Previous studies have shown state-related alterations of peripheral DNA methylation levels in people with Anorexia Nervosa (AN). The aim of the present study was to investigate the extent to which illness duration in AN impacts DNA methylation changes and to examine any effects of illness duration upon the stability of methylation changes following symptom remission. We assessed leukocyte genome-wide DNA methylation in 198 women with active AN, 62 showing one-year weight restoration after a full-threshold episode of AN (AN-remitted) and 92 who never had an eating disorder (NED). Follow-up data (after 15.3 weeks of treatment, on average) were available for 108 AN-active participants. Compared to NED and AN-remitted participants, women with active AN had altered DNA methylation in genes involved in mental status, metabolism and immune function. Subsequent analyses highlighted differentially-methylated regions at LRRC8D, PRKAG2, CCDC6, and STAT3 genes. Additionally, in AN-active participants, longer illness duration was associated with lower methylation levels (7 CpG sites) in the serotonin receptor 2A gene (HTR2A) promoter region. Irrespective of illness duration, increases in body mass index were associated with methylation changes in genes involved in lipid and glucose metabolism, cellular functions, and immune processes. Results suggest chronicity-linked, reversible alterations of DNA methylation in AN, and support a pathophysiological model of AN involving psychiatric, metabolic, and immune components. In particular, our findings point to an epigenetically-regulated effect by which a long-standing eating disorder may adversely affect the serotonin system--which is thought to mediate various features that are prominent in individuals with AN.

Background Nicotinic acetylcholine receptors (nAChRs) are expressed throughout the mammalian central nervous system, mediating cholinergic neurotransmission both in the developing and the adult brain. Among these, alpha 7 (α7) nAChRs demonstrate unique pharmacological properties and are potential targets in the treatment of neuropsychiatric disorders. α7nAChRs are also present in the hippocampus, therefore, we investigated this receptor type in human induced pluripotent stem cell (hiPSC) derived dentate gyrus (DG) granule cells, an in vitro model system of adult hippocampal neurogenesis. Methods DG granule cells were generated from hiPSCs to investigate the nAChR α7 subunit expression via qPCR, RNA-sequencing, and bungarotoxin-staining. To validate receptor function, we employed single-neuron patch-clamp electrophysiology. Calcium-imaging was used to assess spontaneous and ligand-evoked calcium-transients, while multi-electrode array (MEA) measurements were applied to evaluate network activity. Experiments involved choline (agonist), PNU-120596 (allosteric activator), and methyllaconitine (antagonist). Results Our results showed α7nAChRs in hiPSCs-derived PROX1 and MAP2 positive DG granule cells. Patch-clamp electrophysiology revealed that the selective agonist choline evoked inward currents, which were greatly augmented by PNU-120596. Methyllycaconitine inhibited these currents. Ca-imaging showed increased transients in response to both choline and PNU-120596, which were blocked by methyllycaconitine. MEA recordings indicated increased bursting activity with choline, but not with PNU-120596. Conclusion Our results suggest that hiPSC-derived DG granule cells are amenable to functional assays to investigate α7nAChR function and pharmacology. This model system can serve for testing the receptor in a neuronal population relevant for several psychiatric disorders, including schizophrenia, anxiety disorders, and Alzheimer’s disease.

Background Previous epigenetic studies have shown altered DNA methylation levels in disorder-relevant genes in people with Anorexia Nervosa (AN) and have suggested that such alterations become more pronounced with a longer duration of illness but are reversible with remission of the disorder. The present study elaborates upon previous work in this area, providing a detailed examination of the genomic sites at which illness duration may impact DNA methylation in people with AN, as well as a prospective examination of the extent to which illness duration may affect the responsiveness of methylation changes to symptom remission. Methods The study was conducted at the Eating Disorders Continuum of the Douglas Mental Health University Institute in Montreal, Canada. We assessed leukocyte genome-wide DNA methylation in 198 women with active AN (AN-active), 62 showing one-year weight restoration after a previously fully threshold AN (AN-remitted) and 92 who had never experienced an eating disorder (NED). Follow-up DNA methylation data were available (4 months on average) for 108 AN-active participants. Linear mixed-effects models were used to study the links between clinical status and illness duration, on the one hand, and DNA methylation levels, on the other. Estimated cell proportions, age, smoking, and use of psychotropic medication were included as covariates. Array was included as a random factor, as appropriate. Results In line with our previous findings, individuals with active-AN had altered DNA methylation relative to NED individuals (296 probes, Q < .01) and AN-remitted participants (223 probes, Q < .01) in genes involved in mental health, metabolism and immune function. There were no methylation level differences between long-term remitted participants and people with no eating disorder.In participants with active AN, a longer illness duration was associated with more pronounced alterations in methylation levels at genes implicated in serotonin activity (serotonin receptor HTR2A and ALDH8A1, involved in tryptophan catabolism), and genes coding for key transcription regulators, such as Early B-Cell Factor 1, Early Growth Response 3, non-coding RNA involved in autoimmune function LY6E-DT, and drug and hormone metabolizing UDP glucuronosyltransferase UGT1A6. Changes in BMI during treatment were associated with changes in DNA methylation in probes corresponding to genes involved in body mass (e.g., the PRKAG2 subunit regulating AMP-activated protein kinase, zinc finger protein ZNF608), insulin and lipid metabolism (e.g., the key regulator RPTOR, glucose transporter and receptor for high-density lipoprotein cholesterol), cellular function (e.g., transcription initiation factor TFIIF interacting CTDP1, cadherin binding EHD4, integrin interacting TM4SF19, double-strand break repair regulator SPIDR), and development (e.g., dynamin 3). Illness duration did not moderate symptoms or DNA methylation change over time. Conclusion Findings corroborate past results on state-related methylation alterations in AN and support a previously proposed pathophysiological model for AN that includes psychiatric, metabolic, and immune components. Epigenetic mechanisms– and DNA methylation in particular– may have the potential to impact the progression from genetic susceptibility to full-blown illness, and back. Our findings suggest that DNA methylation measures may be a potential biological marker of illness entrenchment or response to treatment.

INTRODUCTION:Eating disorders are characterized by maladaptive eating behaviors and preoccupations around body shape, weight, and eating. The serotonin system has been among the most widely studied neurobiological factors in relation to eating disorders. Recent research also highlighted the role of oxytocin. AIMS AND METHODS:This article aims to review animal and human studies on the involvement of central serotonin and oxytocin, and their interplay in eating disorders in particular. We synthesize results from studies using animal models of eating disorders and from research conducted in healthy individuals and clinical populations. RESULTS/OUTCOMES:Altered serotonin neurotransmission and oxytocin levels in the brain-particularly in the hypothalamus, brainstem, and limbic regions-were associated with disturbances in eating behaviors and related maladaptive cognitions and emotions. These brain regions were found to constitute a typical neural network through which both central serotonin and oxytocin might operate in a bidirectional manner. CONCLUSIONS/INTERPRETATION:Based on the preceding findings, we describe a developmental biopsychosocial model relevant to eating disorders, including the role of serotonin-oxytocin interactions in the brain. While it is clear that eating disorders are multifactorial in which many biopsychosocial pathways are involved, the current review highlights the importance of well-designed translational research when studying mechanisms of serotonin-oxytocin interactions in the brain. Such research would help to better understand the effects of joint central oxytocin and serotonin administration as a possible preventive or therapeutic intervention for eating disorders.

BACKGROUND:Birth weight is considered as an important indicator of environmental conditions during prenatal development. Molecular mechanisms, including epigenetic modifications, play central roles in the body's adaptation to ever-changing environmental conditions. Twin study designs offer a powerful approach for distinguishing environmental from genetic effects. Specifically, within-pair comparisons of monozygotic twins can be used to differentiate unique individual environmental factors from shared environmental and genetic contributions. Notably, numerous studies in monozygotic twins have shown associations between prenatal environment and birth weight discordance (BWD), and suggested a potential involvement of gene expression and epigenetic factors mediating the association. OBJECTIVE:To conduct a scoping review of the literature on definitions of BWD and on epigenetic modifications and gene expression changes associated with BWD in twins. METHOD:Following PRISMA guidelines, we searched PubMed and Ovid MEDLINE(R) databases and included 34 twin studies focusing on birth weight and epigenetic or gene expression outcomes. RESULTS:There is a lack of consensus on BWD values when comparing groups of twins for their risks of perinatal mortality and morbidity, which vary between 15-30% depending on the type of placentation and gestational age. The gene expression twin studies measured mostly metabolism-related candidate genes in placental tissues. Only small-scale twin studies measured BWD associated with gene expression patterns on genome-wide level using neonatal cells. Most DNA methylation twin studies conducted epigenome-level analyses, and studies differ substantially in terms of tissue type and age of the children. Differences in DNA methylation patterns measured in blood or saliva samples of the twins later in life were mostly in genes related to signal transduction, cell differentiation and proliferation processes. CONCLUSION:Transcriptional changes of placental glucose transporters and hypoxia-induced proteins possibly reflect compensatory processes in twin pregnancies. Gene ontology analysis of the differentially methylated genes associated with BWD pointed to transcription regulation and tissue development.

Phenomenology in anorexia nervosa (AN) appears to be subject to epigenetic regulation via DNA methylation. The micronutrients B12 and betaine contribute directly to DNA methylation and have been shown to be abnormally elevated in blood samples from people with AN. We measured plasma B12 and betaine levels, as well as leukocyte DNA methylation levels, among women with active AN (AN-active group), those in 1-year remission from AN (AN-remitted group), and those who had never experienced an eating disorder (NED group). We compared the groups on micronutrient levels and on the strength of association between micronutrients and methylation. We included 64 women in the AN-active group, 49 in the AN-remitted group, and 49 in the NED group. Relative to those with NED (B12: mean 339.6 [standard deviation (SD) 224.3] μmol/L; betaine: mean 33.74 [SD 17.10] μmol/L), participants with active AN showed high B12 and betaine (B12: mean 571.0 [SD 505.2] μmol/L; betaine: mean 43.73 [SD 22.50] μmol/L); AN-remitted participants had elevated B12 alone (B12: mean 588.2 [SD 379.9] μmol/L; betaine: mean 33.50 [SD 19.20] μmol/L). There were also group-based differences in the strength of association between B12 and site-specific DNA methylation at genes regulating insulin function, glucose metabolism, cell regulation, and neurotransmitter function. These associations between B12 and methylation levels were generally stronger among those without an ED than among those with either active or remitted AN. The extent to which plasma nutrient levels provide a meaningful proxy to cellular processes affecting DNA methylation is uncertain and the sample size limits the stability of results. We included only biological females in this investigation. Elevated B12 levels in AN resemble elevations reported among people with autoimmune, neoplastic, or other disorders. Such elevations imply that plasma B12 levels may misrepresent nutritional status among people with AN. Observed associations between levels of B12 and methylation at certain gene regions have ambiguous importance, but may indicate an influence of nutritional status on epigenetic mechanisms or may be the coincidence of separate processes that independently affect levels of micronutrients and DNA methylation.

BackgroundIncreased levels of emotion dysregulation and impulsive behavior are overlapping symptoms in adult Attention-Deficit/Hyperactivity Disorder (aADHD) and Borderline Personality Disorder (BPD), both symptom domains reflecting on inhibitory control, although from different angles. Our aims were to describe their differences in the above conditions, investigate their associations with childhood traumatization, and to explore the potential mediation of emotion dysregulation and impulsivity between childhood traumas and personality functioning.MethodsYoung adults between 18 and 36 years diagnosed with aADHD (n = 100) and BPD (n = 63) were investigated with structured clinical interviews, while age-matched healthy controls (n = 100) were screened for psychiatric disorders. Patients with aADHD-BPD comorbidity were excluded from further analyses. The Difficulties in Emotion Regulation Scale, the Barratt Impulsiveness Scale, the Level of Personality Functioning Scale, and the Childhood Trauma Questionnaire-Short Form were administered to investigate trait measures and childhood traumatization, respectively. Behavioral impulsivity and delay aversion were assessed using selected tests of the Cambridge Neuropsychological Test Automated Battery, and a computerized decision-making paradigm based on the Rogers decision-making task, respectively.ResultsSignificantly higher levels of emotion dysregulation and impulsivity were present both in the aADHD and BPD groups, however with different profiles. Waiting and stopping impulsivity was selectively higher among aADHD patients compared to healthy controls. The BPD group reported higher levels of emotion dysregulation in all domains, and demonstrated increased delay aversion among uncertain conditions in decision-making. Higher levels of childhood trauma were associated with emotion dysregulation, trait impulsivity, and delay aversion across groups. Emotion regulatory capacity played a significant mediating role between childhood traumatization and the level of personality functioning.ConclusionsInhibitory control profiles of the aADHD and BPD groups were divergent. Childhood traumatization was associated with lower levels of personality functioning in adulthood, independently of diagnosis, an effect mediated more by emotion dysregulation, rather than impulsivity. These findings have various clinical implications for the treatment of aADHD and BPD, including psychoeducation, pharmacological interventions, and psychotherapy targeting specific symptom domains.

Plasma levels of glial cell line-derived neurotrophic factor (GDNF), a pivotal regulator of differentiation and survival of dopaminergic neurons, are reportedly decreased in schizophrenia. To explore the involvement of GDNF in the pathogenesis of the disease, a case–control association analysis was performed between five non-coding single nucleotide polymorphisms (SNP) across the GDNF gene and schizophrenia. Of them, the ‘G’ allele of the rs11111 SNP located in the 3′ untranslated region (3′-UTR) of the gene was found to associate with schizophrenia. In silico analysis revealed that the rs11111 ‘G’ allele might create binding sites for three microRNA (miRNA) species. To explore the significance of this polymorphism, transient co-transfection assays were performed in human embryonic kidney 293T (HEK293T) cells with a luciferase reporter construct harboring either the ‘A’ or ‘G’ allele of the 3′-UTR of GDNF in combination with the hsa-miR-1185-1-3p pre-miRNA. It was demonstrated that in the presence of the rs11111 ‘G’ (but not the ‘A’) allele, hsa-miR-1185-2-3p repressed luciferase activity in a dose-dependent manner. Deletion of the miRNA binding site or its substitution with the complementary sequence abrogated the modulatory effect. Our results imply that the rs11111 ‘G’ allele occurring more frequently in patients with schizophrenia might downregulate GDNF expression in a miRNA-dependent fashion.

BACKGROUND:Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder of complex genetic architecture and is characterized by multiple motor tics and at least one vocal tic persisting for more than 1 year. METHODS:We performed a genome-wide meta-analysis integrating a novel TS cohort with previously published data, resulting in a sample size of 6133 individuals with TS and 13,565 ancestry-matched control participants. RESULTS:We identified a genome-wide significant locus on chromosome 5q15. Integration of expression quantitative trait locus, Hi-C (high-throughput chromosome conformation capture), and genome-wide association study data implicated the NR2F1 gene and associated long noncoding RNAs within the 5q15 locus. Heritability partitioning identified statistically significant enrichment in brain tissue histone marks, while polygenic risk scoring of brain volume data identified statistically significant associations with right and left thalamus volumes and right putamen volume. CONCLUSIONS:Our work presents novel insights into the neurobiology of TS, thereby opening up new directions for future studies.

Background: Induced pluripotent stem cell (iPSC) based neuronal differentiation is valuable for studying neuropsychiatric disorders and pharmacological mechanisms at the cellular level. We aimed to examine the effects of typical and atypical antipsychotics on human iPSC-derived neural progenitor cells (NPCs). Methods: Proliferation and neurite outgrowth were measured by live cell imaging, and gene expression levels related to neuronal identity were analyzed by RT-QPCR and immunocytochemistry during differentiation into hippocampal dentate gyrus granule cells following treatment of low- and high-dose antipsychotics (haloperidol, olanzapine, and risperidone). Results: Antipsychotics did not modify the growth properties of NPCs after 3 days of treatment. However, the characteristics of neurite outgrowth changed significantly in response to haloperidol and olanzapine. After three weeks of differentiation, mRNA expression levels of the selected neuronal markers increased (except for MAP2), while antipsychotics caused only subtle changes. Additionally, we found no changes in MAP2 or GFAP protein expression levels as a result of antipsychotic treatment. Conclusions: Altogether, antipsychotic medications promoted neurogenesis in vitro by influencing neurite outgrowth rather than changing cell survival or gene expression. This study provides insights into the effects of antipsychotics on neuronal differentiation and highlights the importance of considering neurite outgrowth as a potential target of action.

The attention-deficit/hyperactivity disorder (ADHD) clinical phenotype has limitations for deciphering ADHD etiology and predicting prognosis. Although relative to the clinical phenotype, intermediate phenotypes may have better explanatory and prognostic power, the extent to which ADHD intermediate phenotypes are associated with ADHD risk and prognosis is unknown. The aim of this study was to evaluate evidence for event-related potential (ERP) measures of reward anticipation as ADHD risk and prognostic biomarkers. We examined, whether (1) in a sample of adolescents (N = 304; Mage = 15.78 years, SD = 1.08; 39.5

Adult attention-deficit/hyperactivity disorder (aADHD) represents a heterogeneous entity incorporating different subgroups in terms of symptomatology, course, and neurocognition. Although neurocognitive dysfunction is generally associated with aADHD, its severity, association with self-reported symptoms, and differences between subtypes remain unclear. We investigated 61 outpatients (65.6% male, mean age 31.5 ± 9.5) diagnosed using DSM-5 criteria together with age-, sex-, and education-matched healthy controls (HC) ( n = 58, 63.8% male, mean age 32.3 ± 9.6). Neurocognitive alterations were assessed using the Cambridge Neuropsychological Test Automated Battery (CANTAB) and compared between groups using the generalized linear model (GLM) method. Multivariate effects were tested by principal component analysis combined with multivariate pattern analysis. Self-reported symptom severity was tested for correlations with neurocognitive performance. GLM analyses revealed nominally significant differences between the aADHD and HC groups in several domains, however, only the Rapid Visual Information Processing measures survived correction, indicating impaired sustained attention and response inhibition in the aADHD group. Comparison of the predominantly inattentive and the hyperactive-impulsive/combined subtypes yielded nominally significant differences with higher levels of dysfunction in the inattentive group. In the stepwise discriminant analysis aADHD and HC groups were best separated with 2 factors representing sustained attention and reaction time. We found only weak correlations between symptom severity and CANTAB factors. aADHD patients are neuropsychologically heterogeneous and subtypes show different neurocognitive profiles. Differences between the aADHD and HC groups were driven primarily by the inattentive subtype. Sustained attention and its factor derivative showed the most significant alterations in aADHD patients.

Tourette Syndrome (TS) is a complex neurodevelopmental disorder characterized by vocal and motor tics lasting more than a year. It is highly polygenic in nature with both rare and common previously associated variants. Epidemiological studies have shown TS to be correlated with other phenotypes, but large-scale phenome wide analyses in biobank level data have not been performed to date. In this study, we used the summary statistics from the latest meta-analysis of TS to calculate the polygenic risk score (PRS) of individuals in the UK Biobank data and applied a Phenome Wide Association Study (PheWAS) approach to determine the association of disease risk with a wide range of phenotypes. A total of 57 traits were found to be significantly associated with TS polygenic risk, including multiple psychosocial factors and mental health conditions such as anxiety disorder and depression. Additional associations were observed with complex non-psychiatric disorders such as Type 2 diabetes, heart palpitations, and respiratory conditions. Cross-disorder comparisons of phenotypic associations with genetic risk for other childhood-onset disorders (e.g.: attention deficit hyperactivity disorder [ADHD], autism spectrum disorder [ASD], and obsessive-compulsive disorder [OCD]) indicated an overlap in associations between TS and these disorders. ADHD and ASD had a similar direction of effect with TS while OCD had an opposite direction of effect for all traits except mental health factors. Sex-specific PheWAS analysis identified differences in the associations with TS genetic risk between males and females. Type 2 diabetes and heart palpitations were significantly associated with TS risk in males but not in females, whereas diseases of the respiratory system were associated with TS risk in females but not in males. This analysis provides further evidence of shared genetic and phenotypic architecture of different complex disorders.

Background Compelling evidence supports the role of childhood traumatization in the etiology of psychiatric disorders, including adult attention-deficit hyperactivity disorder (aADHD) and borderline personality disorder (BPD). The aim of this study was to examine the psychometric properties of the Hungarian version of the Childhood Trauma Questionnaire Short Form (H-CTQ-SF) and to investigate the differences between patients diagnosed with aADHD and BPD in terms of early traumatization. Methods Altogether 765 (mean age = 32.8 years, 67.7% women) patients and control subjects were enrolled from different areas of Hungary. Principal component analysis and confirmatory factor analysis were carried out to explore the factor structure of H-CTQ-SF and test the validity of the five-factor structure. Discriminative validity was assessed by comparing clinical and non-clinical samples. Subsequently, aADHD and BPD subgroups were compared with healthy controls to test for the role of early trauma in aADHD without comorbid BPD. Convergent validity was explored by measuring correlations with subscales of the Personality Inventory for DSM-5 (PID-5). Results The five scales of the H-CTQ-SF demonstrated adequate internal consistency and reliability values. The five-factor model fitted the Hungarian version well after exclusion of one item from the physical neglect scale because of its cross-loading onto the emotional neglect subscale. The H-CTQ-SF effectively differentiated between the clinical and non-clinical samples. The BPD, but not the aADHD group showed significant differences in each CTQ domain compared with the healthy control group. All CTQ domains, except for physical abuse, demonstrated medium to high correlations with PID-5 emotional lability, anxiousness, separation insecurity, withdrawal, intimacy avoidance, anhedonia, depressivity, suspiciousness, and hostility subscales. Conclusions Our study confirmed the psychometric properties of the H-CTQ-SF, an easy-to-administer, non-invasive, ethically sound questionnaire. In aADHD patients without comorbid BPD, low levels of traumatization in every CTQ domain were comparable to those of healthy control individuals. Thus, the increased level of traumatization found in previous studies of aADHD might be associated with the presence of comorbid BPD. Our findings also support the role of emotional neglect, emotional abuse and sexual abuse in the development of BPD.

Neurobiological studies have shown the importance of serotonergic neurotransmission in impulsivity, aggressive behavior and borderline personality traits. Genetic findings strongly support an interaction between sensitivity alleles and childhood adversities. High levels of impulsive behavior represent a core symptom of different psychiatric conditions, such as Attention-Deficit/Hyperactivity Disorder (ADHD) and Borderline Personality Disorder (BPD). Our aim was to explore the association between the most studied genetic variants of the metabolizing enzyme monoamine oxidase-A (MAO-A) and the level of personality functioning, and the different impulsivity factors in adult ADHD, BPD and healthy control group taking into consideration the moderating effects of childhood traumatization. 100 adult ADHD, 63 BPD patients and 100 control subjects involved in the study were assessed by structured clinical interviews, such as MINI 5.0 and SCID-5-PD. Participants were further investigated with online questionnaires including the Level of Personality Functioning Scale – short version (LPFS-SR), the Buss-Perry Aggression Questionnaire (BPQ), the Childhood Trauma Questionnaire (CTQ) and examined by neuropsychological tests, like CANTAB Rapid Visual Processing (RVP) and Stop Signal Tasks (SST). There was a significant association between the functional MAO-A polymorphism and the self-domain of personality functioning F(4,238) = 8.023, p = 0.005. In the pooled sample of patients and controls, subjects carrying the high activity alleles (MAOA-H) had elevated scores on the self-direction F(4, 238) = 8.433, p = 0.04 and identity F(4,238) = 5.931 p = 0.016 subscales of LPFS-SR. Among female subjects physical aggression F(4, 135) = 3.947, p = 0.022 and anger F(4, 135) = 3.247 p = 0.042 measured by the BPQ was also associated with MAOA-H allele carriers. Neuropsychological measures of impulsivity, such as CANTAB RVP items showed significant associations in the ADHD group. The MAO-H genotype was associated with elevated response latency F(1, 87) = 4.807, p = 0.031. In our study, the high activity allele was associated with impaired personality functioning, elevated level of anger, aggression and greater latency of response. We found no association of withholding actions measured by the CANTAB SST subtest, in any of the three study groups, despite previous results showing the association of MAO-A with inhibitory control problems.

Background: De novo mutations (DNMs) have been implicated in the etiology of schizophrenia (SZ), a chronic debilitating psychiatric disorder characterized by hallucinations, delusions, cognitive dysfunction and decreased community functioning. Several DNMs have been identified by examining SZ cases and their unaffected parents, however in most cases the biological significance of these mutations remains elusive. To overcome this limitation, we have developed an approach of using induced pluripotent stem cell (iPSC) lines from each member of a SZ case-parent trio, in order to investigate the effects of DNMs in cellular progenies of interest, particularly in dentate gyrus neuronal progenitors. Methods: We identified a male SZ patient characterized by early disease onset and negative symptoms, who is a carrier of 3 non-synonymous DNMs in genes LRRC7, KHSRP, and KIR2DL1. iPSC lines were generated from his and his parents’ peripheral blood mononuclear cells using Sendai virus-based reprogramming and differentiated into neuronal progenitor cells (NPCs) and hippocampal dentate gyrus granule cells. We used RNASeq to explore transcriptomic differences, and calcium (Ca 2+ ) imaging, cell proliferation, migration, oxidative stress, and mitochondrial assays to characterize the investigated NPC lines. Results: NPCs derived from the SZ patient exhibited transcriptomic differences related to Wnt-signaling, neuronal differentiation, axonal guidance and synaptic function, and decreased Ca 2+ reactivity to glutamate. Moreover, we could observe increased cellular proliferation, and alterations in mitochondrial quantity and morphology. Conclusions: The approach of reprograming case-parent trios represents an opportunity for investigating the molecular effects of disease-causing mutations, and comparing these in cell lines with reduced variation in genetic background. Our results are indicative of a partial overlap between schizophrenia and autism-related phenotypes in the investigated family. Limitations: Our study investigated only one family, therefore the generalizability of findings is limited. We could not derive iPSCs from two other siblings to test for possible genetic effects in the family that are not driven by DNMs. The transcriptomic and functional assays were limited to the NPC stage, although these variables should also be investigated at the mature neuronal stage.

BACKGROUND:Studies in adult depressed patients have indicated that altered DNA methylation patterns at genes related to serotonin and HPA axis functioning (e.g., SLC6A4, FKBP5) are associated with changes in frontolimbic functional connectivity and structure. Here, we examined whether these associations can be generalized to adolescents. METHODS:25 adolescents with depression (Mean age = 15.72 ± 0.94 SD; 20 girls) and 20 healthy controls (Mean age = 16.05 ± 1.5 SD; 16 girls) underwent a functional and structural magnetic resonance imaging protocol, which included a resting-state assessment and measures of brain morphometry. DNA was obtained from saliva. Levels of SLC6A4 and FKBP5 methylation were determined using pyrosequencing. RESULTS:SLC6A4 methylation was linked to amygdala-frontal operculum resting-state functional connectivity (rs-FC), regardless of diagnosis, and was differentially associated with inferior orbitofrontal gyrus (IFOG) gray matter (GM) volume in adolescents with depression and controls. Replicating and extending previous findings in adults, FKBP5 methylation was associated with IFOG GM volume in depressed and healthy adolescents, as well as orbitofrontal cortex (OFC)-rostral prefrontal cortex (RPFC) connectivity in healthy adolescents only. LIMITATIONS:Effects of medication use or genotype cannot be ruled out. Further, the relatively small sample size and predominately female sample may limit generalizability. CONCLUSIONS:These findings suggest that previously observed associations between SLC6A4 and FKBP5 methylation and frontolimbic processes in adult depressed patients can be in part generalized to adolescent patients. Further, findings suggest that measuring peripheral methylation at these genes deserves further attention as potential markers of typical and atypical development.

The field of psychiatric genetics investigates the genetic background of psychiatric disorders. In a broader sense, this discipline aims to understand the molecular pathways underlying psychopathology, therefore, it is also referred to as molecular psychiatry. The most important question of this field was originally the following: What type of inheritance is responsible for the overrepresentation of psychiatric disorders in certain families, and which variants of the human genome account for the heritability of these disorders? Moreover, can we get closer to understanding the biological mechanisms of psychiatric disorders by studying and identifying such genetic variants? Technological development during the past decades has enabled us to collect, analyze and compare genetic data from large sample sets of patients and healthy control individuals. Genome-wide association studies (GWAS) have identified common variants that convey increased risk of small effect for the development of different psychiatric disorders. Furthermore, we are now able to compose polygenic risk scores (PRS) from these disease-causing variants and quantify the overall genetic risk of individuals. The implementation of this method supports the polygenic nature of psychiatric disorders. Finally, cross-disorder analyses have the potential to compare the genetic background of different psychiatric disorders and to determine overlapping and distinct marker sets between disorders. These new research methods are described in our review paper through the examples of schizophrenia and attention deficit-hyperactivity disorder (ADHD). Psychiatric genetics has not yet entered the everyday clinical practice in psychiatry, however, it informs us about the biological underpinnings and genetic architecture of psychiatric disorders.