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Association of Unipolar Major Depressive Disorder with Genes Of Molecular Psychiatry (1999) 4, 389–392 1999 Stockton Press All rights reserved 1359–4184/99 $15.00 seem to be good candidates for mediating genetic sus- ORIGINAL RESEARCH ARTICLE ceptibility to MDD. Association of polymorphisms in seven genes from the serotonergic and dopaminergic pathways was stud- Association of unipolar ied in 102 unipolar patients and 172 healthy control major depressive disorder subjects. The patient population was subdivided according to ethnic origin (63 Ashkenazi and 39 non- with genes of the Ashkenazi Jews) and compared to the corresponding group of mentally healthy controls. The distribution of serotonergic and genotypes and alleles in the different populations is shown in Table 1. Comparison of healthy individuals dopaminergic pathways of Ashkenazi and non-Ashkenazi origin revealed that 1,2 3 1,2 although frequencies of genotypes and alleles showed A Frisch , D Postilnick , R Rockah , some differences, they did not reach statistical signifi- 1,2 4 3 E Michaelovsky , S Postilnick , E Birman , cance. Nevertheless, in order to avoid possible errors 2,5 3 4 N Laor , B Rauchverger , A Kreinin , caused by population stratifications we compared the M Poyurovsky4, M Schneidman4, I Modai2,3 patients with their ethnic counterparts. and R Weizman2,5 When unipolar MDD patients were compared to healthy controls of the same ethnic origin (Table 1), the 1 Laboratory of Biochemical Genetics, Felsenstein Medical distribution of genotypes and alleles of the seven poly- Research Center, Rabin Medical Center, Petah Tikva; morphisms studied (TPH, HTR2A, HTR2C, 5-HTTLPR, 2 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv; DAT1, DRD4 and COMT) did not show statistically sig- 3 4 Shaar Menashe Mental Health Center, Hadera; Tirat nificant differences. 5 Hacarmel Medical Health Center, Haifa; Tel Aviv Mental Molecular genetic studies in mood disorders perfor- Health Center, Tel Aviv, Israel med thus far, have focused mainly on bipolar depression (BPI and BPII). Association studies of uni- polar depression with several polymorphisms were Keywords: major depressive disorder (MDD); tryptophan hydroxylase (TPH); serotonin transporter promoter region performed previously with conflicting results. The (5-HTTLPR); serotonin receptor 2A (HTR2A); serotonin allelic distribution of the insertion/deletion polymor- receptor 2C (HTR2C); catechol-O-methyl transferase phism in the promoter region of the serotonin trans- (COMT); dopamine D4 receptor (DRD4); dopamine trans- porter (5-HTTLPR) in MDD patients was investigated porter (DAT1) by several groups of researchers. Our results are similar to those of Kunugi et al,5 Rees et al,6 Furlong et al7 and Major depressive disorder (MDD) is a severe psychiatric 8 disorder with a lifetime prevalence of about 15%.1 The Hoehe et al, who found no association of this poly- importance of the genetic component is well accepted,2 morphism with unipolar MDD in Japanese, UK and but the mode of inheritance is complex and non-Mendel- West European populations respectively. In contrast, a ian. A line of evidence suggests the involvement of European multi-center study (Collier et al9) and a meta- serotonin and dopamine neurotransmitters in the patho- analysis of individuals of European Caucasian origin7 physiology of depression. In the present study, 102 uni- reported an increased frequency of the short allele in polar MDD patients and 172 healthy controls were geno- bi- and unipolar depressed patients, whereas a typed for polymorphisms in four serotonergic and three decrease of this allele was reported in a subgroup of dopaminergic candidate genes [tryptophan hydroxylase unipolar probands.6 The fact that three different results (TPH), serotonin receptor 2A (HTR2A), serotonin recep- were obtained in different populations, shows that tor 2C (HTR2C), serotonin transporter promoter region these associations may be the result of a linkage dis- (5-HTTLPR), dopamine receptor D4 (DRD4), dopamine transporter (DAT1) and catechol-O-methyl transferase equilibrium with as yet unknown population-specific (COMT)]. There were no statistical differences between mutations, rather than a consequence of the proposed 9 MDD patients and healthy controls in the genotypic and biological activity of the different alleles. allelic distribution of all polymorphisms investigated. With regard to the other components of the sero- Thus, our study does not support a major role for these tonergic system, Zhang et al,10 found an increase in the polymorphisms in contributing to susceptibility to MDD, T102 allele of HTR2A (C1 allele in our terminology) although it does not preclude minor effects. in unipolar depressed patients. We also noted such an Pharmacological studies have suggested that MDD is increase, but it was not statistically significant. The associated with an impairment of brain neurotransmit- lack of association of TPH with unipolar depression in ters. The role of serotonin (5-HT), which is based the present study is in accordance with the results of mainly on the efficacy of selective and nonselective 5- Furlong et al.11 HT reuptake inhibitors in the treatment of MDD, was Manki et al12 reported an association between the reviewed by Maes and Meltzer.3 Dopamine (DA), has DRD4 alleles and major depression in Japanese sub- also been implicated in the pathophysiology of mood jects, with a decrease in allele 4 and an increase in disorders and hypoactivity of the mesolimbic DA path- allele 5 in the patient population. Oruc et al13 found way may be connected to depressive symptoms.4 Thus, no association of recurrent unipolar depression with genes that control the brain 5-HT and DA pathways DRD4 alleles in a Croatian population. In our study, Association of depression with 5-HT and DA genes A Frisch et al 390 Table 1 Distribution of genotypes and alleles in unipolar MDD patients and healthy controls Genotypes Alleles TPH CC CA AA n C (%) A (%) n Control-Ash 24 54 34 112 102 (46) 122 (54) 224 MDD-Ash 10 32 19 61 52 (43) 70 (57) 122 Control-non Ash 22 31 7 60 75 (63) 45 (37) 120 MDD-non Ash 9 20 8 37 38 (51) 36 (49) 74 HTR2A C1C1 C1C2 C2C2 n C1 (%) C2 (%) n Control-Ash 26 49 37 112 101 (45) 123 (55) 224 MDD-Ash 18 28 15 61 64 (53) 58 (47) 122 Control-non Ash 20 28 12 60 68 (57) 52 (43) 120 MDD-non Ash 16 17 5 38 49 (65) 27 (35) 76 5-HTTLPR SS SL LL n S (%) L (%) n Control-Ash 28 60 24 112 116 (52) 108 (48) 224 MDD-Ash 15 26 22 63 56 (44) 70 (56) 126 Control-non Ash 11 36 13 60 58 (48) 62 (52) 120 MDD-non Ash 7 24 8 39 38 (49) 40 (51) 78 HTR2C CSn (M) CC CS SS n (F) C (%) S (%) n Control-Ash 41 17 58 37 17 – 54 132 (80) 34 (20) 166 MDD-Ash 19 3 22 22 17 2 41 80 (77) 24 (23) 104 Control-non Ash 11 5 16 29 13 2 44 82 (79) 22 (21) 104 MDD-non Ash 5 1 6 21 11 1 33 58 (80) 14 (20) 72 DAT1 9/9 9/10 10/10 others n 9 (%) 10 (%) others n Control-Ash 13 48 44 6 111 77 (35) 139 (62) 6 (3) 222 MDD-ASH 8 38 15 2 63 54 (43) 69 (55) 3 (2) 126 Control-non Ash 11 17 27 4 59 39 (33) 75 (63) 4 (3) 118 MDD-non Ash 5 17 12 5 39 29 (37) 43 (55) 6 (8) 78 DRD4 2/2 2/4 4/4 4/7 7/7 others n 2 (%) 4 (%) 7 (%) others n Control-Ash 1 8 59 31 8 5 112 10 (4) 160 (71) 48 (21) 6 (3) 224 MDD-Ash – 11 30 14 5 3 63 12 (9) 86 (68) 24 (19) 4 (3) 126 Control-non Ash – 5 25 19 1 10 60 11 (9) 78 (65) 27 (22) 4 (3) 120 MDD-non Ash 1 7 17 9 – 4 38 9 (12) 53 (70) 10 (13) 4 (5) 76 COMT AA AB BB n A (%) B (%) n Control-Ash 34 52 26 112 120 (54) 104 (46) 224 MDD-Ash 19 36 8 63 74 (59) 52 (41) 126 Control-non Ash 14 37 9 60 65 (54) 55 (46) 120 MDD-non Ash 8 25 6 39 41 (53) 37 (47) 78 F, female. M, male. overall differences in allelic distribution did not reach population helping to reduce artifacts stemming from statistical significance, although a trend of an increase population stratification. of allele 2 and a decrease of allele 7 in depressed The fact that we had tested our sample with a rela- patients was noted. This might be just a spurious result tively large number of candidate genes, allowed us to but, if replicated in a larger sample it may support the explore the role of both serotonergic and dopaminergic notion that large alleles of DRD4 are associated with genes in depression. The drawback of such study ‘novelty seeking’ traits. design is that testing more parameters entails stringent Ohara et al14 found an association of the low activity statistical requirements thus increasing the risk of a allele of COMT with depressive disorder in Japanese type II error of overlooking genuine effects.15 patients. We could not replicate this finding in our In summary, our study does not support a major role sample. To our knowledge no association studies of for any of the polymorphisms studied in unipolar MDD unipolar disorder were performed with the serotonin patients of Ashkenazi and non-Ashkenazi origin. This receptor 2C (HTR2C) and dopamine transporter does not imply that polymorphisms in serotonergic (DAT1). and dopaminergic genes do not contribute to the sus- In this study we divided the Israeli-Jewish popu- ceptibility to MDD, but rather that we should expect lation into two ethnic groups of Ashkenazi and non- minor effects, probably synergistic, dependent on a Ashkenazi origin.
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