Portability of Polygenic Risk Scores for Sleep Duration, Insomnia and Chronotype in 33,493 Individuals

Polygenic risk scores (PRSs) estimate genetic liability for diseases and traits. However, the portability of PRSs in sleep traits has remained elusive. We generated PRSs for self-reported insomnia, chronotype and sleep duration using summary data from genome-wide association studies (GWASs) performed in 350,000 to 697,000 European-ancestry individuals. We then projected the scores in two independent Finnish population cohorts (N = 33,493) and tested whether the PRSs were associated with their respective sleep traits. We observed that all the generated PRSs were associated with their corresponding traits (p < 0.05 in all cases). Furthermore, we found that there was a 22.2 min difference in reported sleep between the 5% tails of the PRS for sleep duration (p < 0.001). Our findings indicate that sleep-related PRSs show portability across cohorts. The findings also demonstrate that sleep measures using PRSs for sleep behaviors may provide useful instruments for testing disease and trait associations in cohorts where direct sleep parameters have not yet been measured

Signaled night awakening and its association with social information processing and socio-emotional development across the first two years

Study objectives: Night awakening is common in infancy, and some infants continue to have signaled night awakenings throughout early childhood. However, the influence of signaled night awakening on children's social development is less explored. In the present study, longitudinal associations between signaled night awakening, social information processing, and socio-emotional development were measured within the CHILD-SLEEP birth cohort in two groups formed based on parent-reported night awakenings. Methods: At 8 months, there were 77 infants in the waking group (≥3 awakenings) and 69 infants in the nonwaking group (≤1 awakening). At 8 and 24 months, social information processing was measured as children's attention to neutral and emotional faces, and at 24 months, parent-reported socio-emotional behavior was measured with the Brief Infant Toddler Social Emotional Assessment (BITSEA) questionnaire. Results: The two groups showed different patterns of attention to emotional faces. The waking group had a more pronounced attentional bias to fearful vs. happy faces, whereas in the nonwaking group, attention to fearful and happy faces did not differ. In addition, at 24 months, the waking group had more dysregulation problems and lower social competence than the nonwaking group, but no clear differences in internalizing or externalizing problems were found. Conclusions: Our results contribute to the literature by showing that during the first two years of life, signaled night awakening is associated with social information processing and socio-emotional behavior.Study objectives: Night awakening is common in infancy, and some infants continue to have signaled night awakenings throughout early childhood. However, the influence of signaled night awakening on children's social development is less explored. In the present study, longitudinal associations between signaled night awakening, social information processing, and socio-emotional development were measured within the CHILD-SLEEP birth cohort in two groups formed based on parent-reported night awakenings. Methods: At 8 months, there were 77 infants in the waking group (≥3 awakenings) and 69 infants in the nonwaking group (≤1 awakening). At 8 and 24 months, social information processing was measured as children's attention to neutral and emotional faces, and at 24 months, parent-reported socio-emotional behavior was measured with the Brief Infant Toddler Social Emotional Assessment (BITSEA) questionnaire. Results: The two groups showed different patterns of attention to emotional faces. The waking group had a more pronounced attentional bias to fearful vs. happy faces, whereas in the nonwaking group, attention to fearful and happy faces did not differ. In addition, at 24 months, the waking group had more dysregulation problems and lower social competence than the nonwaking group, but no clear differences in internalizing or externalizing problems were found. Conclusions: Our results contribute to the literature by showing that during the first two years of life, signaled night awakening is associated with social information processing and socio-emotional behavior.Peer reviewe

Anxiety symptoms in a major mood and schizophrenia spectrum disorders

Background: Comorbid anxiety symptoms and disorders are present in many psychiatric disorders, but methodological variations render comparisons of their frequency and intensity difficult. Furthermore, whether risk factors for comorbid anxiety symptoms are similar in patients with mood disorders and schizophrenia spectrum disorders remains unclear. Methods: The Overall Anxiety Severity and Impairment Scale (OASIS) was used to measure anxiety symptoms in psychiatric care patients with schizophrenia or schizoaffective disorder (SSA, n = 113), bipolar disorder (BD, n = 99), or depressive disorder (DD, n = 188) in the Helsinki University Psychiatric Consortium Study. Bivariate correlations and multivariate linear regression models were used to examine associations of depressive symptoms, neuroticism, early psychological trauma and distress, self-efficacy, symptoms of borderline personality disorder, and attachment style with anxiety symptoms in the three diagnostic groups. Results: Frequent or constant anxiety was reported by 40.2% of SSA, 51.5% of BD, and 55.6% of DD patients; it was described as severe or extreme by 43.8%, 41.4%, and 41.2% of these patients, respectively. SSA patients were significantly less anxious (P = 0.010) and less often avoided anxiety-provoking situations (P = 0.009) than the other patients. In regression analyses, OASIS was associated with high neuroticism, symptoms of depression and borderline personality disorder and low self-efficacy in all patients, and with early trauma in patients with mood disorders. Conclusions: Comorbid anxiety symptoms are ubiquitous among psychiatric patients with mood or schizophrenia spectrum disorders, and in almost half of them, reportedly severe. Anxiety symptoms appear to be strongly related to both concurrent depressive symptoms and personality characteristics, regardless of principal diagnosis. (C) 2016 Elsevier Masson SAS. All rights reserved.Peer reviewe

Gene expression changes related to immune processes associate with cognitive endophenotypes of schizophrenia

Schizophrenia is a heterogeneous disorder characterized by a spectrum of symptoms and many different underlying causes. Thus, instead of using the broad diagnosis, intermediate phenotypes can be used to possibly decrease the underlying complexity of the disorder. Alongside the classical symptoms of delusions and hallucinations, cognitive deficits are a core feature of schizophrenia. To increase our understanding of the biological processes related to these cognitive deficits, we performed a genome-wide gene expression analysis. A battery of 14 neuropsychological tests was administered to 844 individuals from a Finnish familial schizophrenia cohort. We grouped the applied neuropsychological tests into five factors for further analysis. Cognitive endophenotypes, whole blood mRNA, genotype, and medication use data were studied from 47 individuals. Expression level of several RNA probes were significantly associated with cognitive performance. The factor representing Verbal Working Memory was associated with altered expression levels of 11 probes, of which one probe was also associated with a specific sub-measure of this factor (WMS-R Digit span backward). While, the factor Processing speed was related to one probe, which additionally associated among 55 probes with a specific sub-measure of this factor (WAIS-R Digit symbol). Two probes were associated with the measure recognition memory performance. Enrichment analysis of these differentially expressed probes highlighted immunological processes. Our findings are in line with genome-wide genetic discoveries made in schizophrenia, suggesting that immunological processes may be of biological interest for future drug design towards schizophrenia and the cognitive dysfunctions that underlie it.Peer reviewe

Self-reported psychosis-like experiences in patients with mood disorders

Background: Self-reported psychosis-like experiences (PEs) may be common in patients with mood disorders, but their clinical correlates are not well known. We investigated their prevalence and relationships with self-reported symptoms of depression, mania, anxiety, borderline (BPD) and schizotypal (SPD) personality disorders among psychiatric patients with mood disorders. Methods: The Community Assessment of Psychic Experiences (CAPE-42), Mood Disorder Questionnaire (MDQ), McLean Screening Instrument (MSI), The Beck Depressive Inventory (BDI), Overall Anxiety Severity and Impairment Scale (OASIS) and Schizotypal Personality Questionnaire-Brief form (SPQ-B) were filled in by patients with mood disorders (n = 282) from specialized care. Correlation coefficients between total scores and individual items of CAPE-42 and BDI, SPQ-B, MSI and MDQ were estimated. Hierarchical multivariate regression analysis was conducted to examine factors influencing the frequency of self-reported PE. Results: PEs are common in patients with mood disorders. The "frequency of positive symptoms" score of CAPE-42 correlated strongly with total score of SPQ-B (rho = 0.63; P <0.001) and moderately with total scores of BDI, MDQ OASIS and MSI (rho varied from 0.37 to 0.56; P <0.001). Individual items of CAPE-42 correlated moderately with specific items of BDI, MDQ SPQ-B and MSI (r(phi) varied from 0.2 to 0.5; P <0.001). Symptoms of anxiety, mania or hypomania and BPD were significant predictors of the "frequency of positive symptoms" score of CAPE-42. Conclusions: Several, state- and trait-related factors may underlie self-reported PEs among mood disorder patients. These include cognitive-perceptual distortions of SPD; distrustfulness, identity disturbance, dissociative and affective symptoms of BPD; and cognitive biases related to depressive or manic symptoms. (C) 2016 Elsevier Masson SAS. All rights reserved.Peer reviewe

Enhanced Memory Consolidation Via Automatic Sound Stimulation During Non-REM Sleep

Introduction: Slow-wave sleep (SWS) slow waves and sleep spindle activity have been shown to be crucial for memory consolidation. Recently, memory consolidation has been causally facilitated in human participants via auditory stimuli phase-locked to SWS slow waves. Aims: Here, we aimed to develop a new acoustic stimulus protocol to facilitate learning and to validate it using different memory tasks. Most importantly, the stimulation setup was automated to be applicable for ambulatory home use. Methods: Fifteen healthy participants slept 3 nights in the laboratory. Learning was tested with 4 memory tasks (word pairs, serial finger tapping, picture recognition, and face-name association). Additional questionnaires addressed subjective sleep quality and overnight changes in mood. During the stimulus night, auditory stimuli were adjusted and targeted by an unsupervised algorithm to be phase-locked to the negative peak of slow waves in SWS. During the control night no sounds were presented. Results: Results showed that the sound stimulation increased both slow wave (p =.002) and sleep spindle activity (p Conclusions: We showed that the memory effect of the SWS-targeted individually triggered single-sound stimulation is specific to verbal associative memory. Moreover, the ambulatory and automated sound stimulus setup was promising and allows for a broad range of potential follow-up studies in the future.Peer reviewe

Alu element in the RNA binding motif protein, X-linked 2 (RBMX2) gene found to be linked to bipolar disorder

Objective We have used long-read single molecule, real-time (SMRT) sequencing to fully characterize a similar to 12Mb genomic region on chromosome Xq24-q27, significantly linked to bipolar disorder (BD) in an extended family from a genetic sub-isolate. This family segregates BD in at least four generations with 24 affected individuals. Methods We selected 16 family members for targeted sequencing. The selected individuals either carried the disease haplotype, were non-carriers of the disease haplotype, or served as married-in controls. We designed hybrid capture probes enriching for 5-9Kb fragments spanning the entire 12Mb region that were then sequenced to screen for candidate structural variants (SVs) that could explain the increased risk for BD in this extended family. Results Altogether, 201 variants were detected in the critically linked region. Although most of these represented common variants, three variants emerged that showed near-perfect segregation among all BD type I affected individuals. Two of the SVs were identified in or near genes belonging to the RNA Binding Motif Protein, X-Linked (RBMX) gene family-a 330bp Alu (subfamily AluYa5) deletion in intron 3 of the RBMX2 gene and an intergenic 27bp tandem repeat deletion between the RBMX and G protein-coupled receptor 101 (GPR101) genes. The third SV was a 50bp tandem repeat insertion in intron 1 of the Coagulation Factor IX (F9) gene. Conclusions Among the three genetically linked SVs, additional evidence supported the Alu element deletion in RBMX2 as the leading candidate for contributing directly to the disease development of BD type I in this extended family.Peer reviewe

Impulsive alcohol-related risk-behavior and emotional dysregulation among individuals with a serotonin 2B receptor stop codon

Peer reviewe

Genome-wide association study of antisocial personality disorder

The pathophysiology of antisocial personality disorder (ASPD) remains unclear. Although the most consistent biological finding is reduced grey matter volume in the frontal cortex, about 50% of the total liability to developing ASPD has been attributed to genetic factors. The contributing genes remain largely unknown. Therefore, we sought to study the genetic background of ASPD. We conducted a genome-wide association study (GWAS) and a replication analysis of Finnish criminal offenders fulfilling DSM-IV criteria for ASPD (N = 370, N = 5850 for controls, GWAS; N = 173, N = 3766 for controls and replication sample). The GWAS resulted in suggestive associations of two clusters of single-nucleotide polymorphisms at 6p21.2 and at 6p21.32 at the human leukocyte antigen (HLA) region. Imputation of HLA alleles revealed an independent association with DRB1*01:01 (odds ratio (OR) = 2.19 (1.53-3.14), P = 1.9 x 10(-5)). Two polymorphisms at 6p21.2 LINC00951-LRFN2 gene region were replicated in a separate data set, and rs4714329 reached genome-wide significance (OR = 1.59 (1.37-1.85), P = 1.6 x 10(-9)) in the meta-analysis. The risk allele also associated with antisocial features in the general population conditioned for severe problems in childhood family (beta = 0.68, P = 0.012). Functional analysis in brain tissue in open access GTEx and Braineac databases revealed eQTL associations of rs4714329 with LINC00951 and LRFN2 in cerebellum. In humans, LINC00951 and LRFN2 are both expressed in the brain, especially in the frontal cortex, which is intriguing considering the role of the frontal cortex in behavior and the neuroanatomical findings of reduced gray matter volume in ASPD. To our knowledge, this is the first study showing genome-wide significant and replicable findings on genetic variants associated with any personality disorder.Peer reviewe