صفات ژنتیک و شخصیتی در بیماران مبتلا به اختلال اضطراب اجتماعی: یک مطالعه مورد شاهدی در آفریقای جنوبی

Abstract Background Social anxiety disorder (SAD) is among the most common of all psychiatric disorders with lifetime prevalence estimates ranging from 7% to 13%. Although there is evidence that SAD has a strong familial basis, there are few studies of potential candidate genes. In addition to a genetic association, there is also the possibility that temperamental risk factors for the disorder may be genetically transmitted. Against this background, our aims were threefold: i.) to compare patients and controls with respect to personality traits, ii.) to genotype a subgroup of these participants to investigate the role of genes encoding components of serotonergic (5-HT) and dopaminergic (DA) pathways in patients with SAD and iii.) to compare differences in temperament dimensions between carriers of different (dominant vs. recessive) alleles for selected polymorphisms in SAD patients. Methods Sixty-three patients (n = 63; 35 male, 28 female) with a DSM-IV diagnosis of generalized SAD and SPIN-scores > 18, and age-matched control participants (n = 150; 31 male, 119 female) were included in the study. The Temperament and Character Inventory (TCI) was used to measure behaviours associated with specific personality dimensions (i.e. temperament/character). DNA was extracted and genotyped to investigate the role of select candidate genes encoding components in serotonergic and dopaminergic pathways in mediating the development of SAD. To achieve this, the frequency of variants in 5-HT and DA genes was compared between a Caucasian subset of SAD patients (n = 41) and a convenience sample of Caucasian controls (n = 88), using case-control association analyses. We also investigated the frequency of variants in 5-HT and DA-related genes across temperament characteristics in SAD patients, using analyses of variance (ANOVA). Results Patients scored significantly higher on harm avoidance (p < 0.001) but lower on novelty seeking (p = 0.04) and self-directedness (p = 0.004) compared to controls. In the Caucasian subset, there was a difference between patients and controls in distribution of the 5-HT2AT102C polymorphism, with significantly more patients harboring T-containing genotypes (T-containing genotypes: [T / T + T / C] vs. [C / C]) (χ2 = 7.55; p = 0.012). Temperament dimensions did not, however, differ significantly between carriers of different (dominant vs. recessive) alleles for the 5-HT2AT102C polymorphism in SAD patients. Conclusions The results suggest a possible role for the 5-HT2AT102C polymorphism in the development of SAD. To date genetic findings in SAD have been inconsistent; nevertheless, serotonergic variants, and their associations with temperaments (e.g. reward dependence) deserve further exploration, in the hope that endophenotypes relevant to SAD can ultimately be delineated.

Results 3.1. SAD symptomatology Data obtained from 63 patients with generalized SAD (35 male, 28 female), with ages ranging between 17 and 62 years (mean: 35.22 years, SD: 11.63) were used in the clinical analyses. The mean age of onset of SAD was mid-adolescence (mean: 14.58 years, SD: 7.89). A mean score of 46.89 (SD: 11.6) on the SPIN indicated that the majority of patients had moderate to severe SAD. 3.2. Comorbidity Lifetime axis I and II disorders diagnosed with the highest frequency in the study population were major depressive disorder (MDD; 66.7%), generalized anxiety disorder (GAD; 38.1%), alcohol abuse (20.6%) (or dependence (11.1%)), specific phobia (17.5%), avoidant personality disorder (64.5%) and obsessive–compulsive disorder (9.7%). Current rates of comorbidity were generally much lower than lifetime; in particular with regards to MDD (28.6%), and alcohol abuse (3.2%) and dependence (4.8%). For the genetics analyses, we did not make a distinction between those patients with a diagnosis of SAD only, and those with SAD and one or more comorbid disorders. 3.3. Genetic polymorphisms: SAD patients versus controls Both SAD-affected and control groups were in Hardy–Weinberg equilibrium at each locus investigated. In the Caucasian subset, there was a difference between patients and controls in terms of 5-HT2AT102C, with significantly more patients characterized by T-containing genotypes ([T / T + T / C] vs. [C / C]) (χ2 = 7.55; p = 0.012) ( Table 1 and Table 2). No statistically significant results were obtained for the genetic variants investigated in 5-HTT LPR, TH, DAT, and 5HT1B genes. Table 1. Genotype distribution of the 5-HT2A polymorphism in Caucasians with SAD and controls (if the T-containing genotypes are dominant) 5-HT2A variants SAD patients Controls χ2 P 1.) T / T + T / C 32 (84.2%) 53 (60.2%) 7.54 0.012⁎ 2.) C / C 6 (15.8%) 35 (39.8%) Total 38 88 ⁎ With Bonferroni correction: p = 0.006 × 2: p = 0.012. Table options Table 2. Genotype distribution of the 5-HT2A polymorphism in Caucasians with SAD and controls (if the T-containing genotypes are recessive) 5-HT2A variants SAD patients Controls χ2 P 1.) T / T 7 14 0.12 0.73 2.) T / C + C / C 31 74 Total 38 88 Table options 3.4. Genetic Polymorphisms and TCI dimensions Patients (of all populations) with SAD scored significantly higher on harm avoidance (p < 0.001) but significantly lower on novelty seeking (p = 0.04) and self-directedness (p = 0.004) compared to controls ( Table 3). Findings were similar for the Caucasian subset, i.e. Caucasian patients scored significantly higher on harm avoidance (p < 0.001) but lower on self-directedness (p = 0.006) compared to controls. Table 3. Temperament and Character Inventory: SAD patients vs. controls (all population groups) Temperament / character trait⁎ SAD patients (n = 33) Controls (n = 76) F P NS 15.53 ± 4.07 17.99 ± 6.06 2.66 0.038 HA 26.03 ± 5.22 17.25 ± 9.19 18.74 < 0.001 RD 19.97 ± 4.27 21.65 ± 4.68 0.01 0.078 SD 22.36 ± 8.62 27.55 ± 8.40 0.03 0.004 C 27.74 ± 5.89 29.97 ± 5.32 0.83 0.059 ST 13.64 ± 6.83 16.30 ± 6.23 0.03 0.052 ⁎ NS = novelty seeking total score, SD = self-directedness total score. HA = harm avoidance total score, C = cooperativeness total score. RD = reward dependence total score, ST = self-transcendence total score. Table options In the Caucasian group of patients, we focused the analyses of genes vs. TCI dimensions on the 5-HT2AT102C polymorphism, given i.) the significant finding with 5-HT2A in the categorical analysis (above), and ii.) the low sample size. Before statistically correcting for multiple testing, comparison of the associations between T-containing genotypes, with the C / C genotype of 5-HT2AT102C, and the different temperament dimensions in 21 patients suggested a significant association between decreased reward dependence and the T-containing genotypes ([T / T + T / C] vs. [C / C]) (n = 17; F = 4.49; p = 0.048). However, after correcting for multiple testing, the significance disappeared ( Table 4). Table 4. Associations between dominant and recessive carriers of 5-HT2AT102C and temperament in 21 Caucasian patients with SAD Temperament / character trait⁎ 5-HT2A T102C variant Mean (SD) F F NS [T/T + T/C] 15.41 (3.99) 0.02 NS [C/C] 15.75 (5.5) HA [T/T + T/C] 26.0 (4.92) 0.95 NS [C/C] 28.5 (2.65) RD [T/T + T/C] 19.06 (4.1) 4.49 NS¥ [C/C] 24.0 (4.69) SD [T/T + T/C] 22.71 (9.43) 1.06 NS [C/C] 17.25 (10.01) C [T/T + T/C] 27.25 (6.52) 0.22 NS [C/C] 29.0 (7.35) ST [T/T + T/C] 15.34 (7.72) 2.08 NS [C/C] 8.67 (4.93) ⁎ NS = novelty seeking total score, SD = self-directedness total score. HA = harm avoidance total score, C = cooperativeness total score. RD = reward dependence total score, ST = self-transcendence total score. ¥ After Bonferroni correction.