Krisztina Hejjas

Association between depression and the Gln460Arg polymorphism of P2RX7 gene: a dimensional approach.

The P2RX7 gene (coding for P2X7 purinergic receptor) has been suggested as a novel candidate gene for major depressive disorder (MDD) and bipolar disorder (BPD). The proposed risk allele (G‐allele) of the rs2230912 polymorphism results in an amino acid change at the 460th position, marking this genetic variation a possibly functional one. Here we present a case–control analysis of 171 patients diagnosed with MDD or BPD and 178 controls, as well as a dimensional approach using the Hospital Anxiety and Depression Scale (HADS) for studying the Gln460Arg polymorphism of the P2RX7 gene as a genetic risk factor in depression. While case–control analysis did not show significant difference between the groups, a significant association was found between the P2RX7 polymorphism and the HADS scales in the clinical group (MANOVA P = 0.001). Both anxiety and depression scores increased as the number of G‐allele increased in the genotype groups (ANOVA for HADS‐anxiety: P = 0.01, HADS‐depression: P < 0.001). A significant interaction of clinical status and the P2RX7 polymorphism was also found for the depression scale (MANOVA P = 0.025, subsequent ANOVA for anxiety: P = 0.252; depression: P = 0.002). Whereas patients with G‐allele‐present genotypes showed more elevated depression scores, level of depression in the control group was not affected by the P2RX7 genotype. In conclusion, case–control analysis did not reveal significant results, but using a symptom severity scale we could support the association between depressive disorder and the G‐allele of the Gln460Arg polymorphism in the P2RX7 gene.

Molecular and behavioral analysis of the intron 2 repeat polymorphism in the canine dopamine D4 receptor gene

Genetic polymorphisms in the human dopamine D4 receptor (DRD4) gene, especially the exon 3 variable number of tandem repeats (VNTR), have been related to several psychiatric disorders and personality traits. A homologous exon 3 VNTR has been described in dogs, and we previously showed an association between the DRD4 exon 3 polymorphism and activity/impulsivity trait in German shepherds. In this study, we present a detailed analysis of the intron 2 VNTR of the DRD4 gene. A short and a long form of the intronic variation were identified in 678 unrelated dogs from five breeds and in 22 wolves. For molecular analysis, the intron 2 region was cloned into a promoterless luciferase reporter vector that led to an elevation in transcriptional activity. Moreover, an allelic difference in promoter activity was detected, and a repressive effect of the long allele was observed. Behavioral analysis of 96 unrelated German shepherds showed a significant association between the social impulsivity endophenotype of the Greeting Test and both the exonic (P = 0.002) and the intronic (P = 0.003) VNTRs of the DRD4 gene. Moreover, an additive effect of the two polymorphisms was also shown (Spearman’s rho = 0.356, P = 0.0004). In conclusion, these results give further support to our previous findings that the DRD4 gene is associated with dog behavior. We also present molecular evidence for the functional role of the intron 2 VNTR in the canine DRD4 gene.

Polymorphism in the tyrosine hydroxylase (TH) gene is associated with activity-impulsivity in German Shepherd Dogs

We investigated the association between repeat polymorphism in intron 4 of the tyrosine hydroxylase (TH) gene and two personality traits, activity-impulsivity and inattention, in German Shepherd Dogs. The behaviour of 104 dogs was characterized by two instruments: (1) the previously validated Dog-Attention Deficit Hyperactivity Disorder Rating Scale (Dog-ADHD RS) filled in by the dog owners and (2) the newly developed Activity-impulsivity Behavioural Scale (AIBS) containing four subtests, scored by the experimenters. Internal consistency, inter-observer reliability, test-retest reliability and convergent validity were demonstrated for AIBS. Dogs possessing at least one short allele were proved to be more active-impulsive by both instruments, compared to dogs carrying two copies of the long allele (activity-impulsivity scale of Dog-ADHD RS: p = 0.007; AIBS: p = 0.023). The results have some potential to support human studies; however, further research should reveal the molecular function of the TH gene variants, and look for the effect in more breeds.

DRD4 and TH gene polymorphisms are associated with activity, impulsivity and inattention in Siberian Husky dogs

Both dopamine receptor D4 (DRD4) exon 3 and tyrosine hydroxylase (TH) intron 4 repeat polymorphisms have been linked to activity and impulsivity in German Shepherd dogs (GSDs). However, the results in GSDs may not be generalisable to other breeds, as allelic frequencies vary markedly among breeds. We selected the Siberian Husky for further study, because it is highly divergent from most dog breeds, including the GSD. The study sample consisted of 145 racing Siberian Huskies from Europe and North America. We found that this breed possesses seven DRD4 length variants, two to five more variants than found in other breeds. Among them was the longest known allele, previously described only in wolves. Short alleles of the DRD4 and TH repeat polymorphisms were associated with higher levels of activity, impulsivity and inattention. Siberian Huskies possessing at least one short allele of the DRD4 polymorphism displayed greater activity in a behavioural test battery than did those with two long alleles. However, the behavioural test was brief and may not have registered variation in behaviour across time and situations. Owners also completed the Dog-Attention Deficit Hyperactivity Disorder Rating Scale (Dog-ADHD RS), a more general measure of activity and attention. Siberian Huskies from Europe with two short alleles of the TH polymorphism received higher ratings of inattention on the Dog-ADHD RS than did those with the long allele. Investigation of the joint effect of DRD4 and TH showed that dogs possessing long alleles at both sites were scored as less active-impulsive than were others. Our results are aligned with previous studies showing that DRD4 and TH polymorphisms are associated with activity-impulsivity related traits in dogs. However, the prevalence of variants of these genes differs across breeds, and the functional role of specific variants is unclear.

Novel repeat polymorphisms of the dopaminergic neurotransmitter genes among dogs and wolves

Genetic polymorphisms of the neurotransmission systems are intensively studied in the human because of a possible influence on personality traits and the risk of psychiatric disorders. The investigation of genetic variations of the dog genome has recently been a promising approach, as a considerable similarity can be observed between dogs and humans, in both genetic and social aspects, suggesting that the dog could become an appropriate animal model of human behavioral genetic studies. The aim of our study was the identification and analysis of variable number of tandem repeats polymorphisms (VNTRs) in the genes of the dopaminergic neurotransmitter system of dogs. The in silico search was followed by the development of PCR-based techniques for the analysis of the putative VNTRs. Highly variable repetitive sequence regions were found in the tyrosine hydroxylase (TH), dopamine transporter (DAT), and dopamine β-hydroxylase (DBH) genes. Allele frequency and genotype distribution of these novel polymorphisms together with the exon 3 and exon 1 VNTR of the dopamine D4 receptor gene were determined in a large sample involving four dog breeds (German Shepherd, Belgian Tervueren, Groenandael, and Malinois) and European Grey Wolves. A significant difference of allele and genotype frequencies was demonstrated among the analyzed breeds; therefore, an association analysis was also carried out between the activity–impulsivity phenotype and the described VNTRs. Preliminary findings are presented that polymorphisms of the DRD4, DBH, and DAT genes can be associated with attention deficit among Belgian Tervuerens.

Association of the STin2 polymorphism of the serotonin transporter gene with a neurocognitive endophenotype in major depressive disorder

BACKGROUND The aim of our study was to investigate the association of STin2 polymorphism and cognitive dysfunction in major depression. METHODS 71 patients with major depression and 99 controls were genotyped for STin2. All depressive subjects and 30 controls also completed tests measuring neurocognitive performance. RESULTS We found a significantly higher frequency of the STin2.10/Stin2.10 homozygous genotype in the depressed group compared to controls. In the depressed group subjects with at least one copy of the 10-repeat allele showed decreased interference threshold in Stroop III compared to patients without the 10-repeat allele. Average performance of the depressed group without the 12-repeat allele was significantly weaker in the Rey Auditory Verbal Learning Test working memory and recall tasks compared to patients having at least one copy of the 12-repeat allele. CONCLUSION Our results suggest that the presence of STin2.10 and absence of STin2.12 allele may be related to a possible genetic endophenotype for characteristic cognitive dysfunctions detected in MDD.