Fernández-Piqueras J

Genetic association study between pathological gambling and a functional DNA polymorphism at the D4 receptor gene.

A Spanish sample consisting of 68 Caucasian pathological gambling patients (47 males and 21 females) and 68 unaffected controls were screened by the molecular analysis of a functional DNA polymorphism in the locus for the D4 dopamine receptor gene. Our results are consistent with the existence of a significant association between genetic variants at a DRD4 gene polymorphism and pathological gambling (chi 2 = 11.82; P = 0.037). This association seems to be sex-influenced, since there was no significant association when only males were considered (chi 2 = 9.45; P = 0.09), but there was a more significant association if we only considered female subjects (chi 2 = 8.73; P = 0.033). Individuals with the longest allele (D7) were the most frequent in affected females (chi 2 = 4.50; P = 0.033). This work provides a new evidence of the implication of the dopaminergic reward pathways, now through the involvement of DRD4, in the aetiology of this impulsive disorder.

Pathological gambling and DNA polymorphic markers at MAO-A and MAO-B genes

This study was conducted to detect a possible association of MAOA and/or MAOB genes with pathological gambling (PG). DNA polymorphisms in MAOA and MAOB genes were screened by molecular analysis in 68 individuals (47 males and 21 females) meeting ICD-10 and DSM-IV criteria for pathological gambling and 68 healthy comparison controls matched for age and sex. There were no significant differences between pathological gamblers and healthy volunteers in overall allele distribution at the MAOA gene polymorphism. However there was a significant association between allele distribution and the subgroup of severe male gamblers (n = 31) compared to the males in the group of healthy volunteers (χ2 = 5246; df = 1; P < 0.05 [bonferroni corrected]). No association was found between the MAOB polymorphic marker and PG. Allele variants at the MAOA, but not the MAOB gene may be a genetic liability factor in PG, at least in severe male gamblers.

Extensive Genotyping of the BDNF and NTRK2 Genes Define Protective Haplotypes Against Obsessive-Compulsive Disorder

BACKGROUNDnFamily, twin and molecular studies provide increasing evidence for the importance of genetic factors in obsessive-compulsive disorder (OCD). Recent work suggests that brain-derived neurotrophic factor (BDNF) may be involved in OCD pathophysiology. We used a linkage disequilibrium (LD)-mapping approach to investigate the role that BDNF and its specific receptor neurotrophic tyrosine kinase receptor type 2 (NTRK2) may play in increasing susceptibility to OCD.nnnMETHODSnEight tag single nucleotide polymorphisms (tagSNPs) covering the BDNF gene region and 46 tagSNPs in the NTRK2 region were genotyped in 215 OCD patients and 342 control subjects. Single nucleotide polymorphism association and haplotype analysis were performed. The possible relationship between genetic factors and clinical characteristics including age of OCD onset, tic disorders, clinical dimensions, and family history of OCD were investigated.nnnRESULTSnHaplotype analysis revealed a significant association between OCD and a five-marker protective haplotype located toward the 5 of the BDNF gene (odds ratio [OR] = .80; 95% confidence interval [CI] = .69-.92; permutation p value = .006) containing the functional valine (Val)66-to-methionine (Met) variant. A significant association between a NTRK2 intronic SNP (rs2378672) and OCD was identified (p < .0001) in female patients under an additive model. A protective haplotype located in intron 19 of NTRK2 was also associated with OCD (OR = .76; 95% CI = .66-.87; permutation p value = .001).nnnCONCLUSIONSnThese findings support a role for the BDNF/NTRK2 signaling pathway in genetic susceptibility to OCD.

A weak association between TH and DRD2 genes and bipolar affective disorder in a Spanish sample.

Genetic factors play an important role in the aetiology of bipolar affective disorder (BP). So far, results of linkage studies have been largely disappointing. We have searched for a possible association between polymorphic DNA markers of two candidate genes (tyrosine hydroxylase, TH; dopamine D2 receptor gene, DRD2) and BP in a population from central Spain. Our results are consistent with the existence of a weak association between these two genes and BP, in such a way that TH and DRD2 could be considered as minor genes contributing to susceptibility.

No association between particular DRD3 and DAT gene polymorphisms and manic-depressive illness in a Spanish sample

We have carried out an association study of a polymorphism in the 3UTR of the dopamine transporter gene (DAT) and a polymorphism in the coding region of the D3 receptor gene (DRD3) in Spanish patients with manic depression and in controls. No significant differences in allelic and genotypic frequencies of either of these polymorphisms was found in patients compared with controls.

Association study of two polymorphisms of the serotonin-2A receptor gene and suicide attempts

Serotonin (5‐HT) receptors may have a role in suicidal behavior. Previous studies have shown an association between the T102C polymorphism of the 5‐HT2a receptor gene and suicidal behavior. However, negative findings have also been reported. We examined the association between the T102C and C1354T (His452Tyr) polymorphisms of the 5‐HT2a receptor gene and suicide attempts. Four hundred forty‐one suicide attempters, 339 psychiatric patients, and 410 healthy controls were compared for genotypes of the T102C and C1354T (His452Tyr) polymorphisms. There were significant differences in the distribution of the three genotypes (TT, TC, and CC) of the T102C polymorphism in the three groups (controls, psychiatric patients, and suicide attempters). There was an excess of C/C genotypes in the suicide attempter group compared with the control group, but there were no significant differences between suicide attempters and psychiatric controls. We found no association between the C1354T polymorphism and suicide attempts. The C allele of the T102C polymorphism of the 5‐HT2A receptor gene may be associated with biological susceptibility for suicidal behavior or psychiatric conditions.

Positive association between SAT-1 -1415T/C polymorphism and anxiety.

Limbic glutamatergic neurotransmission plays a pivotal role in the pathogenesis of anxiety disorders. Polyamines modulate the activity of several ionotropic glutamate receptors and have been involved in the regulation of fear‐conditioning response. Spermidine/spermine N1‐acetyltransferase (SSAT‐1) is the main enzyme regulating polyamine catabolism. The aim of the present study was to examine the association between anxiety disorders and the −1415T/C (rs1960264) single nucleotide polymorphism (SNP) of the gene (SAT1) coding for SSAT‐1. A case–control design was used in order to compare the genotypes for the −1415T/C (rs1960264) SNP between anxiety patients (nu2009=u2009218), other non‐anxiety psychiatric patients (nu2009=u2009362), and healthy controls (nu2009=u2009251). DSM‐IV diagnoses were provided using MINI 4.4. Genomic DNA was extracted from peripheral blood samples collected from participants. In males, there was a significant difference in the distribution of the two genotypes (T and C) for the SAT‐1 −1415T/C SNP between anxiety patients, non‐anxiety psychiatric controls, and healthy controls. The T genotype was significantly more frequent in males suffering from anxiety disorders than in male psychiatric controls and healthy controls. This is the first study linking polymorphic variants of genes involved in polyamine metabolism with anxiety disorders.

NO ASSOCIATION BETWEEN DOPAMINE D4 RECEPTOR POLYMORPHISM AND MANIC DEPRESSIVE ILLNESS

Several reports have been published describing the newly recognised autosomal recessive limb/pelvis-hypoplasia/aplasia syndrome (LPHAS).-5 Raas-Rothschild et al3 have speculated that the rare LPHAS gene has its origin in the Middle East, on the basis of both their report on three sibs of Iranian Jewish background and the report by AlAwadi et al on two sibs of Arabic origin with the LPHAS phenotype. Farag et al and Camera et al,5 however, have disputed this hypothesis on the grounds that two of the identified families have their origin outside the Middle East, one being Brazilian and the other Italian. I still think there is a strong basis for the original suggestion by Raas-Rothschild et al.3 The very long coexistence of both Arabs and Jews in what is now known as the Middle East has been certified, if not by history, then by the holy scriptures. Also the historical Arabic interaction with peoples of both Italy and Spain (the presumed origin of the Latin American ancestors of the Brazilian family) in the Middle Ages suggests a possible Arabic genetic influence in these parts of the world. I discussed this idea with senior members of the Kuwait Medical Genetics Centre who

Nucleotide variation in central nervous system genes among male suicide attempters

Despite marked morbidity and mortality associated with suicidal behavior, accurate identification of individuals at risk remains elusive. The goal of this study is to identify a model based on single nucleotide polymorphisms (SNPs) that discriminates between suicide attempters and non‐attempters using data mining strategies. We examined functional SNPs (nu2009=u2009840) of 312 brain function and development genes using data mining techniques. Two hundred seventy‐seven male psychiatric patients aged 18 years or older were recruited at a University hospital psychiatric emergency room or psychiatric short stay unit. The main outcome measure was history of suicide attempts. Three SNPs of three genes (rs10944288, HTR1E; hCV8953491, GABRP; and rs707216, ACTN2) correctly classified 67% of male suicide attempters and non‐attempters (0.50 sensitivity, 0.82 specificity, positive likelihood ratiou2009=u20092.80, negative likelihood ratiou2009=u20091.64). The OR for the combined three SNPs was 4.60 (95% CI: 1.31–16.10). The models accuracy suggests that in the future similar methodologies may generate simple genetic tests with diagnostic utility in identification of suicide attempters. This strategy may uncover new pathophysiological pathways regarding the neurobiology of suicidal acts.

Gender effect on association between DRD2 polymorphism and substance dependence in a Spanish sample.

Our aim was to examine a possible association between substance dependence and the TaqIA polymorphism of the D2 dopamine receptor (DRD2), a single nucleotide polymorphism (SNP) located at the 3 UTR region of the DRD2 gene. A case-control design stratified by gender was used to analyze the genotypes of this SNP in a sample of 125 substance-dependent patients according to DSM-IV and 203 blood donors recruited as controls in two general city hospitals in Madrid, Spain. Genomic DNA from peripheral blood samples was amplified through PCR to identify the variants of the SNP in the DRD2 gene. Analyses performed with Chi(2) tests revealed that the A1 allele (A1/A1 and A1/A2 genotypes) of the Taq 1A SNP of the DRD2 gene was significantly associated with substance dependence in males, but not in the whole sample. Male patients had significantly higher rates of the A1-containing genotypes than male controls. The finding of an association between substance dependence and the DRD2 gene TaqIA SNP only in males suggests the existence of gender-specific differences in the genetic underpinnings of substance dependence.