Original article 61 NOTCH4 gene promoter polymorphism is associated with the age of onset in schizophrenia Sami Anttila a , Olli Kampman a,b , Ari Illi a , Markus Roivas c , Kari M. Mattila a,d , Vesa Lassila e , Terho Lehtima ¨ki a,d and Esa Leinonen a,c Objectives The NOTCH4 gene has a promoter polymor- phism at position – 25, which leads to the three genotypes TT, CT and CC. These have been suggested to present a novel independent genetic risk factor for schizophrenia. We conducted a prospective case–control study to explore the impact of NOTCH4 T-25C polymorphism on the factors associated with schizophrenia. Method NOTCH4 gene promoter T-25C polymorphism was determined by polymerase chain reaction among 94 patients with schizophrenia and 94 healthy age-matched and sex-matched blood donors. Results The T allele was highly associated with an earlier age of onset in male patients of schizophrenia (Kaplan– Meier log-rank test P< 0.0001). Moreover, the male patients carrying the T allele were born significantly more often in June–November compared with other months of the year [odds ratio = 3.92 (95% confidence interval = 1.025– 15.018), P= 0.046]. No association was determined, how- ever, between the NOTCH4 gene polymorphism under study and schizophrenia. Conclusion The NOTCH4 T-25C polymorphism has an important effect on the age of onset in schizophrenia and thus may be related to an early pathogenesis of schizophrenia in young patients. Alternatively, these findings may represent a significant genetic marker for managing subgroups and etiological clues in schizo- phrenia. Psychiatr Genet 13:61–64  c 2003 Lippincott Williams & Wilkins. Psychiatric Genetics 2003, 13:61–64 Keywords: schizophrenia, NOTCH4, onset, gender, seasonal, association study a University of Tampere, Medical School, Tampereen yliopisto, Finland, b Tampere Community Mental Health Care, Tampere, Finland, c Tampere University Hospital, Department of Psychiatry, Pitka ¨ niemi, Finland, d Laboratory of Atherosclerosis Genetics, Department of Clinical Chemistry, Centre for Laboratory Medicine, Tampere University Hospital, Tampere, Finland and e Etela ¨ -Pohjanmaa Central Hospital, Seina ¨ joki, Finland. Sponsorship: This research was supported by grants from the Scandinavian College of Neuro-Psychopharmacology (Lundbeck Foundation) and the Medical Research Fund of the Tampere University Hospital. Correspondence to Sami Anttila, MD, Department of Psychiatry, Tampere University Hospital, Fin-33380 Pitka ¨ niemi, Finland. Tel: + 358 50 5695181; fax: + 358 3 2473610; e-mail: samia@koti.tpo.fi Received 1 February 2002 Accepted 26 June 2002 Introduction The NOTCH4 gene is located on a small arm of chromosome 6 (6p21.3), a locus associated with genetic susceptibility to schizophrenia. This gene is a candidate gene for schizophrenia due to its chromosomal location and neurobiological roles. NOTCH activity affects the implementation of differentiation, proliferation, and apoptotic programs, influencing organ formation and morphogenesis (Imai et al., 2001). In a previous study, NOTCH4 gene polymorphisms were highly associated with schizophrenia (Wei and Hemmings, 2000). One very recent study could replicate the finding in a combined sample of 60 mixed Caucasian and 96 Portuguese families with schizophrenia (Klempan et al., 2001). On the contrary, these results could not been replicated in most other previous studies (Imai et al., 2001; McGinnis et al., 2001; Sklar et al., 2001; Ujike et al., 2001). In Japan, Imai et al. (2001) could find no association between the triplet repeat (CTG) n polymorphism in the NOTCH4 gene and schizophrenia subtypes, longitudinal disease course characteristics, or positive family history of the patients. Sklar et al. (2001) genotyped three independent family-based samples (German, German Israeli and Bulgarian) but could not confirm the original finding made by Wei and Hemmings (2000). In a large sample (300 schizo- phrenics and 601 controls) of Scottish patients, no association could be found between (CTG) n and (TAA) n polymorphism (McGinnis et al., 2001). Ujike et al. (2001) re-examined the finding in a Japanese population: SNP1 in the 5 0 flanking region, SNP2 in the promoter region and CTG repeats in exon 1 of the NOTCH4 gene of schizophrenics (n= 188) and of patients with schizoaffective disorder (n= 39). There was no association between these NOTCH4 polymorph- isms and schizophrenia subcategories, hebephrenic and paranoid-type schizophrenia, or with subgroups of schizo- phrenia with and without a positive family history of psychoses. 0955-8829  c 2003 Lippincott Williams & Wilkins DOI: 10.1097/01.ypg.0000056681.82896.6b Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.