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AVPR1A main effect and OXTR-by-environment interplay in individual differences in depression level.

ABSTRACT: Background: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. Methods: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. Results:We observed ethnicity-specific main effect of the AVPR1A rs3803107 (P = 0.003; PFDR = 0.047) and gene-based effect of the OXTR gene (? = 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. Limitations:A hypothesis driven candidate gene approach, which examined a limited number of genetic variants in a moderately large sample, was used. Conclusions:Our preliminary findings indicate that familial environment may play a permissive role modulating the manifestation of OXTR-based depression variance in mentally healthy subjects.

SUBMITTER: Kazantseva A

PROVIDER: S-EPMC7567928 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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AVPR1A main effect and OXTR-by-environment interplay in individual differences in depression level.

Kazantseva A A Davydova Yu Y Enikeeva R R Lobaskova M M Mustafin R R Malykh S S Takhirova Z Z Khusnutdinova E E

Heliyon 20201013 10

<h4>Background</h4>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 o ...[more]

PMID: 33088973

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Project description:The risk of depression could be evaluated through its multifactorial nature using the polygenic score (PGS) approach. Assuming a "clinical continuum" hypothesis of mental diseases, a preliminary assessment of individuals with elevated risk for developing depression in a non-clinical group is of high relevance. In turn, epidemiological studies suggest including social/lifestyle factors together with PGS to address the "missing heritability" problem. We designed regression models, which included PGS using 27 SNPs and social/lifestyle factors to explain individual differences in depression levels in high-education students from the Volga-Ural region (VUR) of Eurasia. Since issues related to population stratification in PGS scores may lead to imprecise variant effect estimates, we aimed to examine a sensitivity of PGS calculated on summary statistics of depression and neuroticism GWAS from Western Europeans to assess individual proneness to depression levels in the examined sample of Eastern Europeans. A depression score was assessed using the revised version of the Beck Depression Inventory (BDI) in 1065 young adults (age 18-25 years, 79% women, Eastern European ancestry). The models based on weighted PGS demonstrated higher sensitivity to evaluate depression level in the full dataset, explaining up to 2.4% of the variance (p = 3.42 × 10-7); the addition of social parameters enhanced the strength of the model (adjusted r2 = 15%, p < 2.2 × 10-16). A higher effect was observed in models based on weighted PGS in the women group, explaining up to 3.9% (p = 6.03 × 10-9) of variance in depression level assuming a combined SNPs effect and 17% (p < 2.2 × 10-16)-with the addition of social factors in the model. We failed to estimate BDI-measured depression based on summary statistics from Western Europeans GWAS of clinical depression. Although regression models based on PGS from neuroticism (depression-related trait) GWAS in Europeans were associated with a depression level in our sample (adjusted r2 = 0.43%, p = 0.019-for unweighted model), the effect was mainly attributed to the inclusion of social/lifestyle factors as predictors in these models (adjusted r2 = 15%, p < 2.2 × 10-16-for unweighted model). In conclusion, constructed PGS models contribute to a proportion of interindividual variability in BDI-measured depression in high-education students, especially women, from the VUR of Eurasia. External factors, including the specificity of rearing in childhood, used as predictors, improve the predictive ability of these models. Implementation of ethnicity-specific effect estimates in such modeling is important for individual risk assessment.

Project description:In this article, we focus on the causes of individual differences in Down syndrome (DS), exemplifying the multi-level, multi-method, lifespan developmental approach advocated by Karmiloff-Smith (1998, 2009, 2012, 2016). We evaluate the possibility of linking variations in infant and child development with variations in the (elevated) risk for Alzheimer's disease (AD) in adults with DS. We review the theoretical basis for this argument, considering genetics, epigenetics, brain, behaviour and environment. In studies 1 and 2, we focus on variation in language development. We utilise data from the MacArthur-Bates Communicative Development Inventories (CDI; Fenson et al., 2007), and Mullen Scales of Early Learning (MSEL) receptive and productive language subscales (Mullen, 1995) from 84 infants and children with DS (mean age 2;3, range 0;7 to 5;3). As expected, there was developmental delay in both receptive and expressive vocabulary and wide individual differences. Study 1 examined the influence of an environmental measure (socio-economic status as measured by parental occupation) on the observed variability. SES did not predict a reliable amount of the variation. Study 2 examined the predictive power of a specific genetic measure (apolipoprotein APOE genotype) which modulates risk for AD in adulthood. There was no reliable effect of APOE genotype, though weak evidence that development was faster for the genotype conferring greater AD risk (ε4 carriers), consistent with recent observations in infant attention (D'Souza, Mason et al., 2020). Study 3 considered the concerted effect of the DS genotype on early brain development. We describe new magnetic resonance imaging methods for measuring prenatal and neonatal brain structure in DS (e.g., volumes of supratentorial brain, cortex, cerebellar volume; Patkee et al., 2019). We establish the methodological viability of linking differences in early brain structure to measures of infant cognitive development, measured by the MSEL, as a potential early marker of clinical relevance. Five case studies are presented as proof of concept, but these are as yet too few to discern a pattern.

Project description:Background: There are limited treatments available for autism spectrum disorder (ASD). Studies have reported significant associations between the receptor genes of oxytocin (OT) and vasopressin (AVP) and ASD diagnosis, as well as ASD-related phenotypes. Researchers have also found the manipulation of these systems affects social and repetitive behaviors, core characteristics of ASD. Consequently, research involving the oxytocin/vasopressin pathways as intervention targets has increased. Therefore, further examination into the relationship between these neuropeptides and ASD was undertaken. In this study, we examined associations between variants in the receptor genes of vasopressin (AVPR1A, AVPR1B), oxytocin (OXTR), and ASD diagnosis along with related subphenotypes. Methods: Probands were assessed using Autism Diagnostic Interview-Revised, Autism Diagnostic Observation Schedule, and clinical DSM-IV-TR criteria. Single nucleotide polymorphisms (SNPs) in AVPR1B and OXTR, and microsatellites in AVPR1A were genotyped in ~200 families with a proband with ASD. Family-based association testing (FBAT) was utilized to determine associations between variants and ASD. Haplotypes composed of OXTR SNPs (i.e., rs53576-rs2254298-rs2268493) were also analyzed due to previously published associations. Results: Using the additive inheritance model in FBAT we found associations between AVPR1B SNPs (rs28632197, p = 0.005, rs35369693, p = 0.025) and diagnosis. As in other studies, OXTR rs2268493 (p = 0.050) was associated with diagnosis. rs2268493 was also associated with ASD subphenotypes of social withdrawal (p = 0.013) and Insistence on Sameness (p = 0.039). Further analyses demonstrated that the haplotype, rs2254298-rs2268493 was found to be significantly associated with diagnosis (A-T; p = 0.026). FBAT was also used to analyze AVPR1A microsatellites (RS1 and RS3). Both length variants were found to be associated with restrictive, repetitive behaviors, but not overall diagnosis. Correction for multiple comparisons was performed for SNPs tested in each gene region, only AVPR1B SNPs remained significantly associated with ASD diagnosis. Conclusions: Autism is a heterogeneous disorder with many genes and pathways that contribute to its development. SNPs and microsatellites in the receptor genes of OT and AVP are associated with ASD diagnosis and measures of social behavior as well as restricted repetitive behaviors. We reported a novel association with ASD and AVPR1B SNPs. Understanding of genotype-phenotype relationships may be helpful in the development of pharmacological interventions for the OT/AVP system.

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AVPR1A main effect and OXTR-by-environment interplay in individual differences in depression level.

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AVPR1A main effect and OXTR-by-environment interplay in individual differences in depression level.

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