Association between the COMT gene and rumination in a Hungarian sample.

Introduction: Rumination is a multidimensional trait which is a proven risk factor in the vulnerability to depression. The aim to identify the main risk genes for depression in addition to the gene-environment interactions pointed to the importance of intermediate phenotypes, like rumination, to improve our understanding of the biological mechanisms of depression. Catechol-O-Methyltransferase (COMT) gene is extensively investigated in depression with contradictory results but its association with rumination, as an intermediate phenotype in depression, has not been investigated yet. Methods: In our study, four tagging SNPs in the COMT gene (rs933271, rs740603, rs4680, rs4646316) were genotyped in a nonclinical Hungarian sample (n=939). We investigated the association between the COMT gene and rumination scores measured by the Ruminative Response Scale using haplotype trend regression. Results: We found a significant association between COMT haplotypes and rumination scores (p=0.013) but no significant association was apparent between the functional Val158Met polymorphism (rs4680) and rumination in any genetic model. Discussion: Variations in the COMT gene exert complex effects on susceptibility to depression involving intermediate phenotypes, such as rumination and also impulsivity, as we previously demonstrated. Both rumination and impulsivity represent maladaptive cognitive styles that can lead to depressive state by influencing the response to negative life events and life stressors. In conclusion, our findings provide evidence that in addition to other genes, COMT also has a significant role in the development of depression, and demonstrate that analysing the complex phenotype associations of genes by haplotype tagging is a powerful method

A kis „n”, nagy „P” probléma a neuropszichofarmakológiában, avagy hogyan kontrolláljuk a hamis felfedezések arányát

Számos korszerű neuropszichofarmakológiai vizsgálati módszer jellegzetessége, hogy aránylag kevés vizsgálati egyénről (n) nagyon sok adatot (paramétert, P) gyűjt. Példaképpen említhetjük a képalkotó módszereket (pl. funkcionális mágneses rezonancia és egyéb képalkotó eljárásokat), az elektroenkefalográfiát (EEG), vagy a genomikai vizsgálatokat. Egyetlen microarray chip például több ezer próbát tartalmazhat, azaz a P ezres nagyságrendekkel haladhatja meg az n-t. Az ilyen elrendezésű vizsgálatok elemzése komoly statisztikai problémákat vet fel, amit a statisztikai szakirodalomban kis "n" nagy "P" problémának neveznek. A többszörös tesztelés problémája akkor lép fel, ha két vagy több csoportba tartozó egyéneket hasonlítunk össze a mért P számú jellemző alapján. Amennyiben az összehasonlítás az egyes jellemzők alapján történik, akkor akár több ezer statisztikai hipotézisvizsgálat elvégzése is szükségessé válhat. Amennyiben a többszörös tesztelés okozta megnövekedett klasszifikációs hibát nem vesszük figyelembe, akkor számos statisztikailag szignifikáns különbséget fedezhetünk fel a vizsgálati csoportok között. Azonban ezeknek a felfedezéseknek egy része valójában a véletlen műve és ezek a kísérleti eredmények általában nem reprodukálhatóak. A problémára több megoldás is született. Ezek közül cikkünkben a klaszter szintű összehasonlítást, valamint a hamis találati arányon alapuló statisztikai tesztet mutatjuk be

A new clinical evidence-based gene-environment interaction model of depression.

In our current understanding of mood disorders, the role of genes is diverse including the mediation of the effects of provoking and protective factors. Different or partially overlapping gene sets play a major role in the development of personality traits including also affective temperaments, in the mediation of the effects of environmental factors, and in the interaction of these elements in the development of depression. Certain genes are associated with personality traits and temperaments including e.g., neuroticism, impulsivity, openness, rumination and extroversion. Environmental factors consist of external (early and provoking life events, seasonal changes, social support etc.) and internal factors (hormones, biological rhythm generators, comorbid disorders etc). Some of these environmental factors, such as early life events and some prenatal events directly influence the development of personality traits and temperaments. In the NEWMOOD cohort polymorphisms of the genes of the serotonin transporter, 5-HT1A, 5-HT1B and 5-HT2A and endocannabinoid CB1 receptors, tryptophan hydroxylase, CREB1, BDNF and GIRK provide evidence for the involvement of these genes in the development of depression. Based on their role in this process they could be assigned to different gene sets. The role of certain genes, such as promoter polymorphisms of the serotonin transporter (5-HTTLPR) and CB1 receptor has been shown in more than one of the above factors. Furthermore, gene-gene interactions of these promoters associated with anxiety suggest the application of these polymorphisms in personalized medicine. In this review we introduce a new model including environmental factors, genes, trait and temperament markers based on human genetic studies

Antidepresszivumok, stresszorok es a szerotonin 1A receptor.

5-HT1A receptor is a receptor of surprises. Buspirone, an anxiolytic drug with a then yet unidentified mechanism of action had been marketed for years when it was discovered that it is a 5-HT1A partial agonist. Several more years had to pass before it was accepted that this receptor plays the key role in the action mechanism of buspirone. This was followed by further surprises. It was discovered that in spite of its anxiolytic effect buspirone activates the hypothalamic-pituitary-adrenal (HPA) stress axis, furthermore, it increases peripheral noradrenaline and adrenaline concentration via a central mechanism. Thus activation of this receptor leads to ACTH/corticosterone and catecholamine release and also increases beta-endorphine, oxytocin and prolactin secretion while decreasing body temperature, increasing food uptake, eliciting characteristic behavioural responses in rodents and also playing a role in the development of certain types of epilepsy. Human genetic studies revealed the role of 5-HT1A receptors in cognitive processes playing a role in the development of depression such as impulsiveness or response to environmental stress. This exceptionally wide spectrum of effects is attributable to the presence of 5-HT1A receptors in serotonergic as well as other, for example glutamatergic, cholinergic, dopaminergic and noradrenergic neurons. The majority of the effects of 5-HT1A receptors is manifested via the mediation of Gi proteins through the hyperpolarisation or inhibition of the neuron carrying the receptor. 5-HT1A receptors on serotonergic neurons can be found in the somatodendritic area and play a significant role in delaying the effects of antidepressants which is an obvious disadvantage. Therefore the newest serotonergic antidepressants including vilazodone and vortioxetine have been designed to possess 5-HT1A receptor partial agonist properties. In the present paper we focus primarily on the role of 5-HT1A receptors in stress and antidepressant response