Begoña Paredes

Association study between obsessive-compulsive disorder and serotonergic candidate genes.

BACKGROUND To date, research examining the relationship between serotonergic genes and obsessive-compulsive disorder (OCD) has yielded conflicting results. The purpose of this study is to investigate the association between four serotonergic polymorphisms (STin2 VNTR and 5-HTTLPR of the SLC6A4 gene, and A-1438G (rs6311) and T102C (rs6313) of the HTR2A gene) and OCD. METHODS 99 OCD patients, 456 non-OCD psychiatric patients, and 420 healthy controls from a homogeneous Spanish Caucasian population were genotyped using standard methods. RESULTS All groups showed Hardy-Weinberg equilibrium for the analyzed genetic variability. A-1438G and T102C polymorphisms were in complete linkage disequilibrium. OCD patients showed an excess of STin2.12 carriers (12/12, 12/10, and 12/9 genotypes) compared with healthy controls (chi(2) (1)=7.21, corrected p=0.021; OR=3.38, 95% CI=1.32-8.62) and non-OCD psychiatric patients (chi(2) (1)=6.70, corrected p=0.030; OR=3.24, 95% CI=1.27-8.26). However, no differences were found between non-OCD patients and healthy controls (chi(2) (1)=0.05, corrected p>1; OR=1.04, 95% CI=0.72-1.51). No significant differences were found with respect to A-1438G and 5-HTTLPR polymorphisms. CONCLUSIONS Our data provide supporting evidence of an association between the STin2 VNTR polymorphism of the SLC6A4 gene and OCD.

Association between the A-1438g polymorphism of the serotonin 2a receptor gene and nonimpulsive suicide attempts

Objective To investigate the association between four serotonergic polymorphisms [A-1438G (rs6311) and T102C (rs6313) of the serotonin 2A receptor gene, and STin2 VNTR and 5-HTTLPR of the SLC6A4 gene] and suicidal behavior. Participants and methods One hundred and ninety-three suicide attempters (SA) and 420 unrelated healthy controls from Asturias (Northern Spain) were genotyped using standard methods. Results A-1438G and T102C polymorphisms were in complete linkage disequilibrium in our population. Genotype and allele distributions showed no differences between SA and control participants. In nonimpulsive suicide attempts, however, we found an excess of the -1438A allele as compared with impulsive suicide attempts and the control group [χ2(2)=11.92, corrected P=0.021]. No other differences were found with regard to the impulsivity of the attempt. An excess of short allele carriers were found in the group of SA with high clinical lethality as compared with the low-lethality group [χ2(1)=4.93, P=0.026, not significant after Bonferroni correction]. The haplotype analysis showed no association between suicide attempt and haplotype distribution [likelihood ratio test (5)=4.40, P=0.493]. Conclusion Our findings suggest that the -1438A allele may predispose for nonimpulsive suicidal behavior.

Role of serotonergic-related systems in suicidal behavior: Data from a case-control association study

OBJECTIVE To investigate whether functional polymorphisms directly (HTR2A and SLC6A4 genes) or indirectly (IL-1 gene complex, APOE and ACE genes) related with serotonergic neurotransmission were associated with suicidal behavior. SUBJECTS AND METHODS 227 suicide attempters, 686 non-suicidal psychiatric patients, and 420 healthy controls from a homogeneous Spanish Caucasian population were genotyped using standard methods. RESULTS There were no differences in genotype frequencies between the three groups. The -1438A/G [χ(2) (df)=9.80 (2), uncorrected p=0.007] and IL-1α -889C/T [χ(2) (df)=8.76 (2), uncorrected p=0.013] genotype frequencies between impulsive and planned suicide attempts trended toward being different (not significant after Bonferroni correction). Suicide attempts were more often impulsive in the presence of -1438G/G or IL-1α -889C/T or C/C genotypes. There was interaction between the polymorphism 5-HTTLPR and age [LRT (df)=6.84 (2), p=0.033] and between the polymorphisms APOE and IL-1RA (86bp)(n) [LRT (df)=12.21 (4), p=0.016] in relation to suicide attempt lethality. CONCLUSION These findings further evidence the complexity of the association between genetics and suicidal behavior, the need to study homogenous forms of the behavior and the relevance of impulsive and aggressive traits as endophenotypes for suicidal behavior.

Interactions between functional serotonergic polymorphisms and demographic factors influence personality traits in healthy Spanish Caucasians.

Background Data from epidemiological genetic studies suggest that variability in personality traits is explained, at least partly, by genetic factors. Recently, a growing number of molecular genetic studies have suggested the involvement of the serotonin system in specific traits. Objective To investigate the association between three serotonergic polymorphisms [A-1438G (rs6311) of the HTR2A gene, and STin2 VNTR and 5-HTTLPR of the SLC6A4 gene] and personality traits assessed with the Temperament and Character Inventory. Materials and methods Four hundred and four unrelated healthy volunteers [50% males, mean age (standard deviation)=40.5 (11.3)] from Asturias (northern Spain) were genotyped using standard methods. Cloningers Temperament and Character Inventory was used for investigation of temperament and character traits. Results The genetic variants were in Hardy–Weinberg equilibrium and genotypic frequencies were similar in both the sexes. 5-HTTLPR was associated with a direct effect on self directedness (F=6.20, P=0.002), and interacting with educational level (F=3.10, P=0.016) and A-1438G (F=3.34, P=0.011) with respect to novelty seeking. STin2 VNTR interacted with age in relation to reward dependence (F=2.74, P=0.013) and with sex in relation to cooperation (F=5.10, P=0.007). In addition, SLC6A4 haplotypes had significant effects on harm avoidance (lower in volunteers with L12), self directedness (higher in volunteers with L12), and self transcendence (higher in volunteers with S10). Conclusion Our findings suggest a strong genetic component in personality traits manifested primarily through interaction effects that occur between genetic factors alone and between genetic and demographic factors.

Association study of the interleukin-1 gene complex and tumor necrosis factor alpha gene with suicide attempts

To investigate the association between four functional polymorphisms in interleukin-1 (IL-1) [IL-1&agr; −889 C/T, IL-1&bgr; +3953 C/T, IL-1RA (86 bp)n] and tumor necrosis factor alpha (TNF&agr;) (−308A/G) genes and suicide attempts. Distribution of the aforesaid polymorphisms was analyzed in 193 suicide attempters compared with 420 unrelated healthy controls from Asturias (Northern Spain). Genotypes were determined using standard methods. No significant differences were found in genotype or in allelic distribution of IL-1&agr;, IL-1&bgr;, IL-1RA, or TNF&agr; gene polymorphisms. No relationship was found between genotypes and the impulsivity of the suicide attempt. Estimated IL-1 haplotype frequencies were similar in both groups (likelihood ratio test=13.26, df=14, P=0.506). Our data do not suggest that genetically determined changes in the IL-1 or TNF&agr; genes confer increased susceptibility to suicidal behavior.

Lack of association between endothelial nitric oxide synthase (NOS3) gene polymorphisms and suicide attempts

ObjectiveThe aim of this study is to investigate the association between two polymorphisms of endothelial nitric oxide synthase (NOS3) and suicide attempts.MethodsWe genotyped 186 suicide attempters and 420 unrelated healthy controls. The following polymorphisms were analysed: T-786C and 27-bp repeat in intron 4.ResultsNo significant differences were found in genotype or in allelic distribution of the aforesaid polymorphisms. There were also no differences in the genotype distribution or allelic frequencies when separately assessing males and females or impulsive and non-impulsive attempters and normal controls. Estimated haplotype frequencies were similar in both groups.ConclusionOur data do not support the hypothesis that genetically determined changes in the NOS3 gene confer increased susceptibility for suicidal behavior.

Implicación de polimorfismos serotoninérgicos en la gravedad clínica del trastorno de pánico

OBJECTIVES To investigate the association between three serotonergic polymorphisms (A-1438G [rs6311] of the HTR2A gene, STin2 VNTR and 5-HTTLPR of the SLC6A4 gene) and the severity of panic and depression symptomatology among mental health outpatients with diagnosis of panic disorder (PD). METHODS 92 unrelated PD outpatients (DSM-IV criteria) from a homogeneous Spanish Caucasian population (mean age±SD, 35.9±12.4 years; 28 [30.4%] males) were assessed using the Panic and Agoraphobia Scale (PAS), and the Hamilton Depression Rating Scale (HDRS), and genotyped using standard methods. RESULTS Age of onset of PD varied by STin2 VNTR genotype (F=3.21; p=0.045). On average, onset of PD occurred earlier for those with the 10/10 than for those with the 12/12 genotype (25.1 νs 33.3; p=0.043). No relationship was found between A-1438G, 5-HTTLPR, and STin2 VNTR genotypes and PAS or HDRS total scores. Variation in scores on the HDRS Anxiety subscale by A-1438G genotype almost reached statistical significance (F=3.03; p=0.053). Post hoc pairwise comparisons showed higher anxiety levels among A/G than among A/A carriers (4.1 νs 2.9; p=0.043). Finally, variation in scores on the Preoccupied with Health subscale of the PAS by 5-HTTLPR genotype approached statistical significance (F=2.56; p=0.083). Post hoc pairwise comparisons showed higher scores among L/S than among L/L carriers (2.4 νs 1.4; p=0.078). CONCLUSIONS Our data provide support of an involvement of the serotonin system, particularly, the HTR2A gene in the severity of PD.

Role of serotonergic polymorphisms in the clinical severity of the panic disorder.

Introduction and objectives: To investigate the association between three serotonergic polymorphisms (A-1438G (rs6311) of the HTR2A gene, STin2 VNTR and 5-HTTLPR of the SLC6A4 gene) and the severity of panic and depression symptomatology among mental health outpatients with diagnosis of panic disorder (PD). Methods: 92 unrelated PD outpatients (DSM-IV criteria) from a homogeneous Spanish Caucasian population (mean age ± SD, 35.9 ± 12.4 years; 28 (30.4%) males) were assessed using the Panic and Agoraphobia Scale (PAS), and the Hamilton Depression Rating Scale (HDRS), and genotyped using standard methods. Results: Age of onset of PD varied by STin2 VNTR genotype (F = 3.21; p = 0.045). On average, onset of PD occurred earlier for those with the 10/10 than for those with the 12/12 genotype (25.1 versus 33.3; p = 0.043). No relationship was found between A-1438G, 5-HTTLPR, and STin2 VNTR genotypes and PAS or HDRS total scores. Variation in scores on the HDRS Anxiety subscale by A-1438G genotype almost reached statistical significance (F = 3.03; p = 0.053). Post hoc pairwise comparisons showed higher anxiety levels among A/G than among A/A carriers (4.1 versus 2.9; p = 0.043). Finally, variation in scores on the Preoccupied with Health subscale of the PAS by 5-HTTLPR genotype approached statistical significance (F = 2.56; p = 0.083). Post hoc pairwise comparisons showed higher scores among L/S than among L/L carriers (2.4 versus 1.4; p = 0.078).