Interaction between NOTCH4 and catechol-O- methyltransferase genotypes in schizophrenia patients with poor response to typical neuroleptics Sami Anttila a,c , Ari Illi a,b , Olli Kampman a,e , Kari M Mattila a,c , Terho Lehtima ¨ki a,c and Esa Leinonen a,d Objective: In this study we attempted to show that the interaction between NOTCH4 and catechol-O- methyltransferase (COMT) polymorphism predicts the response to typical neuroleptics in schizophrenia. Our sample consisted of 94 Finnish patients with DSM-IV schizophrenia and 98 controls. Methods: Several studies have connected COMT and NOTCH4 genes to schizophrenia. We have previously shown that COMT polymorphism is significantly associated with treatment response in schizophrenia. NOTCH4 SNP2 polymorphism has been associated with age of onset in schizophrenia, but there is also a trend that this polymorphism may predict response to typical neuroleptics. In the present sample, there is a strong gene- gene interaction between these genes (P 0.003) and they have additive effect in treatment response. Results: Patients carrying both NOTCH4 C/C genotype and COMT low/low genotype, had more than ten times higher risk of being a non-responder than responder to treatment with typical neuroleptics [OR 10.25 (95% CI 2.21–47.53), P < 0.001]. This combination of genotypes is also more common in patients considered non-responders than in controls [OR 3.00 (95% CI 1.33–6.76), P 0.007]. Conclusion: Our results suggest that an interaction between COMT and NOTCH4 genotypes may predict the treatment response to typical neuroleptics in patients with schizophrenia. Pharmacogenetics 14:303–307 & 2004 Lippincott Williams & Wilkins Pharmacogenetics 2004, 14:303–307 Keywords: NOTCH4, COMT, treatment response, typical neuroleptic, polymorphism, schizophrenia a University of Tampere, Medical School, 33014 University of Tampere, Finland, b Kanta-Ha ¨ me Central Hospital, Department of Psychiatry, 13530 Ha ¨ meenlinna, Finland, c Laboratory of Atherosclerosis Genetics, Department of Clinical Chemistry, Centre for Laboratory Medicine, Tampere University Hospital, Teiskontie 35, PL 2000, 33521 Tampere, Finland, d Department of Psychiatry, Tampere University Hospital, 33380 Pitka ¨ niemi, Finland and e Seina ¨ joki Hospital District, Department of Psychiatry, Hanneksenrinne 7, 60220 Seina ¨ joki, Finland. Correspondence: Sami Anttila, MD, Dept. of Psychiatry, Tampere University Hospital, FIN-33380 Pitka ¨ niemi, Finland. Tel.: +358–50–5695181; fax: +358–3–2473610; e-mail: samia@koti.soon.fi Received 21 October 2003 Accepted 10 March 2004 Introduction The NOTCH4 and catechol-O-methyltransferase (COMT) genes have been associated with the risk of schizo- phrenia as well as modifying effects in the disease. The original finding of Wei and Hemmings [1] showed a strong association between NOTCH4 polymorphism and schizophrenia. In most subsequent studies, their finding could not been replicated (for a review, see Skol et al. [2]). If the association between NOTCH4 polymorphism and schizophrenia was replicated, the statistical signifi- cance was markedly weaker than in the original study by Wei and Hemmings [2]. The actions of COMT and NOTCH4 make them significant candidates for the etiology and pathology of schizophrenia. COMT affects the levels of dopamine, especially in the prefrontal cortex, indicating that low activity of the COMT gene may result in an override of dopamine in the synaptic cleft that can not be compen- sated by antipsychotics [3]. Notch signaling regulates the generation of neurons and glia from neural stem cells and, thus, has an important role in the develop- ment of the central nervous system [4]. Moreover, both of these genes are candidate genes for schizophrenia. NOTCH4 gene is located in the region of 6p21.3, which several linkage studies have suggested to be a suscept- ibility locus for schizophrenia [1]. The chromosomal location of COMT gene, 22q11, was shown in a meta- analysis to be one of the three most promising regions for risk genes for schizophrenia [5]. Moreover, patients with velocardiofacial syndrome have microdeletions in this region, and significantly higher rates of schizophre- nia [6]. One previous study showed that NOTCH4 allelic varia- bility was correlated with differences in measures of frontal lobe cognitive performance and frontal lobe brain tissue volumes in schizophrenia patients [7]. Two studies found an association between NOTCH4 poly- morphism and the age of onset in schizophrenia Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Original article 303 0960-314X & 2004 Lippincott Williams & Wilkins DOI: 10.1097/01.fpc.0000114735.08559.83