Scientific Correspondence 930 Molecular Psychiatry with PD ( 2 = 5.14, 1 df, 2 P = 0.02), suggesting a tend- ency to heterozygosity in PD (Table 1). To date, most of the efforts to elucidate the genetic factors underlying PD have been focused on genes whose products are involved in its pathophysiology or that could mediate the biological effects caused by pan- icogenic agents. Changes in the expression or function of NTRK3 may alter synaptic plasticity through the change of local trophic support. This could possibly cause the abnormal release rates of certain neuro- transmitters, like NA, in target areas that lead to the alteration of the individual’s arousal threshold. The SNP we found more frequently in the PD sample is located in the putative promoter region of the gene, giv- ing support to the hypothesis that the alteration of the normal amounts of messenger could participate in the pathophysiology of PD. Since most samples used in our study also have DUP25, the 5′ UTR SNP described above might be one of several genetic factors that con- tribute to modify the development and severity of panic disorder. L Armengol 1 , M Grataco `s 1 , MA Pujana 1 , M Ribase ´ s 1 , RMartı´n-Santos 2 and X Estivill 1 1 Genes and Disease Program, Genomic Regulation Center (CRG), 08003 Barcelona, Catalunya, Spain; 2 Department of Psychiatry, Hospital del Mar, 08003 Barcelona, Catalunya, Spain Correspondence should be addressed to X Estivill. E-mail: xavier. estivillcrg.es/estivilliro.es 1 Weissman MM et al. Arch Gen Psychiatry 1997; 54: 305–309. 2 Charney DS et al. J Clin Psychiatry 1990; 51 Suppl A: 5–11. 3 Bremner JD et al. Synapse 1996; 23: 28–38. 4 Crowe RR et al. Arch Gen Psychiatry 1983; 40: 1065–1069. 5 Maier W et al. J Psychiatr Res 1993; 27 Suppl 1: 79–87. 6 Gratacos M et al. Cell 2001; 106: 367–379. 7 Hattori M, Nanko S. Biochem Biophys Res Commun 1995; 209: 513–518. 8 Nanko S et al. Acta Psychiatr Scand 1994; 89: 390–392. Analysis of structural polymorphisms and C-1018G promoter variant of the 5-HT 1A receptor gene as putative risk factors in major depression Molecular Psychiatry (2002) 7, 930–932. doi:10. 1038/sj.mp.4001146 SIR – Alterations in the serotonergic system have been related to the origin of depression. The serotonin 1A receptor gene is a strong candidate for major depression because of involvement in antidepressant response and control of intersynaptic serotonin release. Genetic alterations in the 5-HT 1A gene may be related to the receptor involvement in depression. A sample of 249 patients with major depression and 170 controls were analysed for four different polymorphisms of the 5-HT 1A receptor gene. No differences in genotype or allele frequencies were found between patients and controls. Our results suggest that genetic variability in the 5-HT 1A receptor gene does not play a major role in the aetiology of major depression. Serotonin neurotransmission is involved in the regu- lation of mood, sleep, vigilance, memory and learning, feeding and sexual behaviour. All those functions have found to be altered to varying extents in depressed patients. The serotonin 1A receptor has been postu- lated as playing a major role in anxiety, depression and other psychiatric disorders. 1 This receptor regulates the firing of serotonergic neurones and mediates the action of non-serotonergic neurones prominently in the limbic regions. 2 Moreover, the 5-HT 1A receptor has been hypothesised to have an important role in the modulation of clinical response to antidepressant drugs. Long-term treatment with SSRIs desensitises the somatodendritic 5-HT 1A receptors leading to an enhanced release of serotonin. 3 In addition, it has been reported that a combination of SSRI drugs and block- ade of these receptors may accelerate the therapeutic efficacy in depressive patients. 4 All these facts lead us to consider the 5-HT 1A receptor gene as a good candi- date gene for association studies in major depression. The 5-HT 1A receptor gene (chromosome 15q11) is intronless and codes a 422-amino acid protein. 5 A number of low frequency single nucleotide polymor- phisms (SNPs) have been described on this gene. 6,7 Pre- vious association studies investigating the putative role of the 5-HT 1A receptor gene in schizophrenia and major depression have failed to demonstrate any relation between these polymorphisms and the disorders. 6–8 Recently, a novel and relatively common polymor- phism (C-1018G) that may provide useful information on the involvement of this receptor gene in mental dis- orders, has been described on the promoter region of the 5-HT 1A receptor gene. 9 We hypothesised that genetic variation in the 5-HT 1A receptor gene could be involved in the aetiology of major depression or in clinical features related to this complex disorder. To test this hypothesis, we have per- formed individual association studies of the novel pro- moter region polymorphism C-1018G and three pre- viously reported structural polymorphisms (Ile28Val, Asp272Gly, and Pro16Leu) in a large sample of depressive patients. Two hundred and forty-nine unrelated patients (64 men and 185 women; mean age: 46.6 ± 10.09) with major depression from the Mental Health Service of the Eixample District (Barcelona, Spain) were included in the study. Major depression was diagnosed according to DSM-IV 10 criteria and the Spanish version of the Structural Clinical Interview for DSM-III-R (SCID) was used for this purpose. 11 One hundred and seventy healthy individuals (89 males and 81 females; mean age: 38.2 ± 10.35) were recruited as controls. Patients and control subjects