3FIDMAG Germanes Hospitala`ries, Research Foundation, 14 Barcelona, Spain; 4Servei de Psiquiatria i Psicologia Infantil i Juvenil, Hospital Clı´nic de Barcelona, Barcelona, Spain; 5Institut 68 15 d’investigacions Biome`diques August Pi Sunyer (IDIBAPS), Barcelona, Spain; Departament de Psiquiatria i Psicobiologia Clı´nica, Facultat De 69 16 Medicina, Universitat de Barcelona, Barcelona, Spain; 6Servicio de Psiquiatrı´a del Nin˜o y del Adolescente, Hospital General Universitario 70 17 Gregorio Maran˜o´n, Madrid, Spain; Instituto de Investigacio´n Sanitaria del Hospital Gregorio Maran˜o´n (IiSGM); Departamento de Psiquiatrı´a, 71 Facultad de Medicina, Universidad Complutense, Madrid, Spain; 7Psychiatry Service, University Hospital of Alava-Santiago, EMBREC, EHU/ 18 UPV University of the Basque Country, Kronikgune, Vitoria, Spain; 8Centre de Salut Mental d’Adults de Lleida, Servei de Psiquiatria, Salut 72 19 Mental i Addiccions, Hospital Universitari Santa Maria, de Lleida, Lleida, Spain; 9A`rea d’Adolescents, Complex Assistencial en Salut Mental 73 20 Benito Menni, Sant Boi De Llobregat, Spain; 10Departament de Psicologia Ba`sica, Clı´nica i Psicobiologia, Facultat de Cie`ncies de la Salut, 11 74 21 Universitat Jaume I, Castello´, Spain; and Servicio de Psiquiatrı´a, Complejo Hospitalario de Navarra, Pamplona Spain; Instituto de Investigacio´n Sanitaria de Navarra (IdiSNA), Pamplona, Spain 75 22 76 23 77 ABSTRACT ARTICLE HISTORY 24 Objectives: Neuritin 1 gene (NRN1) is involved in neurodevelopment processes and synaptic Received 14 April 2015 78 25 plasticity and its expression is regulated by brain-derived neurotrophic factor (BDNF). We aimed to Revised 21 July 2015 79 26 investigate the association of NRN1 with schizophrenia-spectrum disorders (SSD) and bipolar Accepted 9 September 2015 80 disorders (BPD), to explore its role in age at onset and cognitive functioning, and to test the 27 epistasis between NRN1 and BDNF. Methods: The study was developed in a sample of 954 SSD/BPD 81 KEYWORDS 28 patients and 668 healthy subjects. Genotyping analyses included 11 SNPs in NRN1 and one 82 Schizophrenia-spectrum and 29 functional SNP in BDNF. Results: The frequency of the haplotype C-C (rs645649–rs582262) was bipolar disorders; NRN1; age 83 30 significantly increased in patients compared to controls (P ¼ 0.0043), while the haplotype T-C-C-T- at onset; intelligence; BDNF C-A (rs3763180–rs10484320–rs4960155–rs9379002–rs9405890–rs1475157) was more frequent in 84 31 controls (P ¼ 3.1 Â 10À5). The variability at NRN1 was nominally related to changes in age at onset 85 32 and to differences in intelligence quotient, in SSD patients. Epistasis between NRN1 and BDNF was 86 33 significantly associated with the risk for SSD/BPD (P ¼ 0.005). Conclusions: Results suggest that: (i) 87 NRN1 variability is a shared risk factor for both SSD and BPD, (ii) NRN1 may have a selective impact 34 on age at onset and intelligence in SSD, and (iii) the role of NRN1 seems to be not independent of 88 35 BDNF. 89 36 90 37 91 38 92 39 Introduction 93 40 important questions about the boundaries and distinct- 94 41 Schizophrenia and bipolar disorder are psychiatric iveness of these psychiatric disorders. 95 42 disorders characterised by a prevalence of 2–3%, On the one hand, they have a number of symptoms in 96 43 which increases up to 3.5% when other affective and common particularly in acute episodes, with regard to the 97 44 non-affective psychotic disorders such as schizoaffective presence of psychotic symptoms; their age at onset is 98 45 or schizophreniform disorders are also included (Perala quite similar; and, although there must be neurochemical 99 46 et al. 2007). A growing body of research suggests that differences, several findings emphasise the likelihood of 100 47 schizophrenia-spectrum disorders (SSD) and bipolar dopamine dysregulation in both (Murray et al. 2004). 101 48 disorders (BPD) share several epidemiological, clinical, Available evidence also supports that a generalised 102 49 neurobiological and genetic characteristics, raising deficit is present across SSD and BPD, even though 103 50 104 51 105 52 *Joint first authorship. 106 CONTACT Dr Fatjo´-Vilas [email protected] Unitat d’Antropologia, Departament de Biologia Animal, Facultat de Biologia, Universitat de Barcelona, 53 Av. Diagonal 643, 08028 Barcelona, Spain. Tel: +34-934-021-460 107 54 ß 2015 Taylor & Francis 108 2 M. FATJO´ -VILAS ET AL. 109 quantitative differences may exist (Hill et al. 2013). In view for SSD and also in their associated cognitive deficits 163 110 of these similarities, the integration of categorical and (Straub et al. 1995; Schwab et al. 1995; Hallmayer et al. 164 111 dimensional approaches has been suggested of particular 2005). The most studied gene included in this chromo- 165 112 interest to the complete understanding of psychotic somal region is Dysbindin-1 gene (DTNBP1, 6p22.3), 166 113 disorders (Peralta and Cuesta 2007). which has been consistently associated with SSD and 167 114 On the other hand, an important genetic overlap BPD (Schwab and Wildenauer 2009) as well as with age at 168 115 between SSD and BPD has been classically reported by onset and cognitive deficits (Wessman et al. 2009; Fatjo- 169 116 both epidemiological (Gottesman 1991; Lichtenstein Vilas et al. 2011). Also in this region, and far less explored, 170 117 et al. 2006) and molecular studies (Owen et al. 2007). there is the Neuritin 1 gene (NRN1, 6p25.1), also called 171 118 More recently, genome-wide approaches have evidenced candidate plasticity-related gene 15 (cpg15) (Nedivi et al. 172 119 a substantial shared polygenic contribution involving 1993). During early embryonic development, NRN1 is 173 120 thousands of common genetic variants of small effect to expressed in multiple brain regions and acts as a survival 174 121 the aetiology of these disorders (Lee et al. 2013). factor for neural progenitors and differentiated neurons 175 122 These shared genetic risk factors, along with the (Putz et al. 2005). Later in development, NRN1 promotes 176 123 clinical and cognitive similarities, have led to the notion growth and stabilisation of axonal and dendritic arbours 177 124 that these severe mental disorders can be placed in the along with synapse formation and maturation (Cantallops 178 125 same aetiopathological continuum, probably represent- et al. 2000; Javaherian and Cline 2005). NRN1 continues to 179 126 ing different phenotypic manifestations of common be expressed in the adult brain, where its expression is 180 127 underlying processes. correlated with activity-dependent functional synaptic 181 128 In the search for specific genetic factors related to plasticity (Corriveau et al. 1999; Harwell et al. 2005; Flavell 182 129 these disorders, studies face a number of challenges that and Greenberg 2008). Furthermore, the expression of 183 130 arise from the genetic and phenotypic complexity of NRN1 is regulated by neurotrophins such as brain-derived 184 131 these disorders. To this respect, it has been recently neurotrophic factor (BDNF, 11p13) (Naeve et al. 1997; 185 132 indicated that combining disorders with similar genetic Karamoysoyli et al. 2008). BDNF promotes the differen- 186 133 risk profiles improves power to detect shared risk loci tiation and growth of developing neurons in central and 187 134 (Ruderfer et al. 2014). Similarly, genotype–phenotype- peripheral nervous systems (Buckley et al. 2007) and its 188 135 based approaches and the use of features with strong intracellular distribution and activity-dependent secre- 189 136 aetiological significance have been suggested as a useful tion is altered by the Met variant of a functional 190 137 strategy to reduce heterogeneity and to identify specific polymorphism in the BDNF gene, which consists of a 191 138 genetic factors associated with such traits (Rasetti and valine (Val) substitution for methionine (Met) at codon 66 192 139 193 Weinberger 2011; Swerdlow et al. 2015). Then, the (Val66Met). Interestingly, BDNF gene polymorphisms 140 194 observed variability on traits such as cognitive impair- have been associated with clinical characteristics – such 141 195 ments and age at onset among patients may reflect as age at onset – and cognitive functioning in both SSD 142 196 differences in the distribution of aetiological factors and and BPD (Krebs et al. 2000; Rybakowski et al. 2006). 143 197 possibly also differences underlying vulnerability. To this According to all the above mentioned, NRN1 was 144 198 respect, heritability estimates indicate that genetic already defined as a candidate gene for neurodevelop- 145 199 factors contribute significantly to age at onset of ment disorders by Chandler et al. (2010), who reported 146 200 psychotic symptoms (Hare et al. 2010) and to general the effect of NRN1 polymorphic variation on general 147 201 cognitive functioning (Deary et al. 2009). Moreover, intelligence impairments in patients with schizophrenia. 148 202 cognitive impairments are present in 70% of the patients We considered the interest of investigating the implica- 149 203 with schizophrenia (Palmer et al.