GENETICS OF NERVOUS SYSTEM DISEASES NEUROREPORT 0959-4965 & Lippincott Williams & Wilkins Vol 11 No 9 26 June 2000 2017 Association analysis of the 5-HT 5A gene in depression, psychosis and antipsychotic response Joseph T. Birkett, Maria J. Arranz, Janet Munro, Sarah Osbourn, Robert W. Kerwin and David A Collier 1,CA Section of Clinical Neuropharmacology and 1 Section of Molecular Genetics, Division of Psychological Medicine, Institute of Psychiatry, De Crespigny Park, Denmark Hill, London SE5 8AF, UK and 2 Department of Psychological Medicine CA Corresponding Author Received 23 March 2000; accepted 11 April 2000 The serotonergic system is targeted by both antidepressants and atypical antipsychotic drugs such as clozapine. Genetic variation in the 5-HT 5A gene might be involved in susceptibility to depression, the major psychoses or in in¯uencing clinical response to treatment. To examine this hypothesis we genotyped two polymorphisms (19G/C; 12A/T) in the human 5-HT 5A receptor gene in a sample of 269 unrelated schizo- phrenic patients treated with clozapine, 112 bipolar patients, 75 unipolar patients and 187 controls. After ®ve-fold correc- tion for multiple testing, allelic association was found with the 19G/C polymorphism and bipolar affective disorder, ( p  0.025; OR 0.56), unipolar depression ( p  0.004; OR 0.52) and schizophrenia ( p  0.036; OR 0.67) indicating a potential protective effect of the G19 allele. For the 12A/T polymorphism allelic association was observed with unipolar depression only ( p  0.004). We conclude that allelic variation in the human 5-HT 5A receptor gene may be involved in susceptibility to schizophrenia and affective disorders but not in determining response to clozapine. NeuroReport 11:2017± 2020 & 2000 Lippincott Williams & Wilkins. Key words: Atypical neuroleptics; Neurotransmitter receptor; Pharmacogenetics; Psychosis; Serotonin INTRODUCTION The major psychoses (schizophrenia and bipolar affective disorder) are complex genetic disorders, with estimates of heritability up to 85% [1,2]. Unipolar depression is also heritable, but the extent of the genetic contribution is less clear, with estimates of heritability ranging from 36±44% in community-based samples [3] to 66±70% in hospital- ascertained cases [4,5]. There are likely to be common genetic factors shared across the psychoses and affective disorders, since family history of depression is moderately elevated in schizophrenia and highly elevated in bipolar disorder. Furthermore, common loci of genetic linkage, such as chromosome 22q12q13, are seen for both bipolar and schizophrenia [6]. An alternative method of ®nding susceptibility alleles for complex disorders is candidate gene analysis. There is evidence to suggest that dysfunction of the serotonergic neurotransmitter system plays an important role in the pathophysiology of affective disorders [7,8] and schizo- phrenia [8±10]. The serotonin system has attracted most interest as a candidate for aetiological involvement in affective disorders, since antidepressants which inhibit serotonin reuptake or agonise its receptors are ef®cacious in treatment [11]. Some studies have also reported bio- chemical abnormalities in the serotonin system in affective disorders. The most consistent ®nding is that relapse of depression can be triggered by depletion of the amino acid tryptophan, the amino acid precursor of serotonin [12±14]. Furthermore the slower rate of serotonin synthesis in women than in men [15] and regulation of receptor expres- sion by sex steroids [16] might explain the gender differ- ences in the prevalence of depression. A role for pathological changes in the serotonergic system itself in depression is less clear, but include reductions in levels of 5-HT, its metabolite 5-hydroxyindoleacetic acid (5-HIAA), alterations in 5-HT receptors, and peripheral changes in reuptake, receptors density and whole blood serotonin concentration [17,18]. Many antidepressants have been reported to reduce the functional activity of 5-HT 2 recep- tors and altered numbers of 5-HT 2 receptors have been observed in the brains of bipolar patients and in those who commit suicide [19,20]. The serotonin system is also implicated in the aetiology of schizophrenia [21]. Evidence supporting a role for serotonin comes from the ef®cacy of atypical antipsycho- tics, which bind to a variety of its receptor subtypes with high af®nity [9]. Serotonergic receptors have also been shown to be involved in abnormalities of sensorimotor gating and evidence suggests that this process is abnormal in schizophrenic subjects [22]. 5-HT5A is expressed exclu-