Juan M. Fernández

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 study of serotonin 2A receptor (5-HT2A) and serotonin transporter (5-HTT) gene polymorphisms with schizophrenia

OBJECTIVE To investigate (i) the association between four serotonergic polymorphisms (A-1438G and T102C of the 5-HT2A receptor gene, and 5-HTT VNTR and 5-HTTLPR of the 5-HT transporter gene) and schizophrenia and (ii) the potential interaction of those polymorphisms in the development of schizophrenia. SUBJECTS AND METHODS 227 outpatients with schizophrenia (DSM-IV criteria) and 420 unrelated healthy controls from Asturias (Northern Spain) were genotyped using standard methods. RESULTS Both groups showed Hardy-Weinberg equilibrium for the analyzed genetic variability. A-1438G and T102C polymorphisms are in complete linkage disequilibrium in our population. There was an apparent difference in the distribution of genotypes for the A-1438G (or T102C) polymorphisms (p=0.018, not significant after a Bonferroni correction). The 5-HT2A -1438A (or 102T) allele was significantly more frequent in patients than controls (0.53 and 0.45, respectively; corrected p=0.028, OR=1.39 (95% CI=1.11-1.75)). Genotype and allele distributions for 5-HTT polymorphisms were similar in both groups. However, assessment of the combined influence of 5-HT2A A-1438G and 5-HTTLPR polymorphisms demonstrated a significant effect (chi(2) (3)=11.51, p=0.009), whereby the combination of -1438A and 5-HTTLPR S alleles was associated with schizophrenia. CONCLUSIONS Our findings support a possible synergistic effect of genetic factors influencing serotonergic neurotransmission on susceptibility to schizophrenia.

Genetic polymorphisms in the dopamine-2 receptor (DRD2), dopamine-3 receptor (DRD3), and dopamine transporter (SLC6A3) genes in schizophrenia: data from an association study.

OBJECTIVE To investigate the association between dopaminergic polymorphisms [DRD2 -141C Ins/Del, DRD3 Ser9Gly, and SLC6A3 VNTR] and schizophrenia. METHODS Two hundred and eighty-eight outpatients with schizophrenia (DSM-IV criteria) [mean age (SD)=36.4 (12.4), 60.1% males] and 421 unrelated healthy controls [mean age (SD)=40.6 (11.3), 51.3% males] from a homogeneous Spanish Caucasian population were genotyped using standard methods. RESULTS There was a significant difference in genotype distribution for the DRD2 -141C Ins/Del polymorphism [(chi(2) (2)=12.35, corrected p=0.012]. The -141C Del allele was more common in patients than in controls [0.19 vs. 0.13; chi(2) (1)=9.14, corrected p=0.018, OR (95% CI)=1.57 (1.17-2.10)]. Genotype and allele distributions for DRD3 Ser9Gly and SLC6A3 VNTR polymorphisms were similar in both groups. However, there was tentative evidence of an interaction effect between DRD3 Ser9Gly and SLC6A3 VNTR [Wald=9.56 (4), p=0.049]. Compared to the SLC6A3 10/10 genotype category, the risk of schizophrenia was halved among those with 9/10 [OR=0.51 (95% CI=0.30-0.89), p=0.017]. This protective effect was only present in combination with DRD3 Ser/Ser genotype because of the significant interaction between 9/10 and both Ser/Gly [OR=2.45 (95% CI=1.16-5.17), p=0.019] and Gly/Gly [OR=3.80 (95% CI=1.24-11.63), p=0.019]. CONCLUSIONS This study provides evidence that a genetic variant in the DRD2 gene and possible interaction between DRD3 and SLC6A3 genes are associated with schizophrenia. These findings warrant examination in replication studies.

Apolipoprotein E genotype and schizophrenia: further negative evidence

Objective: To investigate the association between apolipoprotein E (ApoE) genotype and schizophrenia.

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.

Interleukin-1 gene complex in schizophrenia : An association study

The aim of this study is to investigate the association between three polymorphisms of the interleukin‐1 (IL‐1) gene complex and schizophrenia. We genotyped 228 outpatients with schizophrenia (DSM‐IV criteria) and 419 unrelated healthy controls. The following polymorphisms were analyzed: IL‐1α −889 C/T, IL‐1β +3953 C/T, and IL‐1RA (86 bp)n. No significant differences in genotype or in allelic distribution of the Il‐1α, IL‐1β, and IL‐1RA polymorphisms were found. Estimated haplotype frequencies were similar in both groups. Our data do not suggest that genetically determined changes in the IL‐1 gene complex confer increased susceptibility for schizophrenia.

A PrototyPicAlity VAlidAtion of the comPrehensiVe Assessment of PsychoPAthic PersonAlity (cAPP) model sPAnish Version

The Comprehensive Assessment of Psychopathic Personality (CAPP) is a newly developed, lexically based, conceptual model of psychopathy. The content validity of the Spanish language CAPP model was evaluated using prototypicality analysis. Prototypicality ratings were collected from 187 mental health experts and from samples of 143 health professionals and 282 community residents. Across the samples the majority of CAPP items were rated as highly prototypical of psychopathy. The Self, Dominance, and Attachment domains were evaluated as being more prototypical than the Behavioral and Cognitive domains. These findings are consistent with findings from similar studies in other languages and provide further support for the content validation of the CAPP model across languages and the lexical approach.

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).