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1.
Artigo em Inglês | MEDLINE | ID: mdl-31399550

RESUMO

Prenatal stress exposure is associated with risk for psychiatric disorders later in life. This may be mediated in part via enhanced exposure to glucocorticoids (GCs), which are known to impact neurogenesis. We aimed to identify molecular mediators of these effects, focusing on long-lasting epigenetic changes. In a human hippocampal progenitor cell (HPC) line, we assessed the short- and long-term effects of GC exposure during neurogenesis on messenger RNA (mRNA) expression and DNA methylation (DNAm) profiles. GC exposure induced changes in DNAm at 27,812 CpG dinucleotides and in the expression of 3,857 transcripts (false discovery rate [FDR] ≤ 0.1 and absolute fold change [FC] expression ≥ 1.15). HPC expression and GC-affected DNAm profiles were enriched for changes observed during human fetal brain development. Differentially methylated sites (DMSs) with GC exposure clustered into 4 trajectories over HPC differentiation, with transient as well as long-lasting DNAm changes. Lasting DMSs mapped to distinct functional pathways and were selectively enriched for poised and bivalent enhancer marks. Lasting DMSs had little correlation with lasting expression changes but were associated with a significantly enhanced transcriptional response to a second acute GC challenge. A significant subset of lasting DMSs was also responsive to an acute GC challenge in peripheral blood. These tissue-overlapping DMSs were used to compute a polyepigenetic score that predicted exposure to conditions associated with altered prenatal GCs in newborn's cord blood DNA. Overall, our data suggest that early exposure to GCs can change the set point of future transcriptional responses to stress by inducing lasting DNAm changes. Such altered set points may relate to differential vulnerability to stress exposure later in life.

2.
Depress Anxiety ; 2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-31374578

RESUMO

BACKGROUND: Anxiety disorders including panic disorder (PD) are the most prevalent psychiatric diseases leading to high disability and burden in the general population. Acute panic attacks are distinctive for PD but also frequent in other anxiety disorders. The neurobiology or specific molecular changes leading to and present during panic attacks are insufficiently known so far. METHODS: In the present pilot study, we investigated dynamic metabolomic and gene expression changes in peripheral blood of patients with PD (n = 25) during two exposure-induced acute panic attacks. RESULTS: The results show that the metabolite glyoxylate was dynamically regulated in peripheral blood. Additionally, glyoxylate levels were associated with basal anxiety levels and showed gender-related differences at baseline. As glyoxylate is part of the degradation circuit of cholecystokinin, this suggests that this neuropeptide might be directly involved in exposure-induced panic attacks. Only gene expression changes of very small magnitude were observed in this experimental setting. CONCLUSIONS: From this first metabolome and gene expression study in exposure-induced acute panic attacks in PD we conclude that metabolites can potentially serve as dynamic markers for different anxiety states. However, these findings have to be replicated in cohorts with greater sample sizes.

3.
Transl Psychiatry ; 9(1): 178, 2019 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-31346158

RESUMO

Post-traumatic stress disorder (PTSD) selectively develops in some individuals exposed to a traumatic event. Genetic and epigenetic changes in glucocorticoid pathway sensitivity may be essential for understanding individual susceptibility to PTSD. This study focuses on PTSD markers in the glucocorticoid pathway, spotlighting glucocorticoid-induced leucine zipper (GILZ), a transcription factor encoded by the gene Tsc22d3 on the X chromosome. We propose that GILZ uniquely "quantifies" exposure to stressors experienced from late gestation to adulthood and that low levels of GILZ predispose individuals to PTSD in males only. GILZ mRNA and methylation were measured in 396 male and female human blood samples from the Grady Trauma Project cohort (exposed to multiple traumatic events). In mice, changes in glucocorticoid pathway genes were assessed following exposure to stressors at distinct time points: (i) CRF-induced prenatal stress (CRF-inducedPNS) with, or without, additional exposure to (ii) PTSD induction protocol in adulthood, which induces PTSD-like behaviors in a subset of mice. In humans, the number of traumatic events correlated negatively with GILZ mRNA levels and positively with % methylation of GILZ in males only. In male mice, we observed a threefold increase in the number of offspring exhibiting PTSD-like behaviors in those exposed to both CRF-inducedPNS and PTSD induction. This susceptibility was associated with reduced GILZ mRNA levels and epigenetic changes, not found in females. Furthermore, virus-mediated shRNA knockdown of amygdalar GILZ increased susceptibility to PTSD. Mouse and human data confirm that dramatic alterations in GILZ occur in those exposed to a stressor in early life, adulthood or both. Therefore, GILZ levels may help identify at-risk populations for PTSD prior to additional traumatic exposures.

4.
Nat Commun ; 10(1): 2548, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-31186427

RESUMO

Epigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function. While many studies have investigated either environmental or genetic contributions to DNAm, few have assessed their integrated effects. Here we examine the relative contributions of prenatal environmental factors and genotype on DNA methylation in neonatal blood at variably methylated regions (VMRs) in 4 independent cohorts (overall n = 2365). We use Akaike's information criterion to test which factors best explain variability of methylation in the cohort-specific VMRs: several prenatal environmental factors (E), genotypes in cis (G), or their additive (G + E) or interaction (GxE) effects. Genetic and environmental factors in combination best explain DNAm at the majority of VMRs. The CpGs best explained by either G, G + E or GxE are functionally distinct. The enrichment of genetic variants from GxE models in GWAS for complex disorders supports their importance for disease risk.


Assuntos
Metilação de DNA/genética , DNA/sangue , Interação Gene-Ambiente , Estudos de Coortes , Epigênese Genética , Feminino , Sangue Fetal , Genótipo , Humanos , Recém-Nascido , Masculino , Gravidez , Fatores de Risco
5.
Am J Psychiatry ; 176(8): 651-660, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31164008

RESUMO

OBJECTIVE: More than 90% of people who attempt suicide have a psychiatric diagnosis; however, twin and family studies suggest that the genetic etiology of suicide attempt is partially distinct from that of the psychiatric disorders themselves. The authors present the largest genome-wide association study (GWAS) on suicide attempt, using cohorts of individuals with major depressive disorder, bipolar disorder, and schizophrenia from the Psychiatric Genomics Consortium. METHODS: The samples comprised 1,622 suicide attempters and 8,786 nonattempters with major depressive disorder; 3,264 attempters and 5,500 nonattempters with bipolar disorder; and 1,683 attempters and 2,946 nonattempters with schizophrenia. A GWAS on suicide attempt was performed by comparing attempters to nonattempters with each disorder, followed by a meta-analysis across disorders. Polygenic risk scoring was used to investigate the genetic relationship between suicide attempt and the psychiatric disorders. RESULTS: Three genome-wide significant loci for suicide attempt were found: one associated with suicide attempt in major depressive disorder, one associated with suicide attempt in bipolar disorder, and one in the meta-analysis of suicide attempt in mood disorders. These associations were not replicated in independent mood disorder cohorts from the UK Biobank and iPSYCH. No significant associations were found in the meta-analysis of all three disorders. Polygenic risk scores for major depression were significantly associated with suicide attempt in major depressive disorder (R2=0.25%), bipolar disorder (R2=0.24%), and schizophrenia (R2=0.40%). CONCLUSIONS: This study provides new information on genetic associations and demonstrates that genetic liability for major depression increases risk for suicide attempt across psychiatric disorders. Further collaborative efforts to increase sample size may help to robustly identify genetic associations and provide biological insights into the etiology of suicide attempt.

6.
Hypertension ; 74(2): 375-383, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31230546

RESUMO

Hypertensive disorders of pregnancy (HDP) are associated with low birth weight, shorter gestational age, and increased risk of maternal and offspring cardiovascular diseases later in life. The mechanisms involved are poorly understood, but epigenetic regulation of gene expression may play a part. We performed meta-analyses in the Pregnancy and Childhood Epigenetics Consortium to test the association between either maternal HDP (10 cohorts; n=5242 [cases=476]) or preeclampsia (3 cohorts; n=2219 [cases=135]) and epigenome-wide DNA methylation in cord blood using the Illumina HumanMethylation450 BeadChip. In models adjusted for confounders, and with Bonferroni correction, HDP and preeclampsia were associated with DNA methylation at 43 and 26 CpG sites, respectively. HDP was associated with higher methylation at 27 (63%) of the 43 sites, and across all 43 sites, the mean absolute difference in methylation was between 0.6% and 2.6%. Epigenome-wide associations of HDP with offspring DNA methylation were modestly consistent with the equivalent epigenome-wide associations of preeclampsia with offspring DNA methylation (R2=0.26). In longitudinal analyses conducted in 1 study (n=108 HDP cases; 550 controls), there were similar changes in DNA methylation in offspring of those with and without HDP up to adolescence. Pathway analysis suggested that genes located at/near HDP-associated sites may be involved in developmental, embryogenesis, or neurological pathways. HDP is associated with offspring DNA methylation with potential relevance to development.

7.
Biol Psychiatry ; 86(6): 433-442, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31202489

RESUMO

The identification and understanding of resilience mechanisms holds potential for the development of mechanistically informed prevention and interventions in psychiatry. However, investigating resilience mechanisms is conceptually and methodologically challenging because resilience does not merely constitute the absence of disease-specific risk but rather reflects active processes that aid in the maintenance of physiological and psychological homeostasis across a broad range of environmental circumstances. In this conceptual review, we argue that the principle used in gene-by-environment interaction studies may help to unravel resilience mechanisms on different investigation levels. We present how this could be achieved by top-down designs that start with gene-by-environment interaction effects on disease phenotypes as well as by bottom-up approaches that start at the molecular level. We also discuss how recent technological advances may improve both top-down and bottom-up strategies.

8.
Artigo em Inglês | MEDLINE | ID: mdl-31127037

RESUMO

Our past experiences shape our current and future behavior. These experiences must leave some enduring imprint on our brains, altering neural circuits that mediate behavior and contributing to our individual differences. As a framework for understanding how experiences might produce lasting changes in neural circuits, Clayton [D. F. Clayton, Neurobiol. Learn. Mem. 74, 185-216 (2000)] introduced the concept of the genomic action potential (gAP)-a structured genomic response in the brain to acute experience. Similar to the familiar electrophysiological action potential (eAP), the gAP also provides a means for integrating afferent patterns of activity but on a slower timescale and with longer-lasting effects. We revisit this concept in light of contemporary work on experience-dependent modification of neural circuits. We review the "Immediate Early Gene" (IEG) response, the starting point for understanding the gAP. We discuss evidence for its involvement in the encoding of experience to long-term memory across time and biological levels of organization ranging from individual cells to cell ensembles and whole organisms. We explore distinctions between memory encoding and homeostatic functions and consider the potential for perpetuation of the imprint of experience through epigenetic mechanisms. We describe a specific example of a gAP in humans linked to individual differences in the response to stress. Finally, we identify key objectives and new tools for continuing research in this area.

9.
Proc Natl Acad Sci U S A ; 116(23): 11370-11379, 2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-31113877

RESUMO

Aging and psychosocial stress are associated with increased inflammation and disease risk, but the underlying molecular mechanisms are unclear. Because both aging and stress are also associated with lasting epigenetic changes, a plausible hypothesis is that stress along the lifespan could confer disease risk through epigenetic effects on molecules involved in inflammatory processes. Here, by combining large-scale analyses in human cohorts with experiments in cells, we report that FKBP5, a protein implicated in stress physiology, contributes to these relations. Across independent human cohorts (total n > 3,000), aging synergized with stress-related phenotypes, measured with childhood trauma and major depression questionnaires, to epigenetically up-regulate FKBP5 expression. These age/stress-related epigenetic effects were recapitulated in a cellular model of replicative senescence, whereby we exposed replicating human fibroblasts to stress (glucocorticoid) hormones. Unbiased genome-wide analyses in human blood linked higher FKBP5 mRNA with a proinflammatory profile and altered NF-κB-related gene networks. Accordingly, experiments in immune cells showed that higher FKBP5 promotes inflammation by strengthening the interactions of NF-κB regulatory kinases, whereas opposing FKBP5 either by genetic deletion (CRISPR/Cas9-mediated) or selective pharmacological inhibition prevented the effects on NF-κB. Further, the age/stress-related epigenetic signature enhanced FKBP5 response to NF-κB through a positive feedback loop and was present in individuals with a history of acute myocardial infarction, a disease state linked to peripheral inflammation. These findings suggest that aging/stress-driven FKBP5-NF-κB signaling mediates inflammation, potentially contributing to cardiovascular risk, and may thus point to novel biomarker and treatment possibilities.

10.
Clin Epigenetics ; 11(1): 83, 2019 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-31122292

RESUMO

BACKGROUND: Epigenetic mechanisms may play a major role in the biological embedding of early-life stress (ELS). One proposed mechanism is that glucocorticoid (GC) release following ELS exposure induces long-lasting alterations in DNA methylation (DNAm) of important regulatory genes of the stress response. Here, we investigate the dynamics of GC-dependent methylation changes in key regulatory regions of the FKBP5 locus in which ELS-associated DNAm changes have been reported. RESULTS: We repeatedly measured DNAm in human peripheral blood samples from 2 independent cohorts exposed to the GC agonist dexamethasone (DEX) using a targeted bisulfite sequencing approach, complemented by data from Illumina 450K arrays. We detected differentially methylated CpGs in enhancers co-localizing with GC receptor binding sites after acute DEX treatment (1 h, 3 h, 6 h), which returned to baseline levels within 23 h. These changes withstood correction for immune cell count differences. While we observed main effects of sex, age, body mass index, smoking, and depression symptoms on FKBP5 methylation levels, only the functional FKBP5 SNP (rs1360780) moderated the dynamic changes following DEX. This genotype effect was observed in both cohorts and included sites previously shown to be associated with ELS. CONCLUSION: Our study highlights that DNAm levels within regulatory regions of the FKBP5 locus show dynamic changes following a GC challenge and suggest that factors influencing the dynamics of this regulation may contribute to the previously reported alterations in DNAm associated with current and past ELS exposure.

11.
Psychoneuroendocrinology ; 106: 28-37, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30953930

RESUMO

OBJECTIVE: Major Depression (MD) results from a complex interplay between environmental stressors and biological factors. Previous studies in adults have shown that adverse life events interact with genetic variation in FKBP5, a gene implicated in the stress-response system, to predict depressive symptoms and MD. This is the first study to investigate interactions between FKBP5 variants and a range of environmental stressors in adolescents with a clinical diagnosis of MD. METHOD: 148 male and female adolescents with MD and 143 typically developing (TD) controls (13-18 years) were included in the present study. For self-reported environmental stressors, subjective severity was assessed to allow a classification of these factors as mild, moderate and severe. Sociodemographic stressors were assessed via parental-report. RESULTS: With a heightened number of sociodemographic, moderate and total number of stressors, participants carrying at least one copy of the FKBP5 CATT haplotype or at least one minor allele of various FKBP5 SNPs had the highest risk for being in the MD group. No genetic main effects were found. Sociodemographic stressors as well as self-reported mild, moderate, and severe stressors were more common in depressed than in TD adolescents. CONCLUSION: This is the first study to show interactions between genetic variation in FKBP5 and environmental stressors in a sample of clinically depressed adolescents. The current study provides important starting-points for preventive efforts and highlights the need for a fine-grained analysis of different forms and severities of environmental stressors and their interplay with genetic variation for understanding the complex etiology of (youth) MD.

12.
Sci Rep ; 9(1): 983, 2019 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-31000782

RESUMO

While biological alterations associated with childhood maltreatment (CM) have been found in affected individuals, it remains unknown to what degree these alterations are biologically transmitted to the next generation. We investigated intergenerational effects of maternal CM on DNA methylation and gene expression in N = 113 mother-infant dyads shortly after parturition, additionally accounting for the role of the FKBP5 rs1360780 genotype. Using mass array spectrometry, we assessed the DNA methylation of selected stress-response-associated genes (FK506 binding protein 51 [FKBP5], glucocorticoid receptor [NR3C1], corticotropin-releasing hormone receptor 1 [CRHR1]) in isolated immune cells from maternal blood and neonatal umbilical cord blood. In mothers, CM was associated with decreased levels of DNA methylation of FKBP5 and CRHR1 and increased NR3C1 methylation, but not with changes in gene expression profiles. Rs1360780 moderated the FKBP5 epigenetic CM-associated regulation profiles in a gene × environment interaction. In newborns, we found no evidence for any intergenerational transmission of CM-related methylation profiles for any of the investigated epigenetic sites. These findings support the hypothesis of a long-lasting impact of CM on the biological epigenetic regulation of stress-response mediators and suggest for the first time that these specific epigenetic patterns might not be directly transmitted to the next generation.

13.
Behav Brain Sci ; 42: e7, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30940272

RESUMO

Progress in psychiatric research has been hindered by the use of artificial disease categories to map distinct biological substrates. Efforts to overcome this obstacle have led to the misconception that relevant psychiatric dimensions are not biologically reducible. Consequently, the return to phenomenology is once again advocated. We propose a process-centered paradigm of biological reduction compatible with non-reductive materialism.


Assuntos
Encefalopatias , Psicopatologia , Humanos , Pesquisa
14.
Am J Psychiatry ; 176(8): 626-634, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30947533

RESUMO

OBJECTIVE: Self-regulation includes the volitional and nonvolitional regulation of emotional, cognitive, and physiological responses to stimulation. It develops from infancy through individual characteristics and the environment, with the stress hormone system as a central player. Accordingly, the authors hypothesized that genes involved in regulating the stress system, such as FK506 binding protein 5 (FKBP5), interact with early-life stress exposure, such as exposure to intimate partner violence (IPV), to predict self-regulation indicators and associated outcomes, including behavioral and learning problems in school. METHODS: Study participants were a longitudinal birth cohort of 910 children for whom FKBP5 genotypes were available and who were assessed for exposure to IPV during the first 2 years of life as well as multiple measures of self-regulation: stress-induced cortisol reactivity and fear-elicited emotional reactivity at 7, 15, and 24 months, executive function at 36, 48, and 60 months, and emotional and behavioral difficulties and reading and math achievement in school grades 1, 2, and 5. Data were analyzed using longitudinal clustering and ordinal logistic regression procedures followed by mixed linear modeling. RESULTS: Children with two copies of a risk FKBP5 haplotype and IPV exposure were significantly more likely to have a developmental trajectory characterized by high, prolonged stress-induced cortisol reactivity and emotional reactivity in toddlerhood, followed by low executive function at school entry and high emotional and behavior problems and low reading ability in the primary school grades. CONCLUSIONS: The interaction of FKBP5 and IPV affects the physiological response to stress early in life, with consequences for emotional and cognitive self-regulation. Targeting self-regulation may present an early intervention strategy for children facing genetic and environmental risk.

15.
Am J Psychiatry ; 176(8): 615-625, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30947532

RESUMO

OBJECTIVE: Identifying risk factors for major depression and depressive symptoms in youths could have important implications for prevention efforts. This study examined the association of polygenic risk scores (PRSs) for a broad depression phenotype derived from a large-scale genome-wide association study (GWAS) in adults, and its interaction with childhood abuse, with clinically relevant depression outcomes in clinical and epidemiological youth cohorts. METHODS: The clinical cohort comprised 279 youths with major depression (mean age=14.76 years [SD=2.00], 68% female) and 187 healthy control subjects (mean age=14.67 years [SD=2.45], 63% female). The first epidemiological cohort included 1,450 youths (mean age=13.99 years [SD=0.92], 63% female). Of those, 694 who were not clinically depressed at baseline underwent follow-ups at 6, 12, and 24 months. The replication epidemiological cohort comprised children assessed at ages 8 (N=184; 49.2% female) and 11 (N=317; 46.7% female) years. All cohorts were genome-wide genotyped and completed measures for major depression, depressive symptoms, and/or childhood abuse. Summary statistics from the largest GWAS to date on depression were used to calculate the depression PRS. RESULTS: In the clinical cohort, the depression PRS predicted case-control status (odds ratio=1.560, 95% CI=1.230-1.980), depression severity (ß=0.177, SE=0.069), and age at onset (ß=-0.375, SE=0.160). In the first epidemiological cohort, the depression PRS predicted baseline depressive symptoms (ß=0.557, SE=0.200) and prospectively predicted onset of moderate to severe depressive symptoms (hazard ratio=1.202, 95% CI=1.045-1.383). The associations with depressive symptoms were replicated in the second epidemiological cohort. Evidence was found for an additive, but not an interactive, effect of the depression PRS and childhood abuse on depression outcomes. CONCLUSIONS: Depression PRSs derived from adults generalize to depression outcomes in youths and may serve as an early indicator of clinically significant levels of depression.

16.
Clin Pharmacol Ther ; 106(4): 855-865, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31012492

RESUMO

We set out to determine whether machine learning-based algorithms that included functionally validated pharmacogenomic biomarkers joined with clinical measures could predict selective serotonin reuptake inhibitor (SSRI) remission/response in patients with major depressive disorder (MDD). We studied 1,030 white outpatients with MDD treated with citalopram/escitalopram in the Mayo Clinic Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS; n = 398), Sequenced Treatment Alternatives to Relieve Depression (STAR*D; n = 467), and International SSRI Pharmacogenomics Consortium (ISPC; n = 165) trials. A genomewide association study for PGRN-AMPS plasma metabolites associated with SSRI response (serotonin) and baseline MDD severity (kynurenine) identified single nucleotide polymorphisms (SNPs) in DEFB1, ERICH3, AHR, and TSPAN5 that we tested as predictors. Supervised machine-learning methods trained using SNPs and total baseline depression scores predicted remission and response at 8 weeks with area under the receiver operating curve (AUC) > 0.7 (P < 0.04) in PGRN-AMPS patients, with comparable prediction accuracies > 69% (P ≤ 0.07) in STAR*D and ISPC. These results demonstrate that machine learning can achieve accurate and, importantly, replicable prediction of SSRI therapy response using total baseline depression severity combined with pharmacogenomic biomarkers.

17.
Mol Psychiatry ; 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30874608

RESUMO

Predicting antidepressant response has been a clinical challenge for mood disorder. Although several genome-wide association studies have suggested a number of genetic variants to be associated with antidepressant response, the sample sizes are small and the results are difficult to replicate. Previous animal studies have shown that knockout of the serotonin receptor 7 gene (HTR7) resulted in an antidepressant-like phenotype, suggesting it was important to antidepressant action. In this report, in the first stage, we used a cost-effective pooled-sequencing strategy to sequence the entire HTR7 gene and its regulatory regions to investigate the association of common variants in HTR7 and clinical response to four selective serotonin reuptake inhibitors (SSRIs: citalopram, paroxetine, fluoxetine and sertraline) in a retrospective cohort mainly consisting of subjects with bipolar disorder (n = 359). We found 80 single-nucleotide polymorphisms (SNPs) with false discovery rate < 0.05 associated with response to paroxetine. Among the significant SNPs, rs7905446 (T/G), which is located at the promoter region, also showed nominal significance (P < 0.05) in fluoxetine group. GG/TG genotypes for rs7905446 and female gender were associated with better response to two SSRIs (paroxetine and fluoxetine). In the second stage, we replicated this association in two independent prospective samples of SSRI-treated patients with major depressive disorder: the MARS (n = 253, P = 0.0169) and GENDEP studies (n = 432, P = 0.008). The GG/TG genotypes were consistently associated with response in all three samples. Functional study of rs7905446 showed greater activity of the G allele in regulating expression of HTR7. The G allele displayed higher luciferase activity in two neuronal-related cell lines, and estrogen treatment decreased the activity of only the G allele. Electrophoretic mobility shift assay suggested that the G allele interacted with CCAAT/enhancer-binding protein beta transcription factor (TF), while the T allele did not show any interaction with any TFs. Our results provided novel pharmacogenomic evidence to support the role of HTR7 in association with antidepressant response.

18.
Artigo em Inglês | MEDLINE | ID: mdl-30858011

RESUMO

OBJECTIVE: Women exposed to childhood maltreatment (CM) are more likely to exhibit insensitive parenting, which may have consequences for their offspring's development. Variation in the oxytocin-receptor gene (OXTR) moderates risk of CM-associated long-term sequelae associated with mother-child attachment, although functionality of previously investigated single nucleotide polymorphisms (SNPs) remained elusive. Here, we investigated the role of OXTR rs237895, a brain tissue expression quantitative trait locus (eQTL), as a moderator of the relationship between CM and maternal behavior (MB) and the association between MB and offspring attachment security. METHOD: Of 110 women with information on rs237895 genotype (T-allele = 64, CC = 46), 107 had information on CM (CTQ) and 99 on standardized observer-based ratings of MB at 6 months postpartum (responsivity and detachment), which were used in principal component analysis to obtain a latent factor representing MB. Offspring (n = 86) attachment was evaluated at 12 months of age. Analyses predicting MB were adjusted for socioeconomic status, age, postpartum depression, and genotype-based ethnicity. Analyses predicting child attachment were adjusted for infant sex, socioeconomic status, and postpartum depression. RESULTS: rs237895 significantly moderated the relationship between CM and MB (F1;66 = 7.99, p < .01), indicating that CM was associated with maternal insensitivity only in high-OXTR-expressing T-allele carriers but not in low-OXTR-expressing CC homozygotes. Moreover, maternal insensitivity predicted offspring insecure attachment (B = -0.551; p < .05). CONCLUSION: Women with a high OXTR expressing genotype are more susceptible to CM-related impairments in MB that, in turn, predict attachment security in their children, supporting the role of the OT system in the intergenerational transmission of risk associated with maternal CM.

19.
Neuropsychopharmacology ; 44(7): 1207-1215, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30710108

RESUMO

Chronic adolescent stress alters behavior in a sex-specific manner at the end of adolescence and in adulthood. Although prolonged behavioral repercussions of chronic adolescent stress have been documented, the potential underlying mechanisms are incompletely understood. In this study we demonstrate that a history of chronic adolescent stress modified the adult stress response, as measured by corticosterone concentration, such that a history of chronic adolescent stress resulted in a blunted response to a novel acute stressor. In order to begin to address potential mechanistic underpinnings, we assessed the extent to which chronic adolescent stress impacted global DNA methylation. Reduced global hippocampal methylation was evident in females with a history of chronic adolescent stress; thus, it was possible that chronic adolescent stress altered global transcription in the whole hippocampi of adult male and female rats. In addition, because acute stress can stimulate a genomic response, we assessed the transcriptome following exposure to an acute novel stressor to determine the extent to which a history of chronic adolescent stress modifies the adult transcriptional response to an acute stressor in males and females. In addition to the reduction in global methylation, chronic adolescent stress resulted in distinct patterns of gene expression in the adult hippocampus that differentiated by sex. Furthermore, both sex and a history of chronic adolescent stress influenced the transcriptional response to an acute novel stressor in adulthood, suggesting both latent and functional effects of chronic adolescent stress at the level of gene transcription. Pathway analysis indicated that ESR1 and IFN-α may be particularly influential transcription factors mediating these transcriptional differences and suggest candidate mechanisms for future studies. Collectively, these studies demonstrate sex-specific and enduring effects of adolescent stress exposure that are more pronounced in females than in males.

20.
Transl Psychiatry ; 9(1): 41, 2019 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-30696808

RESUMO

Early-life adversity is an important risk factor for major depressive disorder (MDD) and schizophrenia (SCZ) that interacts with genetic factors to confer disease risk through mechanisms that are still insufficiently understood. One downstream effect of early-life adversity is the activation of glucocorticoid receptor (GR)-dependent gene networks that drive acute and long-term adaptive behavioral and cellular responses to stress. We have previously shown that genetic variants that moderate GR-induced gene transcription (GR-response eSNPs) are significantly enriched among risk variants from genome-wide association studies (GWASs) for MDD and SCZ. Here, we show that the 63 transcripts regulated by these disease-associated functional genetic variants form a tight glucocorticoid-responsive co-expression network (termed GCN). We hypothesized that changes in the correlation structure of this GCN may contribute to early-life adversity-associated disease risk. Therefore, we analyzed the effects of different qualities of social support and stress throughout life on GCN formation across distinct brain regions using a translational mouse model. We observed that different qualities of social experience substantially affect GCN structure in a highly brain region-specific manner. GCN changes were predominantly found in two functionally interconnected regions, the ventral hippocampus and the hypothalamus, two brain regions previously shown to be of relevance for the stress response, as well as psychiatric disorders. Overall, our results support the hypothesis that a subset of genetic variants may contribute to risk for MDD and SCZ by altering circuit-level effects of early and adult social experiences on GCN formation and structure.


Assuntos
Transtorno Depressivo Maior/genética , Redes Reguladoras de Genes , Receptores de Glucocorticoides/genética , Esquizofrenia/genética , Estresse Psicológico/genética , Animais , Comportamento Animal , Encéfalo/metabolismo , Feminino , Hipocampo/metabolismo , Humanos , Masculino , Camundongos Endogâmicos BALB C , Núcleo Hipotalâmico Paraventricular/metabolismo , Especificidade da Espécie
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