Risk Of Psychiatric Diseases Research Articles

Diagnostic Challenges in Outpatient Stroke: Stroke Chameleons and Atypical Stroke Syndromes.

Failure to diagnose transient ischemic attack (TIA) or stroke in a timely fashion is associated with significant patient morbidity and mortality. In the outpatient or clinic setting, we suspect that patients with minor, transient, and atypical manifestations of cerebrovascular disease are most prone to missed or delayed diagnosis. We therefore detail common stroke chameleon symptoms as well as atypical stroke presentations, broadly review new developments in the study of diagnostic error in the outpatient setting, suggest practical clinical strategies for diagnostic error reduction, and emphasize the need for rapid consultation of stroke specialists when appropriate. We also address the role of psychiatric disease and vascular risk factors in the diagnostic evaluation and treatment of suspected stroke/TIA patients. We advocate incorporating diagnostic time-outs into clinical practice to assure that the diagnosis of TIA or stroke is considered in all relevant patient encounters after a detailed history and examination are conducted in the outpatient setting.

Using social rank as the lens to focus on the neural circuitry driving stress coping styles.

Social hierarchy position in humans is negatively correlated with stress-related psychiatric disease risk. Animal models have largely corroborated human studies, showing that social rank can impact stress susceptibility and is considered to be a major risk factor in the development of psychiatric illness. Differences in stress coping style is one of several factors thatmediate this relationship between social rank and stress susceptibility. Coping styles encompass correlated groupings of behaviors associated with differential physiological stress responses. Here, we discuss recent insights from animal models that highlight several neural circuits that can contribute to social rank-associated differences in coping style.

The systemic cell apoptotic-based neutrophil–lymphocyte ratio: Experience in children diagnosed with ADHD and Autism Spectrum Disorder

Objective: In recent years, the rate of Neutrophil/Lymphocyte ratio (NLR) has been shown to be a marker of systemic inflammation and is associated with prognosis in many diseases like malignancies and chronic inflammatory diseases. Based on previous studies, there is not any finding that the NLR and cellular morphological mechanism studied together in inflammation-related diseases; attention deficit hyperactivity disorder(ADHD) and autism spectrum disorders(ASD). We assessed the effect and association of these parameters on the etiopathogenesis of neurodevelopmental disorders. Material and Method: 30 healthy and 30 patients who were diagnosed with ADHD and ASD were evaluated in the psychiatry department at a tertiary hospital. In whole groups, the hemogram profile have been analyzed. NLR number was statistically compared. However, the apoptotic stage of cells were stained with 2 different methods. Apoptotic mechanisms of ADHD, ASD and control group were comparably displayed. Results: NLR values in patients diagnosed with ADHD and ASD were significantly higher compare to control; lymphocyte count was found significantly lower level in patient groups. Apoptotic morphology becomes evident as the degree of disease increment. Conclusion: This parameter can be used as an easily applicable method is estimated to be at risk for psychiatric diseases. The positive association of NLR with apoptotic imaging indicates a marker of cellular degradation with neurodegenerative disorders.

Chapter 2 - Neurologic complications of congenital heart disease in adults

Congenital heart disease (CHD) is a heterogeneous group of structural abnormalities of the cardiovascular system that are present at birth. Advances in childhood medical and surgical treatment have led to increasing numbers of adults with CHD. Neurological complications of CHD in adults are varied and can include an increased risk of stroke not only related to the underlying congenital defect and its surgical management but also due to atherosclerotic disease associated with advancing age. In addition to cerebrovascular events, CHD in adults is also associated with an increased risk of neurodevelopmental disorders, cognitive impairment, psychiatric disease, and epilepsy. Collaborative multidisciplinary care with contributions from neurologists and cardiologists with expertise in adult CHD is necessary to provide optimal long-term care for this complex and rapidly evolving population.

The Effects of Temperature on Dynamics of Psychiatric Outpatients.

Background: Climate changes affect mental states and alter the risk for psychiatric diseases. Seasonal changes in temperature lead to dynamics in the occurrence of psychiatric conditions and pose challenges in the administration of clinical psychiatry services.Methods: The present study aims to retrospectively analyze outpatient data with weather reports from January 2014 to March 2019 at Shanghai Mental Health Center, one of the largest psychiatric hospitals in the world, in order to provide policy insights into the administration of psychiatric clinics.Results: The results show steady increases in the number of overall patients over the past 5 years with several peaks within each year. Temperature changes and weather information reliably predict the increased number of psychiatric patients.Conclusions: We conclude that mental health hospitals should prepare for patient dynamics based on the weather forecast.

Cell type‐specific enhancer‐promoter connectivity maps in the human brain and associations with Alzheimer’s disease risk

AbstractBackgroundThere is no clear genetic cause for most cases of late‐onset Alzheimer’s disease (AD), however, genome‐wide association studies have identified multiple genetic variants associated with increased risk of AD. These AD‐risk variants are often located in non‐coding DNA regulatory regions called enhancers, which upon transcription factor binding, modulate the expression of nearby genes. One of the major challenges facing the field of AD research is the assignment of cell‐type specificity and functionality to these genetic variants.MethodNuclei of microglia, neurons, astrocytes and oligodendrocytes were isolated from frozen human cortical tissue. Sorted nuclei were processed using chromatin immunoprecipitation and sequencing (ChIP‐seq) to define cell type promoter and enhancer regions. The assay for transposase accessible chromatin sequencing (ATAC‐seq) was used to define open chromatin regions, which indicates likely transcription factor binding sites. Proximity Ligation‐Assisted ChIP‐seq (PLAC‐seq) is a chromatin conformation assay that was used to link distal enhancers to target genes. Enhancers were validated by CRISPR‐mediated deletion of putative regions in induce‐pluripotent stem cells (iPSCs) that were derived into neurons, microglia and astrocytes followed by gene expression analysis.ResultGenetic variants associated with increased risk of AD were largely confined to microglia enhancers, whereas genetic variants for psychiatric disorders such as autism and schizophrenia were enriched in neuronal enhancers. Enhancer‐promoter interactome maps connected disease‐risk variants located in enhancers to gene promoters. Integrative analysis of promoter‐enhancer interactome maps has not only revised and expanded the gene repertoire influenced by AD‐risk variants but has also revealed the probable cell types in which they function. Lastly, the BIN1 locus, the second highest putative AD‐risk gene after APOE, has a microglia‐specific enhancer that harbors AD‐risk variants. CRISPR‐deletion of the microglia BIN1 enhancer in iPSCs ablated BIN1 gene expression in iPSC‐derived microglia and not neurons or astrocytes.ConclusionThere has been intense interest in elucidating mechanisms that link human non‐coding genetic variation to risk of neurodegenerative and psychiatric diseases. Towards this effort, enhancer‐promoter connectivity maps in the human brain has enabled an initial cell‐type‐specific interpretation of human genetic variation associated with disease risk for AD and other brain disorders.

Immediate and longitudinal effects of maltreatment on systemic inflammation in young children.

Exposure to child maltreatment increases the risk for psychiatric and physical diseases. Inflammation has been proposed as a mechanism through which early adverse experiences become biologically embedded. However, most studies providing evidence for the link between early adverse exposures and inflammation have been retrospective or cross-sectional in design, or did not assess inflammation immediately after maltreatment in young children. In the present study we investigated the association between childhood maltreatment and salivary C-reactive protein (CRP) concentrations in a population of N = 173 children, 3-5 years of age, who were recruited in the immediate aftermath of maltreatment and followed-up longitudinally every 6 months over a period of 2 years. We found that the association between maltreatment and CRP concentrations was significantly moderated by child sex, such that in girls, CRP concentrations were higher in the maltreated compared to the control group, and this difference was stable across the 2-year follow-up-period, while in boys, there was no association between maltreatment and CRP. Our findings suggest that the effect of maltreatment on inflammation may already emerge right after exposure at a very young age in girls and manifest over time. Our study provides important evidence for the development of personalized, early interventions strategies targeting the early-life period.

Early-life stress exacerbates the effects of WIN55,212-2 and modulates the cannabinoid receptor type 1 expression

Early-life stress induces an abnormal brain development and increases the risk of psychiatric diseases, including depression, anxiety and substance use disorders. We have developed a reliable model for maternal neglect, named maternal separation with early weaning (MSEW) in CD1 mice. In the present study, we evaluated the long-term effects on anxiety-like behaviours, nociception as well as the Iba1-positive microglial cells in this model in comparison to standard nest (SN) mice. Moreover, we investigated whether MSEW alters the cannabinoid agonist WIN55,212-2 effects regarding reward, spatial and emotional memories, tolerance to different cannabinoid responses, and physical dependence. Adult male offspring of MSEW group showed impaired responses on spatial and emotional memories after a repeated WIN55,212-2 treatment. These behavioural impairments were associated with an increase in basolateral amygdala and hippocampal CB1-expressing fibres and higher number of CB1-containing cells in cerebellum. Additionally, MSEW promotes a higher number of Iba1-positive microglial cells in basolateral amygdala and cerebellum. As for the cannabinoid-induced effects, rearing conditions did not influence the rewarding effects of WIN55,212-2 in the conditioned place preference paradigm. However, MSEW mice showed a delay in the development of tolerance to the cannabinoid effects. Moreover, CB1-positive fibres were reduced in limbic areas in MSEW mice after cannabinoid withdrawal precipitated with the CB1 antagonist SR141617A. These findings support that early-life stress promotes behavioural and molecular changes in the sensitivity to cannabinoids, which are mediated by alterations in CB1 signalling in limbic areas and it induces an increased Iba1-microglial marker which could interfere in emotional memories formation.

Alterations in Retrotransposition, Synaptic Connectivity, and Myelination Implicated by Transcriptomic Changes Following Maternal Immune Activation in Nonhuman Primates

BackgroundMaternal immune activation (MIA) is a proposed risk factor for multiple neuropsychiatric disorders, including schizophrenia. However, the molecular mechanisms through which MIA imparts risk remain poorly understood. A recently developed nonhuman primate model of exposure to the viral mimic poly:ICLC during pregnancy shows abnormal social and repetitive behaviors and elevated striatal dopamine, a molecular hallmark of human psychosis, providing an unprecedented opportunity for studying underlying molecular correlates. MethodsWe performed RNA sequencing across psychiatrically relevant brain regions (prefrontal cortex, anterior cingulate, hippocampus) and primary visual cortex for comparison from 3.5- to 4-year-old male MIA-exposed and control offspring—an age comparable to mid adolescence in humans. ResultsWe identify 266 unique genes differentially expressed in at least one brain region, with the greatest number observed in hippocampus. Co-expression networks identified region-specific alterations in synaptic signaling and oligodendrocytes. Although we observed temporal and regional differences, transcriptomic changes were shared across first- and second-trimester exposures, including for the top differentially expressed genes—PIWIL2 and MGARP. In addition to PIWIL2, several other regulators of retrotransposition and endogenous transposable elements were dysregulated following MIA, potentially connecting MIA to retrotransposition. ConclusionsTogether, these results begin to elucidate the brain-level molecular processes through which MIA may impart risk for psychiatric disease.

Non-psychotic mental disorders in adolescent men and risk of myocardial infarction: a national cohort study

Abstract Background/Purpose Recent studies show that early life stress is associated with later risk of cardiovascular disease (CVD) and stress may also increase the risk of psychiatric disease. We investigated the association between non-psychotic mental disorders in adolescence and subsequent myocardial infarction, and the role of stress resilience and physical fitness in this association. Method This is a register-based cohort study with 238 013 males born between 1952 and 1956 followed from 1987 to 2010 using information from Swedish registers. Stress resilience was measured at a compulsory military conscription examination using a semi-structured interview with a psychologist. Physical fitness was measured at conscription examination with a cycle ergometer test. A total of 34 503 men were diagnosed with a non-psychotic mental disorder at conscription. Using Cox regression, we estimated the association of mental disorders with myocardial infarction after adjustment for other established CVD risk factors in adolescence. Stress resilience and physical fitness were included in the adjusted model in a second set of analyses. Results A total of 5891 diagnoses of first myocardial infarction were identified. Non-psychotic mental disorders were associated with an increased risk of myocardial infarction, with a hazard ratio (HR) and confidence interval (CI) of 1.51 (1.41–1.62). The association remained statistically significant after adjustment for other important potential confounders in adolescence such as systolic and diastolic blood pressure, body mass index, inflammation, cognitive function, parental socioeconomic index and a summary disease score (HR 1.24 (CI 1.13–1.35)). The association was further explained by stress resilience and lifestyle factors assessed with a cardiovascular fitness test in adolescence, as the association attenuated but remained statistically significant when further adjusting for stress resilience and physical fitness (HR 1.18 (CI 1.08–1.29)). Conclusion A non-psychotic mental disorder in adolescences may increase the risk of developing myocardial infarction later in life. This association was partly but not completely explained by poorer stress resilience and physical fitness. Effective prevention might focus on behaviour/lifestyle and psychosocial stress in early life. Funding Acknowledgement Type of funding source: None

Brain activity and transcriptional profiling in mice under chronic jet lag

Shift work is known to be associated with an increased risk of neurological and psychiatric diseases, but how it contributes to the development of these diseases remains unclear. Chronic jet lag (CJL) induced by shifting light-dark cycles repeatedly is a commonly used protocol to mimic the environmental light/dark changes encountered by shift workers. Here we subjected wildtype mice to CJL and performed positron emission tomography imaging of glucose metabolism to monitor brain activities. We also conducted RNA sequencing using prefrontal cortex and nucleus accumbens tissues from these animals, which are brain regions strongly implicated in the pathology of various neurological and psychiatric conditions. Our results reveal the alterations of brain activities and systematic reprogramming of gene expression in brain tissues under CJL, building hypothesis for how CJL increases the susceptibility to neurological and psychiatric diseases.

Assessment of the Risk of Psychiatric Disorders, Use of Psychiatric Hospitals, and Receipt of Psychiatric Medication Among Patients With Lyme Neuroborreliosis in Denmark

The association of Lyme neuroborreliosis with the development of psychiatric disease is unknown and remains a subject of debate. To investigate the risk of psychiatric disease, the percentage of psychiatric hospital inpatient and outpatient contacts, and the receipt of prescribed psychiatric medications among patients with Lyme neuroborreliosis compared with individuals in a matched comparison cohort. This nationwide population-based matched cohort study included all residents of Denmark who received a positive result on an intrathecal antibody index test for Borrelia burgdorferi (patient cohort) between January 1, 1995, and December 31, 2015. Patients were matched by age and sex to a comparison cohort of individuals without Lyme neuroborreliosis from the general population of Denmark. Data were analyzed from February 2019 to March 2020. Diagnosis of Lyme neuroborreliosis, defined as a positive result on an intrathecal antibody index test for B burgdorferi. The 0- to 15-year hazard ratios for the assignment of psychiatric diagnostic codes, the difference in the percentage of psychiatric inpatient and outpatient hospital contacts, and the difference in the percentage of prescribed psychiatric medications received among the patient cohort vs the comparison cohort. Among 2897 patients with Lyme neuroborreliosis (1646 men [56.8%]) and 28 970 individuals in the matched comparison cohort (16 460 men [56.8%]), the median age was 45.7 years (interquartile range [IQR], 11.5-62.0 years) for both groups. The risk of a psychiatric disease diagnosis and the percentage of hospital contacts for psychiatric disease were not higher among patients with Lyme neuroborreliosis compared with individuals in the comparison cohort. A higher percentage of patients with Lyme neuroborreliosis compared with individuals in the comparison cohort received anxiolytic (7.2% vs 4.7%; difference, 2.6%; 95% CI, 1.6%-3.5%), hypnotic and sedative (11.0% vs 5.3%; difference, 5.7%; 95% CI, 4.5%-6.8%), and antidepressant (11.4% vs 6.0%; difference, 5.4%; 95% CI, 4.3%-6.6%) medications within the first year after diagnosis, after which the receipt of psychiatric medication returned to the same level as the comparison cohort. In this population-based matched cohort study, patients with Lyme neuroborreliosis did not have an increased risk of developing psychiatric diseases that required hospital care or treatment with prescription medication. The increased receipt of psychiatric medication among patients with Lyme neuroborreliosis within the first year after diagnosis, but not thereafter, suggests that most symptoms associated with the diagnosis subside within a short period.

Prolonged family separation is associated with increased risk of mental disorders among refugee fathers

Abstract Background Refugees resettled in Western countries experience long periods of family separation due to waiting first for asylum, and then for family reunification. This study aimed to examine if family separation is associated with psychiatric disease among refugee fathers. Methods We traversed full-population Danish administrative data since 1986 to establish a cohort of refugee fathers from nuclear families in which the father was the first to arrive and resettled alone during 1995-2015, and where the mother and children were later family reunified. We followed these fathers for up to 24 years from the day their residence permit was issued until their first psychiatric diagnosis, emigration, death, or study end, whichever came first. Using Cox proportional hazard regression, we estimated the temporary and longer-term risks of psychiatric disorders for i) the total family separation period, and ii) the family separation decomposed into time waiting for, respectively, asylum and family reunification. Results 6176 fathers were included in the study. The HR assessing the temporary risk of psychiatric disorders was 2.23[95% CI: 1.72-2.89] for separated fathers compared with those who were already family reunified. As to the longer-term risk, compared with fathers separated for 0-9 months, the HR of psychiatric disorders was 1.54[1.08-2.21] after +9-12 months of separation, increasing to 1.84[1.29-2.62] after +24 months of separation. The decomposition analysis revealed that +6 months of waiting increased the risk of any psychiatric disorder by approximately 40% for both time waiting for asylum and time waiting for family reunification. Conclusions Strong evidence supports that fathers waiting for their wives and children face an increased risk of psychiatric disease. Countries receiving refugees should be aware that delayed family reunification can lead to adverse mental health effects. Key messages Family separation is associated with an increased risk of psychiatric disease among refugee fathers—both while the fathers are separated from their families and after family reunification. The risk of psychiatric disease is more than double among refugee fathers still separated from their family compared with those who have been family reunified.

Substance use in the Norwegian general population: prevalence and associations with disease

ABSTRACT Objective This study aimed to estimate the prevalence of substance use in the Norwegian general population and examine whether the risk of various psychiatric or somatic diseases varied according to alcohol- and substance use. Methods A survey was distributed to 5500 persons in Norway, and a sample of 1792 persons responded (36% response rate). Data concerned with the use of substances were cross-tabulated with disease occurrence, and relative ratios (RR) of diseases in groups of lifetime substance users versus abstainers/low frequent users were calculated. Results Lifetime prevalence estimates were 83.5% for alcohol, 7.9% for cannabis, 8.5% for sedatives, 33.8% for strong analgesics and 2.4% for opioids and for stimulants. Drinking alcohol weekly or daily was associated with lower risk of several diseases, whereas lifetime use of sedatives, strong analgesics and opioids was associated with higher risk. Lifetime use of cannabis was associated with higher risk of depression and lower risk of diabetes and arthrosis. Conclusions While frequent alcohol use was associated with reduced risk of several diseases, lifetime use of other substances was generally associated with higher risk of disease. The study provides evidence of increased risk of disease among users of illicit substances and prescription drugs. Abbreviations: NORPOP: The Norwegian Population Study; OR: Odds ratio; RR: Relative risk; SES: Socioeconomic status

Novel alternatively-spliced exons of the VRK2 gene in mouse brain and microglial cells

Common sequence variations in the VRK2 gene contribute to genetic risk for various psychiatric diseases including schizophrenia and major depressive disorder. Despite the clear importance of studying the regulation and function of VRK2 for understanding the causes of these diseases, the organisation and expression of the gene remain poorly characterised. Using reverse-transcriptase-PCR, we have amplifed exons of Vrk2 mRNA from regions of mouse brain, and from different cell classes comprising neurones, astrocytes and microglial cells. We find that Vrk2 mRNA is expressed in all cell types, and that the splicing of the mouse Vrk2 gene is much more complex than previously appreciated. In addition to the predicted alternative splicing (absence/presence) of the penultimate 3 prime exon, we also detected a variety of 5 prime structures, including two novel exons spanning the first characterised exon (exon 1), which we term exons 1a and 1b. While expressed in neurones and astrocytes, exon 1b was not expressed in microglial cells. Expression of transcripts containing exon 1a in microglia was increased by immune stimulation. An additional truncated transcript lacking 7 central exons was also identified. As with the human gene, the results confirm complex patterns of alternative splicing which are likely to be relevant for understanding the physiological and pathological function of the gene in the CNS.

A cross-disorder PRS-pheWAS of 5 major psychiatric disorders in UK Biobank.

Psychiatric disorders are highly heritable and associated with a wide variety of social adversity and physical health problems. Using genetic liability (rather than phenotypic measures of disease) as a proxy for psychiatric disease risk can be a useful alternative for research questions that would traditionally require large cohort studies with long-term follow up. Here we conducted a hypothesis-free phenome-wide association study in about 330,000 participants from the UK Biobank to examine associations of polygenic risk scores (PRS) for five psychiatric disorders (major depression (MDD), bipolar disorder (BP), schizophrenia (SCZ), attention-deficit/ hyperactivity disorder (ADHD) and autism spectrum disorder (ASD)) with 23,004 outcomes in UK Biobank, using the open-source PHESANT software package. There was evidence after multiple testing (p<2.55x10-06) for associations of PRSs with 294 outcomes, most of them attributed to associations of PRSMDD (n = 167) and PRSSCZ (n = 157) with mental health factors. Among others, we found strong evidence of association of higher PRSADHD with 1.1 months younger age at first sexual intercourse [95% confidence interval [CI]: -1.25,-0.92] and a history of physical maltreatment; PRSASD with 0.01% lower erythrocyte distribution width [95%CI: -0.013,-0.007]; PRSSCZ with 0.95 lower odds of playing computer games [95%CI:0.95,0.96]; PRSMDD with a 0.12 points higher neuroticism score [95%CI:0.111,0.135] and PRSBP with 1.03 higher odds of having a university degree [95%CI:1.02,1.03]. We were able to show that genetic liabilities for five major psychiatric disorders associate with long-term aspects of adult life, including socio-demographic factors, mental and physical health. This is evident even in individuals from the general population who do not necessarily present with a psychiatric disorder diagnosis.

Regulatory sites for splicing in human basal ganglia are enriched for disease-relevant information

Genome-wide association studies have generated an increasing number of common genetic variants associated with neurological and psychiatric disease risk. An improved understanding of the genetic control of gene expression in human brain is vital considering this is the likely modus operandum for many causal variants. However, human brain sampling complexities limit the explanatory power of brain-related expression quantitative trait loci (eQTL) and allele-specific expression (ASE) signals. We address this, using paired genomic and transcriptomic data from putamen and substantia nigra from 117 human brains, interrogating regulation at different RNA processing stages and uncovering novel transcripts. We identify disease-relevant regulatory loci, find that splicing eQTLs are enriched for regulatory information of neuron-specific genes, that ASEs provide cell-specific regulatory information with evidence for cellular specificity, and that incomplete annotation of the brain transcriptome limits interpretation of risk loci for neuropsychiatric disease. This resource of regulatory data is accessible through our web server, http://braineacv2.inf.um.es/.

Longitudinal genetic studies of cognitive characteristics.

The present review describes longitudinal studies of cognitive traits and functions determining the causes of their variations and their possible correction to prevent cognitive impairment. The present study reviews the involvement of such environmental factors as nutrition, prenatal maternal stress, social isolation and others in cognitive functioning. The role of epigenetic factors in the implementation of environmental effects in cognitive characteristics is revealed. Considering the epigenome significance, several studies were focused on the design of substances affecting methylation and histone modification, which can be used for the treatment of cognitive disorders. The appropriate correction of epigenetic factors related to environmental differences in cognitive abilities requires to determine the mechanisms of chromatin modifications and variations in DNA methylation. Transposons representing stress-sensitive DNA elements appeared to mediate the environmental influence on epigenetic modifications. They can explain the mechanism of transgenerational transfer of information on cognitive abilities. Recently, large-scale meta-analyses based on the results of studies, which identified genetic associations with various cognitive traits, were carried out. As a result, the role of genes actively expressed in the brain, such as BDNF, COMT, CADM2, CYP2D6, APBA1, CHRNA7, PDE1C, PDE4B, and PDE4D in cognitive abilities was revealed. The association between cognitive functioning and genes, which have been previously involved in developing psychiatric disorders (MEF2C, CYP2D6, FAM109B, SEPT3, NAGA, TCF20, NDUFA6 genes), was revealed, thus indicating the role of the similar mechanisms of genetic and neural networks in both normal cognition and cognitive impairment. An important role in both processes belongs to common epigenetic factors. The genes involved in DNA methylation (DNMT1, DNMT3B, and FTO), histone modifications (CREBBP, CUL4B, EHMT1, EP300, EZH2, HLCS, HUWE1, KAT6B, KMT2A, KMT2D, KMT2C, NSD1, WHSC1, and UBE2A) and chromatin remodeling (ACTB, ARID1A, ARID1B, ATRX, CHD2, CHD7, CHD8, SMARCA2, SMARCA4, SMARCB1, SMARCE1, SRCAP, and SS18L1) are associated with increased risk of psychiatric diseases with cognitive deficiency together with normal cognitive functioning. The data on the correlation between transgenerational epigenetic inheritance of cognitive abilities and the insert of transposable elements in intergenic regions is discussed. Transposons regulate genes functioning in the brain due to the processing of their transcripts into non-coding RNAs. The content, quantity and arrangement of transposable elements in human genome, which do not affect changes in nucleotide sequences of protein encoding genes, but affect their expression, can be transmitted to the next generation.

Bipolar multiplex families have an increased burden of common risk variants for psychiatric disorders

Multiplex families with a high prevalence of a psychiatric disorder are often examined to identify rare genetic variants with large effect sizes. In the present study, we analysed whether the risk for bipolar disorder (BD) in BD multiplex families is influenced by common genetic variants. Furthermore, we investigated whether this risk is conferred mainly by BD-specific risk variants or by variants also associated with the susceptibility to schizophrenia or major depression. In total, 395 individuals from 33 Andalusian BD multiplex families (166 BD, 78 major depressive disorder, 151 unaffected) as well as 438 subjects from an independent, BD case/control cohort (161 unrelated BD, 277 unrelated controls) were analysed. Polygenic risk scores (PRS) for BD, schizophrenia (SCZ), and major depression were calculated and compared between the cohorts. Both the familial BD cases and unaffected family members had higher PRS for all three psychiatric disorders than the independent controls, with BD and SCZ being significant after correction for multiple testing, suggesting a high baseline risk for several psychiatric disorders in the families. Moreover, familial BD cases showed significantly higher BD PRS than unaffected family members and unrelated BD cases. A plausible hypothesis is that, in multiplex families with a general increase in risk for psychiatric disease, BD development is attributable to a high burden of common variants that confer a specific risk for BD. The present analyses demonstrated that common genetic risk variants for psychiatric disorders are likely to contribute to the high incidence of affective psychiatric disorders in the multiplex families. However, the PRS explained only part of the observed phenotypic variance, and rare variants might have also contributed to disease development.

Synergistic effects of common schizophrenia risk variants.

The mechanisms by which common risk variants of small effect interact to contribute to complex genetic disorders remain unclear. Here, we apply a genetic approach, using isogenic human induced pluripotent stem cells (hiPSCs), to evaluate the effects of schizophrenia-associated common variants predicted to function as brain expression quantitative trait loci (SZ-eQTLs). By integrating CRISPR-mediated gene editing, activation and repression technologies to study one putative SZ-eQTL (FURIN rs4702) and four top-ranked SZ-eQTL genes (FURIN, SNAP91, TSNARE1, CLCN3), our platform resolves pre- and post-synaptic neuronal deficits, recapitulates genotype-dependent gene expression differences, and identifies convergence downstream of SZ-eQTL gene perturbations. Our observations highlight the cell-type-specific effects of common variants and demonstrate a synergistic effect between SZ-eQTL genes that converges on synaptic function. We propose that the links between rare and common variants implicated in psychiatric disease risk constitute a potentially generalizable phenomenon occurring more widely in complex genetic disorders.