Objective Numerous studies have reported association of the serotonin transporter gene (5-HTT) polymorphisms and neuroticism and traits characterizing sociability and activity. This study aimed to define a single genotype effect of three polymorphic markers in the 5-HTT gene (5-HTTLPR, A/G SNP in 5-HTTLPR and STin2 VNTR) and to check possible association of the 5-HTT haplotypes and personality traits [assessed with Eysenck Personality Inventory (EPI) and Temperament and Character Inventory (TCI) questionnaires] in 301 healthy young individuals. Methods To investigate single genotype and haplotype effects of all polymorphic markers, multivariate analysis of variance and haplotype trend regression analyses were conducted correspondingly. Results Individuals with STin2.10 allele scored significantly lower on Neuroticism (EPI) (P=0.007) and Harm Avoidance (P=0.005) in the overall sample. The same pattern of association was reported in women: carriers of STin2.10 allele scored lower on Harm Avoidance (TCI) (P=0.008). Haplotype trend regression analyses revealed that carriers of S12 haplotype had lower sociability-related traits such as Extraversion (EPI) and Novelty Seeking (TCI), whereas Harm Avoidance (TCI) (anxiety-related trait) was higher. Opposite association was observed for S10 haplotype: Extraversion (EPI) score was higher, whereas Harm Avoidance (TCI) score was lower in carriers of this haplotype. Conclusion As single polymorphism effect of STin2 was observed in relation to anxiety-related traits, opposite S10 and S12 haplotype effects on Neuroticism and Harm Avoidance could be explained by the larger impact of STin2 polymorphism. Controversially, we consider that the variance in sociability-related traits is related to specific haplotypes of 5-HTT gene.

Лонгитюдные генетические исследования когнитивных характеристик

Depression is a common mental disorder being one of the main causes of disability and mortality worldwide. Despite an intensive research during the past decades, the etiology of depressive disorders (DDs) remains incompletely understood; however, genetic factors are significantly involved in the liability to depression. The present review is focused on the studies based on a candidate gene approach, genome-wide association studies (GWAS) and whole exome sequencing (WES), which previously demonstrated associations between gene polymorphisms and DDs. According to the first approach, DD development is affected by serotonergic (TPH1, TPH2, HTR1A, HTR2A, and SLC6A4), dopaminergic (DRD4, SLC6A3) and noradrenergic (SLC6A2) system genes, and genes of enzymatic degradation (MAOA, COMT). In addition, there is evidence of the involvement of HPA-axis genes (OXTR, AVPR1A, and AVPR1B), sex hormone receptors genes (ESR1, ESR2, and AR), neurotrophin (BDNF) and methylenetetrahydrofolate reductase (MTHFR) genes, neuronal apoptosis (CASP3, BCL-XL, BAX, NPY, APP, and GRIN1) and inflammatory system (TNF, CRP, IL6, IL1B, PSMB4, PSMD9, and STAT3) genes in DD development. The results of the second approach (GWAS and WES) revealed that the PCLO, SIRT1, GNL3, GLT8D1, ITIH3, MTNR1A, BMP5, FHIT, KSR2, PCDH9, and AUTS2 genes predominantly responsible for neurogenesis and cell adhesion are involved in liability to depression. Therefore, the findings discussed suggest that genetic liability to DD is a complex process, which assumes simultaneous functioning of multiple genes including those reported previously, and requires future research in this field.

Multiple studies of depression indicated a significant role of gene-by-environment interactions; however, they are mainly limited to the examination of modulating effect of recent stressful life events. Other environmental factors occurring at different stages of ante- and postnatal development may affect the association between multiple genes and depression. The study aimed to analyze the main and haplotype-based effect of serotonergic system and HPA-axis gene polymorphisms on depression and to detect gene-by-environment interaction models explaining individual variance in depression in mentally healthy young adults from Russia. Depression score was assessed using Beck Depression Inventory (BDI) in 623 healthy individuals (81% women; 17-25 years) of Caucasian origin (Russians, Tatars, Udmurts) from Russia. The main- and gene-based effects of 12 SNPs in SLC6A4 (5-HTTLPR, rs1042173), HTR2A (rs7322347), OXTR (rs7632287, rs2254298, rs13316193, rs53576, rs2228485, rs237911), AVPR1A (rs3803107, rs1042615), and AVPR1B (rs33911258) genes, and gene-by-environment interactions were tested with linear regression models (PLINK v.1.9) adjusted for multiple comparisons. We observed ethnicity-specific main effect of the AVPR1A rs3803107 (P = 0.003; PFDR = 0.047) and gene-based effect of the OXTR gene (Р = 0.005; Pperm = 0.034) on BDI-measured depression, and modifying effect of paternal care on OXTR rs53576 (P = 0.004; PFDR = 0.012) and birth order on OXTR rs237911 (P = 0.006; PFDR = 0.018) association with depression level. A hypothesis driven candidate gene approach, which examined a limited number of genetic variants in a moderately large sample, was used. Our preliminary findings indicate that familial environment may play a permissive role modulating the manifestation of OXTR-based depression variance in mentally healthy subjects.