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Genome-wide association studies (GWASs) have uncovered susceptibility loci associated with psychiatric disorders such as bipolar disorder (BP) and schizophrenia (SCZ). However, most of these loci are in non-coding regions of the genome, and the causal mechanisms of the link between genetic variation and disease risk is unknown. Expression quantitative trait locus (eQTL) analysis of bulk tissue is a common approach used for deciphering underlying mechanisms, although this can obscure cell-type-specific signals and thus mask trait-relevant mechanisms. Although single-cell sequencing can be prohibitively expensive in large cohorts, computationally inferred cell-type proportions and cell-type gene expression estimates have the potential to overcome these problems and advance mechanistic studies. Using bulk RNA-seq from 1,730 samples derived from whole blood in a cohort ascertained from individuals with BP and SCZ, this study estimated cell-type proportions and their relation with disease status and medication. For each cell type, we found between 2,875 and 4,629 eGenes (genes with an associated eQTL), including 1,211 that are not found on the basis of bulk expression alone. We performed a colocalization test between cell-type eQTLs and various traits and identified hundreds of associations that occur between cell-type eQTLs and GWASs but that are not detected in bulk eQTLs. Finally, we investigated the effects of lithium use on the regulation of cell-type expression loci and found examples of genes that are differentially regulated according to lithium use. Our study suggests that applying computational methods to large bulk RNA-seq datasets of non-brain tissue can identify disease-relevant, cell-type-specific biology of psychiatric disorders and psychiatric medication.
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Estudo de Associação Genômica Ampla , Lítio , Humanos , Estudo de Associação Genômica Ampla/métodos , RNA-Seq , Locos de Características Quantitativas/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , Predisposição Genética para DoençaRESUMO
Schizophrenia affects approximately 1% of the world population. Genetics, epigenetics, and environmental factors are known to play a role in this psychiatric disorder. While there is a high concordance in monozygotic twins, about half of twin pairs are discordant for schizophrenia. To address the question of how and when concordance in monozygotic twins occur, we have obtained fibroblasts from two pairs of schizophrenia discordant twins (one sibling with schizophrenia while the second one is unaffected by schizophrenia) and three pairs of healthy twins (both of the siblings are healthy). We have prepared iPSC models for these 3 groups of patients with schizophrenia, unaffected co-twins, and the healthy twins. When the study started the co-twins were considered healthy and unaffected but both the co-twins were later diagnosed with a depressive disorder. The reprogrammed iPSCs were differentiated into hippocampal neurons to measure the neurophysiological abnormalities in the patients. We found that the neurons derived from the schizophrenia patients were less arborized, were hypoexcitable with immature spike features, and exhibited a significant reduction in synaptic activity with dysregulation in synapse-related genes. Interestingly, the neurons derived from the co-twin siblings who did not have schizophrenia formed another distinct group that was different from the neurons in the group of the affected twin siblings but also different from the neurons in the group of the control twins. Importantly, their synaptic activity was not affected. Our measurements that were obtained from schizophrenia patients and their monozygotic twin and compared also to control healthy twins point to hippocampal synaptic deficits as a central mechanism in schizophrenia.
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Baby schema features are a specific set of physical features-including chubby cheeks, large, low-set eyes, and a large, round head-that have evolutionary adaptive value in their ability to trigger nurturant care. In this study among nulliparous women (N = 81; M age = 23.60, SD = 0.44), we examined how sensitivity to these baby schema features differs based on individual variations in nurturant care motivation and oxytocin system gene methylation. We integrated subjective ratings with measures of facial expressions and electroencephalography (EEG) in response to infant faces that were manipulated to contain more or less pronounced baby schema features. Linear mixed effects analyses demonstrated that infants with more pronounced baby schema features were rated as cuter and participants indicated greater motivation to take care of them. Furthermore, infants with more pronounced baby schema features elicited stronger smiling responses and enhanced P2 and LPP amplitudes compared to infants with less pronounced baby schema features. Importantly, individual differences significantly predicted baby schema effects. Specifically, women with low OXTR methylation and high nurturance motivation showed enhanced differentiation in automatic neurophysiological responses to infants with high and low levels of baby schema features. These findings highlight the importance of considering individual differences in continued research to further understand the complexities of sensitivity to child cues, including facial features, which will improve our understanding of the intricate neurobiological system that forms the basis of caregiving behavior.
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Metilação de DNA , Eletroencefalografia , Expressão Facial , Motivação , Ocitocina , Receptores de Ocitocina , Humanos , Feminino , Motivação/fisiologia , Ocitocina/metabolismo , Ocitocina/genética , Metilação de DNA/fisiologia , Lactente , Receptores de Ocitocina/genética , Adulto Jovem , Adulto , Comportamento Materno/fisiologia , Comportamento do Lactente/fisiologia , Masculino , Relações Mãe-FilhoRESUMO
BACKGROUND: One of the most robust risk factors for developing a mood disorder is having a parent with a mood disorder. Unfortunately, mechanisms explaining the transmission of mood disorders from one generation to the next remain largely elusive. Since timely intervention is associated with a better outcome and prognosis, early detection of intergenerational transmission of mood disorders is of paramount importance. Here, we describe the design of the Mood and Resilience in Offspring (MARIO) cohort study in which we investigate: 1. differences in clinical, biological and environmental (e.g., psychosocial factors, substance use or stressful life events) risk and resilience factors in children of parents with and without mood disorders, and 2. mechanisms of intergenerational transmission of mood disorders via clinical, biological and environmental risk and resilience factors. METHODS: MARIO is an observational, longitudinal cohort study that aims to include 450 offspring of parents with a mood disorder (uni- or bipolar mood disorders) and 100-150 offspring of parents without a mood disorder aged 10-25 years. Power analyses indicate that this sample size is sufficient to detect small to medium sized effects. Offspring are recruited via existing Dutch studies involving patients with a mood disorder and healthy controls, for which detailed clinical, environmental and biological data of the index-parent (i.e., the initially identified parent with or without a mood disorder) is available. Over a period of three years, four assessments will take place, in which extensive clinical, biological and environmental data and data on risk and resilience are collected through e.g., blood sampling, face-to-face interviews, online questionnaires, actigraphy and Experience Sampling Method assessment. For co-parents, information on demographics, mental disorder status and a DNA-sample are collected. DISCUSSION: The MARIO cohort study is a large longitudinal cohort study among offspring of parents with and without mood disorders. A unique aspect is the collection of granular data on clinical, biological and environmental risk and resilience factors in offspring, in addition to available parental data on many similar factors. We aim to investigate the mechanisms underlying intergenerational transmission of mood disorders, which will ultimately lead to better outcomes for offspring at high familial risk.
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Filho de Pais com Deficiência , Resiliência Psicológica , Criança , Humanos , Filho de Pais com Deficiência/psicologia , Estudos de Coortes , Estudos Longitudinais , Transtornos do Humor/psicologia , Pais/psicologiaRESUMO
This study investigated associations of the Incredible Years (IY) parenting program with children's DNA methylation. Participants were 289 Dutch children aged 3-9 years (75% European ancestry, 48% female) with above-average conduct problems. Saliva was collected 2.5 years after families were randomized to IY or care as usual (CAU). Using an intention-to-treat approach, confirmatory multiple-regression analyses revealed no significant differences between the IY and CAU groups in children's methylation levels at the NR3C1 and FKBP5 genes. However, exploratory epigenome-wide analyses revealed nine differentially methylated regions between groups, coinciding with SLAMF1, MITF, FAM200B, PSD3, SNX31, and CELSR1. The study provides preliminary evidence for associations of IY with children's salivary methylation levels and highlights the need for further research into biological outcomes of parenting programs.
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Background: Clonidine is a centrally acting anti-adrenergic agent that may have applications in post-traumatic stress disorder (PTSD), particularly for sleep.Objective: In this systematic review, we aimed to summarize the effect of clonidine on sleep quality and duration, nightmares, and PTSD symptom severity in adults with PTSD.Method: PubMed (Medline), Embase, PsycINFO, CINAHL, and clinicaltrials.gov were searched up to April 2023. Studies on clonidine use in adult PTSD patients reporting data on the effect on sleep, nightmares, and PTSD symptoms were included. A narrative summary and a meta-analysis of the study findings are presented.Results: Ten reports, accounting for N = 569 patients with PTSD (145 on clonidine and 436 controls), were included in the final selection. There were four case reports, four observational studies, one non-blind clinical trial, and one crossover randomized controlled trial (RCT). Median clonidine dose was 0.15â mg/day (range: 0.1-0.5â mg/day). Median follow-up time was 31 days (range: 3 days to 19 months). The quality of the evidence was rated from very low to low. There was marked between-study heterogeneity and low power in the individual studies, but many reported improved sleep quality, nightmare reduction, and improvement of PTSD symptoms for patients treated with clonidine. Meta-analysis was only possible for two studies reporting the effect of clonidine on nightmares, and showed no difference from the comparator (i.e. prazosin or terazosin) (odds ratio: 1.16; 95% confidence interval: 0.66 to 2.05), potentially pointing towards non-inferiority between these medications.Conclusions: Future research, such as well-powered RCTs, is needed to identify the efficacy in the lower dose range and the most suitable treatment group, and to obtain good evidence on the effects of clonidine in the treatment of sleep disorders related to PTSD.
Post-traumatic stress disorder (PTSD) is associated with hyperarousal and sleep disorders, reflecting adrenergic nervous system involvement.The use of anti-adrenergic drugs to target the sympathetic activation in PTSD is rational. However, previous reports on prazosin, a peripherally acting agent, yielded weak evidence.Clonidine, a central adrenergic antagonist, shows promise in improving sleep, nightmares, and PTSD symptoms, but further research is needed because the quality of the current evidence is low.
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Clonidina , Transtornos de Estresse Pós-Traumáticos , Clonidina/uso terapêutico , Humanos , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Sonhos/efeitos dos fármacos , Qualidade do Sono , Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagemRESUMO
It is unclear whether poverty and mental illness are causally related. Using UK Biobank and Psychiatric Genomic Consortium data, we examined evidence of causal links between poverty and nine mental illnesses (attention deficit and hyperactivity disorder (ADHD), anorexia nervosa, anxiety disorder, autism spectrum disorder, bipolar disorder, major depressive disorder, obsessive-compulsive disorder, post-traumatic stress disorder and schizophrenia). We applied genomic structural equation modelling to derive a poverty common factor from household income, occupational income and social deprivation. Then, using Mendelian randomization, we found evidence that schizophrenia and ADHD causally contribute to poverty, while poverty contributes to major depressive disorder and schizophrenia but decreases the risk of anorexia nervosa. Poverty may also contribute to ADHD, albeit with uncertainty due to unbalanced pleiotropy. The effects of poverty were reduced by approximately 30% when we adjusted for cognitive ability. Further investigations of the bidirectional relationships between poverty and mental illness are warranted, as they may inform efforts to improve mental health for all.
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Post-traumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 new). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (for example, GRIA1, GRM8 and CACNA1E), developmental, axon guidance and transcription factors (for example, FOXP2, EFNA5 and DCC), synaptic structure and function genes (for example, PCLO, NCAM1 and PDE4B) and endocrine or immune regulators (for example, ESR1, TRAF3 and TANK). Additional top genes influence stress, immune, fear and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation.
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Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Transtornos de Estresse Pós-Traumáticos , Humanos , Transtornos de Estresse Pós-Traumáticos/genética , População Branca/genética , Neurobiologia , Loci GênicosRESUMO
Background: The occurrence of post-traumatic stress disorder (PTSD) following a traumatic event is associated with biological differences that can represent the susceptibility to PTSD, the impact of trauma, or the sequelae of PTSD itself. These effects include differences in DNA methylation (DNAm), an important form of epigenetic gene regulation, at multiple CpG loci across the genome. Moreover, these effects can be shared or specific to both central and peripheral tissues. Here, we aim to identify blood DNAm differences associated with PTSD and characterize the underlying biological mechanisms by examining the extent to which they mirror associations across multiple brain regions. Methods: As the Psychiatric Genomics Consortium (PGC) PTSD Epigenetics Workgroup, we conducted the largest cross-sectional meta-analysis of epigenome-wide association studies (EWASs) of PTSD to date, involving 5077 participants (2156 PTSD cases and 2921 trauma-exposed controls) from 23 civilian and military studies. PTSD diagnosis assessments were harmonized following the standardized guidelines established by the PGC-PTSD Workgroup. DNAm was assayed from blood using either Illumina HumanMethylation450 or MethylationEPIC (850K) BeadChips. A common QC pipeline was applied. Within each cohort, DNA methylation was regressed on PTSD, sex (if applicable), age, blood cell proportions, and ancestry. An inverse variance-weighted meta-analysis was performed. We conducted replication analyses in tissue from multiple brain regions, neuronal nuclei, and a cellular model of prolonged stress. Results: We identified 11 CpG sites associated with PTSD in the overall meta-analysis (1.44e-09 < p < 5.30e-08), as well as 14 associated in analyses of specific strata (military vs civilian cohort, sex, and ancestry), including CpGs in AHRR and CDC42BPB. Many of these loci exhibit blood-brain correlation in methylation levels and cross-tissue associations with PTSD in multiple brain regions. Methylation at most CpGs correlated with their annotated gene expression levels. Conclusions: This study identifies 11 PTSD-associated CpGs, also leverages data from postmortem brain samples, GWAS, and genome-wide expression data to interpret the biology underlying these associations and prioritize genes whose regulation differs in those with PTSD.