Publications by authors named "Ole Mors"

327 Publications

Depression and inflammation: Correlation between changes in inflammatory markers with antidepressant response and long-term prognosis.

Eur Neuropsychopharmacol 2021 Sep 28. Epub 2021 Sep 28.

Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Psychosis Research Unit, Aarhus University Hospital - Psychiatry, Aarhus, Denmark. Electronic address:

Inflammation may correlate with a specific subgroup of depression and differential antidepressant response, but no trial has studied changes of many inflammatory markers over several time points and evaluated symptom-specific antidepressant response and long-term prognosis. We performed secondary analyses among 90 outpatients with moderate-severe depression (71% female, mean age 38 years) treated for 26 weeks with escitalopram or nortriptyline. We measured 27 pro- and anti-inflammatory markers at week 0, 8, 12, and 26 and calculated composite inflammation scores. Three depression rating scales were applied and symptom dimensions of depression calculated. Via Danish nationwide registers, 10 years follow-up were included on psychiatric hospital contacts, indicating relapse. Pearson correlation analyses were performed between baseline inflammatory markers and depressive symptom severity, mixed effects models during the 26-week trial, and Cox regression analyses for the register-based outcomes, adjusted for age, sex, BMI, and smoking. Baseline inflammatory markers correlated with differential severity on specific symptom dimensions but not with overall depression severity. A total of 17 of 27 inflammatory markers decreased significantly during treatment. We found no correlation between baseline nor change in inflammatory markers nor composite inflammation scores with differential treatment response on the MADRS, but small correlations between changes in inflammatory markers and differential response on neurovegetative symptoms. Findings were similar among 59 treatment-naïve patients. Inflammatory markers were not associated with differential risks for 10-year relapse. These findings support the importance of studying specific depressive symptoms to further explore the correlation between inflammation with differential antidepressant response in a subgroup of depression. Clinical Trial Registration number: GENDEP is registered at EudraCT2004-001723-38 (http://eudract.emea.europa.eu) and ISRCTN03693000 (www.controlled-trials.com).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.euroneuro.2021.09.006DOI Listing
September 2021

Polygenic Heterogeneity Across Obsessive-Compulsive Disorder Subgroups Defined by a Comorbid Diagnosis.

Front Genet 2021 31;12:711624. Epub 2021 Aug 31.

Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.

Among patients with obsessive-compulsive disorder (OCD), 65-85% manifest another psychiatric disorder concomitantly or at some other time point during their life. OCD is highly heritable, as are many of its comorbidities. A possible genetic heterogeneity of OCD in relation to its comorbid conditions, however, has not yet been exhaustively explored. We used a framework of different approaches to study the genetic relationship of OCD with three commonly observed comorbidities, namely major depressive disorder (MDD), attention-deficit hyperactivity disorder (ADHD), and autism spectrum disorder (ASD). First, using publicly available summary statistics from large-scale genome-wide association studies, we compared genetic correlation patterns for OCD, MDD, ADHD, and ASD with 861 somatic and mental health phenotypes. Secondly, we examined how polygenic risk scores (PRS) of eight traits that showed heterogeneous correlation patterns with OCD, MDD, ADHD, and ASD partitioned across comorbid subgroups in OCD using independent unpublished data from the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH). The comorbid subgroups comprised of patients with only OCD ( = 366), OCD and MDD ( = 1,052), OCD and ADHD ( = 443), OCD and ASD ( = 388), and OCD with more than 1 comorbidity ( = 429). We found that PRS of all traits but BMI were significantly associated with OCD across all subgroups (neuroticism: = 1.19 × 10, bipolar disorder: = 7.51 × 10, anorexia nervosa: = 3.52 × 10, age at first birth: = 9.38 × 10, educational attainment: = 1.56 × 10, OCD: = 1.87 × 10, insomnia: = 2.61 × 10, BMI: = 0.15). For age at first birth, educational attainment, and insomnia PRS estimates significantly differed across comorbid subgroups ( = 2.29 × 10, = 1.63 × 10, and = 0.045, respectively). Especially for anorexia nervosa, age at first birth, educational attainment, insomnia, and neuroticism the correlation patterns that emerged from genetic correlation analysis of OCD, MDD, ADHD, and ASD were mirrored in the PRS associations with the respective comorbid OCD groups. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across OCD comorbid subgroups.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fgene.2021.711624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8438210PMC
August 2021

Time course of symptoms in posttraumatic stress disorder with delayed expression: A systematic review.

Acta Psychiatr Scand 2021 Sep 15. Epub 2021 Sep 15.

Centre for Neuropsychiatric Depression Research, Mental Health Centre Glostrup and Clinical Institute, University of Copenhagen, Copenhagen, Denmark.

Objective: To examine the hypothesis that PTSD with delayed expression in some cases occurs without subthreshold PTSD symptoms above background levels bridging the gap between the traumatic exposure(s) and the clinical diagnosis.

Methods: We performed systematic searches of peer-reviewed papers in English referenced in Pubmed, Embase, or PsycINFO and ascertained 34 prospective studies of PTSD symptom trajectories identified by latent class growth statistical modeling. Studies with delayed and low-stable trajectories provided appropriate data for this study. We computed the difference between the delayed trajectory PTSD symptom sumscore and the low-stable PTSD sumscore at the observed points in time after the traumatic event(s).

Results: In 29 study populations, the latent class growth analyses displayed delayed trajectories, and in these, we identified 110 data points (% PTSD sumscore difference/months since traumatic exposure). The median PTSD symptom sumscore was 25% higher during the initial 6 months among individuals in the delayed trajectory compared to those in low-stable trajectory. From this level, the difference widened and reached a plateau of 40-50% higher. The variation was large, and the baseline participation rate and loss to follow-up were exceeding 25% in the majority of the studies. Heterogeneity of populations, measures, and analyses precluded formal meta-analysis.

Conclusion: Delayed PTSD is preceded by PTSD symptoms during the first year in most cases. Still, few individuals may experience an asymptomatic delay. The results underpin the rationale for monitoring PTSD symptoms and may inform forensic assessments in that delayed PTSD without symptoms bridging the traumatic event is rare.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/acps.13372DOI Listing
September 2021

Examining sex differences in neurodevelopmental and psychiatric genetic risk in anxiety and depression.

PLoS One 2021 2;16(9):e0248254. Epub 2021 Sep 2.

MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom.

Anxiety and depression are common mental health disorders and have a higher prevalence in females. They are modestly heritable, share genetic liability with other psychiatric disorders, and are highly heterogeneous. There is evidence that genetic liability to neurodevelopmental disorders, such as attention deficit hyperactivity disorder (ADHD) is associated with anxiety and depression, particularly in females. We investigated sex differences in family history for neurodevelopmental and psychiatric disorders and neurodevelopmental genetic risk burden (indexed by ADHD polygenic risk scores (PRS) and rare copy number variants; CNVs) in individuals with anxiety and depression, also taking into account age at onset. We used two complementary datasets: 1) participants with a self-reported diagnosis of anxiety or depression (N = 4,178, 65.5% female; mean age = 41.5 years; N = 1,315 with genetic data) from the National Centre for Mental Health (NCMH) cohort and 2) a clinical sample of 13,273 (67.6% female; mean age = 45.2 years) patients with major depressive disorder (MDD) from the Psychiatric Genomics Consortium (PGC). We tested for sex differences in family history of psychiatric problems and presence of rare CNVs (neurodevelopmental and >500kb loci) in NCMH only and for sex differences in ADHD PRS in both datasets. In the NCMH cohort, females were more likely to report family history of neurodevelopmental and psychiatric disorders, but there were no robust sex differences in ADHD PRS or presence of rare CNVs. There was weak evidence of higher ADHD PRS in females compared to males in the PGC MDD sample, particularly in those with an early onset of MDD. These results do not provide strong evidence of sex differences in neurodevelopmental genetic risk burden in adults with anxiety and depression. This indicates that sex may not be a major index of neurodevelopmental genetic heterogeneity, that is captured by ADHD PRS and rare CNV burden, in adults with anxiety and depression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248254PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8412369PMC
September 2021

Psychological adjustment following mechanical restraint in individuals with schizophrenia.

Authors:
Tine Holm Ole Mors

Nord J Psychiatry 2021 Jun 28:1-10. Epub 2021 Jun 28.

Psychosis Research Unit, Aarhus University Hospital Psychiatry, Aarhus, Denmark.

Aim: While it is known that being mechanically restrained during hospitalization can, in severe cases, lead to PTSD in individuals with mental illness, less is known about why some develop posttraumatic stress reactions following restraint while others do not. This study examined whether the amount of exposure to mechanical restraint and patients' interpretations of the episodes' centrality to their identity were related to symptoms of PTSD in individuals with schizophrenia.

Methods: We asked 20 individuals to recall mechanical restraint episodes and rate them on centrality to identity. They also completed scales measuring symptoms of posttraumatic stress, depression, trauma history, and were rated on positive and negative symptoms. Objective information about the number of times they had been restrained was obtained through Danish health registries.

Results: Amount of exposure to mechanical restraint was not significantly related to PTSD symptoms, potentially due to limitations of our small sample. However, interpreting episodes as more central to identity was. This relationship remained significant when controlling for trauma history, positive symptoms, and depression.

Conclusion: The results suggest that clinically significant levels of PTSD are common in this population, and that considering patients' subjective interpretations of restraint episodes, and not merely the objective facts surrounding them is important for patients' psychological adjustment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/08039488.2021.1939417DOI Listing
June 2021

Genetic, Clinical, and Sociodemographic Factors Associated With Stimulant Treatment Outcomes in ADHD.

Am J Psychiatry 2021 09 22;178(9):854-864. Epub 2021 Jun 22.

Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Copenhagen and Aarhus, Denmark (Brikell, Wimberley, Albiñana, Pedersen, Vilhjálmsson, Agerbo, Demontis, Børglum, Schork, LaBianca, Werge, Mors, Hougaard, Mortensen, Dalsgaard); National Center for Register-Based Research, Department of Economics and Business Economics, Aarhus University, Aarhus, Denmark (Brikell, Wimberley, Albiñana, Pedersen, Vilhjálmsson, Agerbo, Mortensen, Dalsgaard); Center for Integrated Register-Based Research (CIRRAU), Aarhus University, Aarhus, Denmark (Wimberley, Agerbo, Mortensen, Dalsgaard); Department of Biomedicine and Center for Integrative Sequencing, Aarhus University, Aarhus, Denmark (Demontis, Børglum); Center for Genomics and Personalized Medicine, Central Region Denmark and Aarhus University, Aarhus, Denmark (Demontis, Børglum); Neurogenomics Division, Translational Genomics Research Institute, Phoenix (Schork); Institute of Biological Psychiatry, Mental Health Services, Copenhagen University Hospital, Copenhagen (Schork, LaBianca, Werge); Department of Clinical Medicine and Center for GeoGenetics, GLOBE Institute, University of Copenhagen, Copenhagen (Werge); Psychosis Research Unit, Aarhus University Hospital, Psychiatry, Aarhus, Denmark (Mors); Department for Congenital Disorders, Statens Serum Institut, Copenhagen (Hougaard); Division of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Child and Adolescent Psychiatry, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff, U.K. (Thapar).

Objective: Stimulant medications are effective for treating attention deficit hyperactivity disorder (ADHD), yet discontinuation and switch to nonstimulant ADHD medications are common. This study aimed to identify genetic, clinical, and sociodemographic factors influencing stimulant treatment initiation, discontinuation, and switch to nonstimulants in individuals with ADHD.

Methods: The authors obtained genetic and national register data for 9,133 individuals with ADHD from the Danish iPSYCH2012 sample and defined stimulant treatment initiation, discontinuation, and switch from prescriptions. For each stimulant treatment outcome, they examined associations with polygenic risk scores (PRSs) for psychiatric disorders and clinical and sociodemographic factors using survival analyses, and conducted genome-wide association studies (GWASs) and estimated single-nucleotide polymorphism heritability (h).

Results: Eighty-one percent of the sample initiated stimulant treatment. Within 2 years, 45% discontinued stimulants and 15% switched to nonstimulants. Bipolar disorder PRS (hazard ratio=1.05, 95% CI=1.02, 1.09) and schizophrenia PRS (hazard ratio=1.07, 95% CI=1.03, 1.11) were associated with discontinuation. Depression, bipolar disorder, and schizophrenia PRSs were marginally but not significantly associated with switch (hazard ratio range, 1.05-1.07). No associations were observed for ADHD and autism PRSs. Individuals diagnosed with ADHD at age 13 or older had higher rates of stimulant initiation, discontinuation, and switch (hazard ratio range, 1.27-2.01). Psychiatric comorbidities generally reduced rates of initiation (hazard ratio range, 0.84-0.88) and increased rates of discontinuation (hazard ratio range, 1.19-1.45) and switch (hazard ratio range, 1.40-2.08). h estimates were not significantly different from zero. No GWAS hits were identified for stimulant initiation or discontinuation. A locus on chromosome 16q23.3 reached genome-wide significance for switch.

Conclusions: The study findings suggest that individuals with ADHD with higher polygenic liability for mood and/or psychotic disorders, delayed ADHD diagnosis, and psychiatric comorbidities have a higher risk for stimulant treatment discontinuation and switch to nonstimulants. Despite the study's limited sample size, one putative GWAS hit for switch was identified, illustrating the potential of utilizing genomics linked to prescription databases to advance ADHD pharmacogenomics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1176/appi.ajp.2020.20121686DOI Listing
September 2021

Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders.

Biol Psychiatry 2021 Mar 23. Epub 2021 Mar 23.

Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, Illinois; Department of Psychiatry and Behavioral Sciences, North Shore University Health System, Evanston, Illinois.

Background: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk.

Methods: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH.

Results: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10; rs73033497, p = 8.8 × 10; rs7914279, p = 6.4 × 10), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05).

Conclusions: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biopsych.2021.02.972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8458480PMC
March 2021

Inactivation of the Schizophrenia-associated BRD1 gene in Brain Causes Failure-to-thrive, Seizure Susceptibility and Abnormal Histone H3 Acetylation and N-tail Clipping.

Mol Neurobiol 2021 Sep 31;58(9):4495-4505. Epub 2021 May 31.

The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark.

Genetic studies have repeatedly shown that the Bromodomain containing 1 gene, BRD1, is involved in determining mental health, and the importance of the BRD1 protein for normal brain function has been studied in both cell models and constitutive haploinsufficient Brd1 mice. Homozygosity for inactivated Brd1 alleles is lethal during embryonic development in mice. In order to further characterize the molecular functions of BRD1 in the brain, we have developed a novel Brd1 knockout mouse model (Brd1) with bi-allelic conditional inactivation of Brd1 in the central nervous system. Brd1 mice were viable but smaller and with reduced muscle strength. They showed reduced exploratory behavior and increased sensitivity to pentylenetetrazole-induced seizures supporting the previously described GABAergic dysfunction in constitutive Brd1 mice. Because BRD1 takes part in protein complexes with histone binding and modifying functions, we investigated the effect of BRD1 depletion on the global histone modification pattern in mouse brain by mass spectrometry. We found decreased levels of histone H3 acetylation (H3K9ac, H3K14ac, and H3K18ac) and increased N-tail clipping in consequence of BRD1 depletion. Collectively, the presented results support that BRD1 controls gene expression at the epigenetic level by regulating histone H3 proteoforms in the brain.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12035-021-02432-8DOI Listing
September 2021

Corrigendum to "Genetic factors underlying the bidirectional relationship between autoimmune and mental disorders - Findings from a Danish population-based study" [Brain Behav. Immun. 91 (2021) 10-23].

Brain Behav Immun 2021 Aug 27;96:307-308. Epub 2021 May 27.

CORE-Copenhagen Research Centre for Mental Health, Mental Health Centre Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark; Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbi.2021.05.019DOI Listing
August 2021

Pharmacogenetic genotype and phenotype frequencies in a large Danish population-based case-cohort sample.

Transl Psychiatry 2021 05 18;11(1):294. Epub 2021 May 18.

Department of Affective Disorders, Aarhus University Hospital Psychiatry, Aarhus, Denmark.

Pharmacogenetics aims to improve clinical care by studying the relationship between genetic variation and variable drug response. Large population-based datasets could improve our current understanding of pharmacogenetics from selected study populations. We provide real-world pharmacogenetic frequencies of genotypes and (combined) phenotypes of a large Danish population-based case-cohort sample (iPSYCH2012; data of the Integrative Psychiatric Research consortium). The genotyped sample consists of 77,684 individuals, of which 51,464 individuals had diagnoses of severe mental disorders (SMD case-cohort) and 26,220 were individuals randomly selected from the Danish population (population cohort). Array-based genotype data imputed to 8.4 million genetic variants was searched for a selected pharmacogenetic panel of 42 clinically relevant variants and a CYP2D6 gene deletion and duplication. We identified 19 of 42 variants. Minor allele frequencies (MAFs) were consistent with previously reported MAFs, and did not differ between SMD cases and population cohorts. Almost all individuals carried at least one genetic variant (> 99.9%) and 87% carried three or more genetic variants. When genotypes were translated into phenotypes, also > 99.9% of individuals had at least one divergent phenotype (i.e. divergent from the common phenotypes considered normal, e.g. extensive metabolizer). The high number of identified individuals with at least one pharmacogenetic variant or divergent phenotype indicates the importance of pharmacogenetic panel-based genotyping. Combined CYP2C19-CYP2D6 phenotypes revealed that 72.7% of individuals had divergent phenotypes for one or both enzymes. As CYP2D6 and CYP2C19 have an important role in the metabolism of psychotropic drugs, this indicates the relevance of pharmacogenetic testing specifically in individuals using psychotropic drugs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41398-021-01417-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131614PMC
May 2021

Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology.

Nat Genet 2021 06 17;53(6):817-829. Epub 2021 May 17.

Department of Neuroscience, Istituto Di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.

Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-021-00857-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192451PMC
June 2021

Post-error adjustment among children aged 7 years with a familial high risk of schizophrenia or bipolar disorder: A population-based cohort study.

Dev Psychopathol 2021 May 17:1-11. Epub 2021 May 17.

Child and Adolescent Mental Health Centre, Mental Health Services Capital Region, Research Unit, Copenhagen University Hospital, Hellerup, Denmark.

The cognitive control system matures gradually with age and shows age-related sex differences. To gain knowledge concerning error adaptation in familial high-risk groups, investigating error adaptation among the offspring of parents with severe mental disorders is important and may contribute to the understanding of cognitive functioning in at-risk individuals. We identified an observational cohort through Danish registries and measured error adaptation using an Eriksen flanker paradigm. We tested 497 7-year-old children with a familial high risk of schizophrenia (N = 192) or bipolar disorder (N = 116) for deficits in error adaptation compared with a control group (N = 189). We investigated whether error adaptation differed between high-risk groups compared with controls and sex differences in the adaptation to errors, irrespective of high-risk status. Overall, children exhibited post-error slowing (PES), but the slowing of responses did not translate to significant improvements in accuracy. No differences were detected between either high-risk group compared with the controls. Boys showed less PES and PES after incongruent trials than girls. Our results suggest that familial high risk of severe mental disorders does not influence error adaptation at this early stage of cognitive control development. Error adaptation behavior at age 7 years shows specific sex differences.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1017/S0954579421000444DOI Listing
May 2021

Polygenic liability, stressful life events and risk for secondary-treated depression in early life: a nationwide register-based case-cohort study.

Psychol Med 2021 May 5:1-10. Epub 2021 May 5.

The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus, Denmark.

Background: In this study, we examined the relationship between polygenic liability for depression and number of stressful life events (SLEs) as risk factors for early-onset depression treated in inpatient, outpatient or emergency room settings at psychiatric hospitals in Denmark.

Methods: Data were drawn from the iPSYCH2012 case-cohort sample, a population-based sample of individuals born in Denmark between 1981 and 2005. The sample included 18 532 individuals who were diagnosed with depression by a psychiatrist by age 31 years, and a comparison group of 20 184 individuals. Information on SLEs was obtained from nationwide registers and operationalized as a time-varying count variable. Hazard ratios and cumulative incidence rates were estimated using Cox regressions.

Results: Risk for depression increased by 35% with each standard deviation increase in polygenic liability (p < 0.0001), and 36% (p < 0.0001) with each additional SLE. There was a small interaction between polygenic liability and SLEs (β = -0.04, p = 0.0009). The probability of being diagnosed with depression in a hospital-based setting between ages 15 and 31 years ranged from 1.5% among males in the lowest quartile of polygenic liability with 0 events by age 15, to 18.8% among females in the highest quartile of polygenic liability with 4+ events by age 15.

Conclusions: These findings suggest that although there is minimal interaction between polygenic liability and SLEs as risk factors for hospital-treated depression, combining information on these two important risk factors could potentially be useful for identifying high-risk individuals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1017/S0033291721001410DOI Listing
May 2021

Taking others into account: combining directly experienced and indirect information in schizophrenia.

Brain 2021 06;144(5):1603-1614

School of Psychology, University of Sussex, Falmer BN1 9RH, UK.

An abnormality in inference, resulting in distorted internal models of the world, has been argued to be a common mechanism underlying the heterogeneous psychopathology in schizophrenia. However, findings have been mixed as to wherein the abnormality lies and have typically failed to find convincing relations to symptoms. The limited and inconsistent findings may have been due to methodological limitations of the experimental design, such as conflating other factors (e.g. comprehension) with the inferential process of interest, and a failure to adequately assess and model the key aspects of the inferential process. Here, we investigated probabilistic inference based on multiple sources of information using a new digital version of the beads task, framed in a social context. Thirty-five patients with schizophrenia or schizoaffective disorder with a wide range of symptoms and 40 matched healthy control subjects performed the task, where they guessed the colour of the next marble drawn from a jar based on a sample from the jar as well as the choices and the expressed confidence of four people, each with their own independent sample (which was hidden from participant view). We relied on theoretically motivated computational models to assess which model best captured the inferential process and investigated whether it could serve as a mechanistic model for both psychotic and negative symptoms. We found that 'circular inference' best described the inference process, where patients over-weighed and overcounted direct experience and under-weighed information from others. Crucially, overcounting of direct experience was uniquely associated with most psychotic and negative symptoms. In addition, patients with worse social cognitive function had more difficulties using others' confidence to inform their choices. This difficulty was related to worse real-world functioning. The findings could not be easily ascribed to differences in working memory, executive function, intelligence or antipsychotic medication. These results suggest hallucinations, delusions and negative symptoms could stem from a common underlying abnormality in inference, where directly experienced information is assigned an unreasonable weight and taken into account multiple times. By this, even unreliable first-hand experiences may gain disproportionate significance. The effect could lead to false perceptions (hallucinations), false beliefs (delusions) and deviant social behaviour (e.g. loss of interest in others, bizarre and inappropriate behaviour). This may be particularly problematic for patients with social cognitive deficits, as they may fail to make use of corrective information from others, ultimately leading to worse social functioning.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/brain/awab065DOI Listing
June 2021

Clinical validation of ratings on the six-item Positive and Negative Syndrome Scale obtained via the Simplified Negative and Positive Symptoms Interview.

J Psychopharmacol 2021 Sep 28;35(9):1081-1090. Epub 2021 Mar 28.

Psychosis Research Unit, Aarhus University Hospital - Psychiatry, Aarhus, Denmark.

Background: The six-item version of the Positive and Negative Syndrome Scale (PANSS-6) has shown promise as a brief measure of the severity of core symptoms of schizophrenia. However, since all prior analyses of the PANSS-6 were based on data extracted from studies using the full 30-item PANSS (PANSS-30), it remains unknown whether it is possible to obtain valid information for the PANSS-6 ratings via a brief interview, such as the Simplified Negative and Positive Symptoms Interview (SNAPSI).

Aims: We aimed to validate the PANSS-6 ratings obtained via the SNAPSI using the PANSS-6 scores extracted from the PANSS-30 ratings obtained via the comprehensive Structured Clinical Interview for PANSS (SCI-PANSS) as the gold-standard reference.

Methods: The PANSS-6 ratings based on the SNAPSI and the PANSS-30 ratings based on the SCI-PANSS were conducted by independent raters with established inter-rater reliability.

Results: Seventy-seven inpatients with schizophrenia ( = 35.1 ± 11.7 years; males = 57%; paranoid schizophrenia = 75%) participated in the study. The intraclass correlation coefficient (ICC) of the PANSS-6 total scores obtained using the SNAPSI and the PANSS-30-derived PANSS-6 total scores via the SCI-PANSS was 0.77 ( < 0.001). The ICC for the PANSS-6 total score and the PANSS-30-derived PANSS-8 (Andreasen's remission criteria) was 0.75 ( < 0.001). Spearman's rank correlation coefficient for changes in PANSS-6 total scores via the SNAPSI and changes in PANSS-30-derived PANSS-6 total scores was 0.70 ( < 0.001).

Conclusions: Using the SNAPSI to rate the PANSS-6 enables a focused and brief assessment of the severity of core symptoms of schizophrenia, which facilitates measurement-based care and clinical decision making in the treatment of schizophrenia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0269881121996890DOI Listing
September 2021

A Nationwide Cohort Study of Nonrandom Mating in Schizophrenia and Bipolar Disorder.

Schizophr Bull 2021 Aug;47(5):1342-1350

Psychosis Research Unit, Aarhus University Hospital-Psychiatry, Palle Juul-Jensens Boulevard 175, 8200 Aarhus N, Denmark.

Nonrandom mating in parents with schizophrenia or bipolar disorder increases the population-level genetic variance among the offspring generation and creates familial (risk) environments likely to be shaped by specific conditions. The objective of this study was to investigate the occurrence of mental disorder and levels of cognitive and social functioning in individuals who have children by partners with schizophrenia or bipolar disorder compared to controls. The Danish High Risk and Resilience Study VIA 7 is a population-based cohort study conducted in Denmark between 2013 and 2016. This study focus on parents diagnosed with schizophrenia (n = 150) or bipolar disorder (n = 100) and control parents (n = 182), as well as their partners without schizophrenia or bipolar disorder (n = 440). We used linear mixed-effect models, and main outcomes were mental disorders, intelligence, processing speed, verbal working memory, and social functioning. We found that parents having children by a partner with schizophrenia or bipolar disorder more often fulfilled the criteria for a mental disorder and had poorer social functioning compared to parents having children by a partner without schizophrenia or bipolar disorder. Furthermore, parents having children by a partner with schizophrenia performed poorer on processing speed compared to parents in the control group. The presence of nonrandom mating found in this study has implications for our understanding of familial transmission of these disorders and our findings should be considered in future investigations of potential risk factors for children with a parent with schizophrenia or bipolar disorder.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/schbul/sbab021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8379547PMC
August 2021

The association between genetically determined ABO blood types and major depressive disorder.

Psychiatry Res 2021 05 24;299:113837. Epub 2021 Feb 24.

Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany; German Centre for Neurodegenerative Diseases (DZNE), Site Rostock/Greifswald, Greifswald, Germany.

ABO blood types and their corresponding antigens have long been assumed to be related to different human diseases. So far, smaller studies on the relationship between mental disorders and blood types yielded contradicting results. In this study we analyzed the association between ABO blood types and lifetime major depressive disorder (MDD). We performed a pooled analysis with data from 26 cohorts that are part of the MDD working group of the Psychiatric Genomics Consortium (PGC). The dataset included 37,208 individuals of largely European ancestry of which 41.6% were diagnosed with lifetime MDD. ABO blood types were identified using three single nucleotide polymorphisms in the ABO gene: rs505922, rs8176746 and rs8176747. Regression analyses were performed to assess associations between the individual ABO blood types and MDD diagnosis as well as putative interaction effects with sex. The models were adjusted for sex, cohort and the first ten genetic principal components. The percentage of blood type A was slightly lower in cases than controls while blood type O was more prominent in cases. However, these differences were not statistically significant. Our analyses found no evidence of an association between ABO blood types and major depressive disorder.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.psychres.2021.113837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071927PMC
May 2021

Clinical validation of the Symptom Self-rating Scale for Schizophrenia (4S) among inpatients.

Nord J Psychiatry 2021 Aug 25;75(6):454-464. Epub 2021 Feb 25.

Psychosis Research Unit, Aarhus University Hospital-Psychiatry, Aarhus, Denmark.

Purpose: Self-reports of psychosis-related symptoms may be a valuable supplement to clinician-ratings, but more validation studies are required. The aim of this study was to conduct clinical validation for the Symptom Self-rating Scale for Schizophrenia (4S) in an inpatient setting.

Materials And Methods: Inpatients diagnosed with schizophrenia were invited to participate in the study. The participants completed the 4S, the 5-item World Health Organization Wellbeing Index (WHO-5) and the Sheehan Disability Scale (SDS) at two time points. Trained raters assessed participants using the 6-item Positive And Negative Syndrome Scale (PANSS-6). The relationship between the 4S and PANSS-6, self-reported side effects, functioning and wellbeing was assessed using Spearman's correlation coefficient (rho).

Results: Sixty-one participants completed the 4S at least once (yielding a total of 91 completed 4S questionnaires). The 4S total score was weakly correlated with the PANSS-6 total score (rho = 0.37,  < 0.001). The rho's for individual 4S and PANSS-6 subscales and item comparisons ranged from -0.24 (thought disorder) to 0.69 (hallucinations). Finally, the 4S hallucination subscale was also sensitive to change. The 4S was strongly inversely correlated with wellbeing (WHO-5) and moderately inversely correlated with functioning (SDS total score).

Conclusion: The 4S holds promise as a valid self-report of core schizophrenia symptoms among inpatients. While the hallucination subscale seems superior to existing scales, the thought disorder subscale needs to be re-developed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/08039488.2021.1881821DOI Listing
August 2021

Are depressive disorders caused by psychosocial stressors at work? A systematic review with metaanalysis.

Eur J Epidemiol 2021 May 12;36(5):479-496. Epub 2021 Feb 12.

Department of Occupational and Environmental Medicine, Bispebjerg and Frederiksberg Hospital, University of Copenhagen, Copenhagen, Denmark.

In the last decade, many studies have examined associations between poor psychosocial work environment and depression. We aimed to assess the evidence for a causal association between psychosocial factors at work and depressive disorders. We conducted a systematic literature search from 1980 to March 2019. For all exposures other than night and shift work and long working hours, we limited our selection of studies to those with a longitudinal design. We extracted available risk estimates for each of 19 psychosocial exposures, from which we calculated summary risk estimates with 95% confidence intervals (PROSPERO, identifier CRD42019130266). 54 studies were included, addressing 19 exposures and 11 different measures of depression. Only data on depressive episodes were sufficient for evaluation. Heterogeneity of exposure definitions and ascertainment, outcome measures, risk parameterization and effect contrasts limited the validity of meta-analyses. Summary risk estimates were above unity for all but one exposure, and below 1.60 for all but another. Outcome measures were liable to high rates of false positives, control of relevant confounding was mostly inadequate, and common method bias was likely in a large proportion of studies. The combination of resulting biases is likely to have inflated observed effect estimates. When statistical uncertainties and the potential for bias and confounding are taken into account, it is not possible to conclude with confidence that any of the psychosocial exposures at work included in this review is either likely or unlikely to cause depressive episodes or recurrent depressive disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10654-021-00725-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159794PMC
May 2021

Standardized training in the rating of the six-item Positive And Negative Syndrome Scale (PANSS-6).

Schizophr Res 2021 02 9;228:438-446. Epub 2021 Feb 9.

Psychosis Research Unit, Aarhus University Hospital - Psychiatry, Palle Juul-Jensens Boulevard 175, 8200 Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Palle Juul-Jensens Boulevard 82, 8200 Aarhus N, Denmark; Department of Affective Disorders, Aarhus University Hospital - Psychiatry, Palle Juul-Jensens Boulevard 175, 8200 Aarhus, Denmark.

The six-item Positive And Negative Syndrome Scale (PANSS-6) allows for a brief assessment of the severity of core symptoms of schizophrenia. However, implementing the PANSS-6 in clinical practice requires that staff members' ratings are accurate and reliable. We aimed to investigate whether such accuracy and reliability can be obtained via a brief video-based training program. One-hundred-and-four staff members from a psychiatric hospital in Denmark participated in the training. Participants performed a baseline PANSS-6 rating based on a video of a patient being interviewed using the Simplified positive And Negative Symptoms interview (SNAPSI). Subsequently, a theoretical introduction video was displayed followed by five successive videotaped SNAPSI patient interviews. After each SNAPSI video, individual ratings were conducted before a video providing the gold standard rating was displayed. The accuracy of ratings was estimated by calculating the proportion of participants not deviating from the gold standard rating with >2 points on individual items or >6 points on the PANSS-6 total score. Reliability was tested after each step in the training by means of Gwet's Agreement Coefficient (Gwet). By the end of the training, 72% of the participants rated within the acceptable deviations of the gold standard, ranging from 60% (nurses) to 91% (medical doctors & psychologists). The reliability improved (Gwet baseline vs. endpoint) for all PANSS-6 items, except for Blunted affect. In conclusion, the majority of the staff members conducted accurate PANSS-6 ratings after a brief standardized training program, supporting the implementation of PANSS-6 in clinical settings to facilitate measurement-based care.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.schres.2020.12.044DOI Listing
February 2021

Heterogeneity of social cognitive and language functions in children at familial high-risk of severe mental illness; The Danish High Risk and Resilience Study VIA 7.

Eur Child Adolesc Psychiatry 2021 Feb 9. Epub 2021 Feb 9.

The Danish High Risk and Resilience Study VIA7, Copenhagen Research Centre for Mental Health-CORE, Mental Health Centre Copenhagen, Copenhagen University Hospital, Gentofte Hospitalsvej 15, 4, 2900, Hellerup, Denmark.

Cognitive heterogeneity characterizes individuals with schizophrenia and bipolar disorder; however, little is known of cognitive heterogeneity within young children at familial high-risk of schizophrenia or bipolar disorder. This study aimed to investigate heterogeneity across social cognitive and language functions in children at familial high-risk of schizophrenia or bipolar disorder, i.e. severe mental illness (FHR-SMI). This may help designate subgroups in need of intervention initiatives. A data-driven, hierarchical cluster analysis was applied across a sample of 322 children at FHR-SMI (FHR-SZ, n = 200; FHR-BP, n = 120) on measures of Theory of Mind, facial emotion recognition, social cognitive processing speed, receptive and pragmatic language. We examined differences between subgroups as well as differences between subgroups and a control group. Exploratively, the subgroups were compared in terms of social responsiveness and global functioning. A Typical-High Functioning Subgroup with intact social cognitive and language functioning (34.5%), a Mildly Impaired Subgroup with selective impairments in explicit Theory of Mind and language functioning (58.7%), and a Significantly Impaired Subgroup with social cognitive and language functioning impairments (6.8%) were identified. The subgroups differed significantly from each other and overall compares to the controls. The Significantly and Mildly Impaired Subgroups presented with poorer social responsiveness and global functioning than the Typical-High Functioning Subgroup. In young children with FHR-SMI, three subgroups with relatively homogeneous social cognitive and language functioning profiles were observed. Only a small proportion of children at FHR-SMI displayed large social cognitive and language functioning impairments in middle childhood.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00787-021-01722-9DOI Listing
February 2021

Psychological adjustment in care providers following restraint of psychiatric patients.

Stress Health 2021 Oct 19;37(4):729-741. Epub 2021 Feb 19.

Department of Clinical Medicine, Psychosis Research Unit, Aarhus University Hospital Psychiatry, Aarhus, Denmark.

Mental healthcare providers face many difficult interactions with patients that can be emotionally demanding and have adverse effects on their well-being. Recent theoretical models suggest that the interpretation of stressful episodes may be more important for psychological adjustment than the nature of the episodes. This study examined whether care providers' interpretations of mechanical restraint episodes were related to their adjustment. We asked 80 mental healthcare providers to recall mechanical restraint episodes and to rate them on centrality to identity and positive and negative influence on self-understanding. They also completed scales measuring current symptoms of post-traumatic stress, depression, life satisfaction, and well-being. The results showed that care providers who interpreted mechanical restraint episodes as having a central negative influence on their identity experienced more symptoms of post-traumatic stress. Care providers who gave higher ratings of positive self-change following episodes reported more well-being. Our findings suggest, that considering care providers' subjective interpretations of episodes and not merely the objective facts surrounding them is critical if we wish to mitigate the negative emotional impact of episodes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/smi.3032DOI Listing
October 2021

Risk variants and polygenic architecture of disruptive behavior disorders in the context of attention-deficit/hyperactivity disorder.

Nat Commun 2021 01 25;12(1):576. Epub 2021 Jan 25.

The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark.

Attention-Deficit/Hyperactivity Disorder (ADHD) is a childhood psychiatric disorder often comorbid with disruptive behavior disorders (DBDs). Here, we report a GWAS meta-analysis of ADHD comorbid with DBDs (ADHD + DBDs) including 3802 cases and 31,305 controls. We identify three genome-wide significant loci on chromosomes 1, 7, and 11. A meta-analysis including a Chinese cohort supports that the locus on chromosome 11 is a strong risk locus for ADHD + DBDs across European and Chinese ancestries (rs7118422, P = 3.15×10, OR = 1.17). We find a higher SNP heritability for ADHD + DBDs (h = 0.34) when compared to ADHD without DBDs (h = 0.20), high genetic correlations between ADHD + DBDs and aggressive (r = 0.81) and anti-social behaviors (r = 0.82), and an increased burden (polygenic score) of variants associated with ADHD and aggression in ADHD + DBDs compared to ADHD without DBDs. Our results suggest an increased load of common risk variants in ADHD + DBDs compared to ADHD without DBDs, which in part can be explained by variants associated with aggressive behavior.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-20443-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835232PMC
January 2021

Identification of genetic loci associated with nocturnal enuresis: a genome-wide association study.

Lancet Child Adolesc Health 2021 03 15;5(3):201-209. Epub 2021 Jan 15.

The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Denmark; Department of Biomedicine, Aarhus University, Aarhus, Denmark; Centre for Integrative Sequencing (iSEQ), Aarhus University, Aarhus, Denmark; Centre for Genomics and Personalized Medicine (CGPM), Aarhus University, Aarhus, Denmark. Electronic address:

Background: Nocturnal enuresis (bedwetting) is a common disorder affecting 10-16% of 7-year-old children globally. Nocturnal enuresis is highly heritable, but its genetic determinants remain unknown. We aimed to identify genetic variants associated with nocturnal enuresis and explore its genetic architecture and underlying biology.

Methods: We did a genome-wide association study (GWAS) of nocturnal enuresis. Nocturnal enuresis cases were identified in iPSYCH2012, a large Danish population-based case cohort established to investigate mental disorders, on the basis of 10th revision of the International Statistical Classification of Diseases (ICD-10) diagnoses and redeemed desmopressin prescriptions in Danish registers. The GWAS was done in a genetically homogeneous sample of unrelated individuals using logistic regression with relevant covariates. All genome-wide significant variants were analysed for their association with nocturnal enuresis in an independent Icelandic sample from deCODE genetics. Standardised polygenic risk scores for attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder were constructed from summary statistics of large GWASs and analysed for association with nocturnal enuresis.

Findings: The GWAS included 3882 nocturnal enuresis cases and 31 073 controls. We found two loci at chromosome 6 and chromosome 13 significantly associated with nocturnal enuresis. Six genetic variants at the two loci (five variants at chromosome 6q16.2 and one variant at chromosome 13q22.3) surpassed the threshold for genome-wide significance (p<5 × 10). There were two lead variants: rs9376454 (chromosome 6q16.2), with an odds ratio (OR) of 1·199 (95% CI 1·135-1·267; p=9·91 × 10), and rs60721117 (chromosome 13q22.3), with an OR of 1·149 (1·095-1·205; p=1·21 × 10). All associated variants in the chromosome 6 locus were replicated (p<8 × 10) in the independent Icelandic cohort of 5475 nocturnal enuresis cases and 303 996 controls, whereas the associated variant in the chromosome 13 locus showed nominal significant association (p=0·031). The percentage of nocturnal enuresis phenotypic variance explained by the common genetic variants was 23·9-30·4%. Polygenic risk for ADHD was associated with nocturnal enuresis (OR 1·06, 95% CI, 1·01-1·10; p=0·011). Among the potential nocturnal enuresis risk genes mapped, PRDM13 and EDNRB have biological functions associated with known pathophysiological mechanisms in nocturnal enuresis, and SIM1 regulates the formation of the hypothalamic neuroendocrine lineage that produces arginine vasopressin, a well known nocturnal enuresis drug target.

Interpretation: This study shows that common genetic variants contribute considerably to nocturnal enuresis, and it identifies potential nocturnal enuresis risk genes with roles in sleep, urine production, and bladder function. Given that available treatments target these mechanisms, any of the identified genes and their functional gene networks are potential drug targets.

Funding: The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Stanley Foundation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2352-4642(20)30350-3DOI Listing
March 2021

Risk of Early-Onset Depression Associated With Polygenic Liability, Parental Psychiatric History, and Socioeconomic Status.

JAMA Psychiatry 2021 Apr;78(4):387-397

Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus, Denmark.

Importance: Combining information on polygenic risk scores (PRSs) with other known risk factors could potentially improve the identification of risk of depression in the general population. However, to our knowledge, no study has estimated the association of PRS with the absolute risk of depression, and few have examined combinations of the PRS and other important risk factors, including parental history of psychiatric disorders and socioeconomic status (SES), in the identification of depression risk.

Objective: To assess the individual and joint associations of PRS, parental history, and SES with relative and absolute risk of early-onset depression.

Design, Setting, And Participants: This case-cohort study included participants from the iPSYCH2012 sample, a case-cohort sample of all singletons born in Denmark between May 1, 1981, and December 31, 2005. Hazard ratios (HRs) and absolute risks were estimated using Cox proportional hazards regression for case-cohort designs.

Exposures: The PRS for depression; SES measured using maternal educational level, maternal marital status, and paternal employment; and parental history of psychiatric disorders (major depression, bipolar disorder, other mood or psychotic disorders, and other psychiatric diagnoses).

Main Outcomes And Measures: Hospital-based diagnosis of depression from inpatient, outpatient, or emergency settings.

Results: Participants included 17 098 patients with depression (11 748 [68.7%] female) and 18 582 (9429 [50.7%] male) individuals randomly selected from the base population. The PRS, parental history, and lower SES were all significantly associated with increased risk of depression, with HRs ranging from 1.32 (95% CI, 1.29-1.35) per 1-SD increase in PRS to 2.23 (95% CI, 1.81-2.64) for maternal history of mood or psychotic disorders. Fully adjusted models had similar effect sizes, suggesting that these risk factors do not confound one another. Absolute risk of depression by the age of 30 years differed substantially, depending on an individual's combination of risk factors, ranging from 1.0% (95% CI, 0.1%-2.0%) among men with high SES in the bottom 2% of the PRS distribution to 23.7% (95% CI, 16.6%-30.2%) among women in the top 2% of PRS distribution with a parental history of psychiatric disorders.

Conclusions And Relevance: This study suggests that current PRSs for depression are not more likely to be associated with major depressive disorder than are other known risk factors; however, they may be useful for the identification of risk in conjunction with other risk factors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamapsychiatry.2020.4172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807393PMC
April 2021

FUT2-ABO epistasis increases the risk of early childhood asthma and Streptococcus pneumoniae respiratory illnesses.

Nat Commun 2020 12 16;11(1):6398. Epub 2020 Dec 16.

Department of Human Genetics, University of Chicago, Chicago, IL, USA.

Asthma with severe exacerbation is the most common cause of hospitalization among young children. We aim to increase the understanding of this clinically important disease entity through a genome-wide association study. The discovery analysis comprises 2866 children experiencing severe asthma exacerbation between ages 2 and 6 years, and 65,415 non-asthmatic controls, and we replicate findings in 918 children from the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC) birth cohorts. We identify rs281379 near FUT2/MAMSTR on chromosome 19 as a novel risk locus (OR = 1.18 (95% CI = 1.11-1.25), P = 2.6 × 10) as well as a biologically plausible interaction between functional variants in FUT2 and ABO. We further discover and replicate a potential causal mechanism behind this interaction related to S. pneumoniae respiratory illnesses. These results suggest a novel mechanism of early childhood asthma and demonstrates the importance of phenotype-specificity for discovery of asthma genes and epistasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-19814-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744576PMC
December 2020

Psychotic experiences in seven-year-old children with familial high risk of schizophrenia or bipolar disorder in: The Danish High Risk and Resilience Study - VIA 7; A population-based cohort study.

Schizophr Res 2021 02 9;228:510-518. Epub 2020 Dec 9.

Copenhagen Research Center for Mental Health - CORE, Mental Health Center Copenhagen, Mental Health Services, Capital Region of Denmark, Copenhagen, Gentofte Hospitalsvej 15, 4th floor, DK-2900 Hellerup, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Fuglesangs Allé 26, DK-8210 Aarhus, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, DK-2200 Copenhagen N, Denmark. Electronic address:

We aimed to examine the prevalence of psychotic experiences (PEs) in children with familial high risk of schizophrenia (FHR-SZ) or bipolar disorder (FHR-BP) and, in exploratory analyses, to examine the possible associations between PEs and mental disorders as well as level of functioning. A cohort of seven-year-old children with FHR-SZ (N = 199), FHR-BP (N = 118) and controls (N = 196) was recruited through Danish nationwide registers. Lifetime PEs were assessed through interviews using the psychosis section of the 'Schedule for Affective Disorders and Schizophrenia for School-Age Children - Present and Lifetime Version' (K-SADS-PL). Lifetime DSM-IV diagnoses were ascertained through K-SADS-PL and the level of functioning of the children through 'Children's Global Assessment Scale'. Both children with FHR-SZ (OR = 2.9, 95% CI = 1.4-6.2, p = 0.005) and FHR-BP (OR = 2.9, 95% CI = 1.3-6.7, p = 0.011) had an increased risk of having experienced "severe" PEs compared with controls. In the overall cohort PEs were associated with any lifetime mental disorder, Attention-Deficit/Hyperactivity Disorder, anxiety disorders and a lower level of functioning. The findings of a higher proportion of high risk children reporting PEs could represent an early manifestation of later more severe psychopathology or simply an unspecific transitory symptom. Future follow-up studies of this cohort will explore the predictive value of the occurrence of PEs at age seven.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.schres.2020.11.045DOI Listing
February 2021

Decision making and its associations to neurocognitive functions, psychopathology, and the home environment in seven-year-old children at familial high risk of schizophrenia or bipolar disorder: The Danish High Risk and Resilience Study VIA 7.

J Affect Disord 2021 02 21;281:609-617. Epub 2020 Nov 21.

Child and Adolescent Mental Health Centre, Mental Health Services, Capital Region of Denmark, Copenhagen, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark; Service of Child and Adolescent Psychiatry, Department of Psychiatry, University Medical Center, University of Lausanne, Lausanne, Switzerland.

Background: Slower and suboptimal decision making has been identified in adults with schizophrenia and bipolar disorder. Owing to the limited evidence on decision making in first-degree relatives, we aimed to investigate, whether alterations in decision making are present in young children at familial high risk of bipolar disorder or schizophrenia.

Methods: In this population-based cohort study we assessed decision making in 197 children at familial high risk of schizophrenia (FHR-SZ), 115 children at familial high risk of bipolar disorder (FHR-BP), and 190 controls aged seven using the Cambridge Gambling Task. Potential associations to neurocognition, psychopathology, and the home environment were investigated.

Results: Children at FHR-SZ or FHR-BP displayed intact decision making. Quality of decision making showed significant but weak cross-sectional associations to neurocognition and adequacy of the home environment. Associations to aspects of executive functions and the home environment differed across groups.

Limitations: Due to the cross-sectional nature of this study, the predictive value of efficient and inefficient decision making remains to be investigated in planned follow-up studies of this cohort.

Conclusions: Young children at FHR-SZ or FHR-BP do not differ from controls in decision making efficacy, which does not appear to be an early risk marker of bipolar disorder or schizophrenia. Decision making is weakly associated to neurocognition and the home environment, but not to general intelligence or psychopathology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jad.2020.11.107DOI Listing
February 2021
-->