Adult-onset Psychiatric Disorders Research Articles

Neurodevelopmental continuum and pathogenic CNV detection in adult onset psychiatric disorders: microarray analysis in psychiatric clinical practice

IntroductionStructural variations of DNA, such as copy number variations (CNVs), are important contributors to risk for human diseases. Several CNVs have been associated with an increased risk of early-onset neurodevelopmental disorders (NDD), adult-onset psychiatry disorders and physical comorbidities. While in Pediatrics the microarray is the first-line genetic analysis technique in the study of child onset NDD, its use in psychiatry care of young/adult onset NDD has been limited to research purposes.ObjectivesReview of the diagnostic yield of the use of microarrays analysis in psychiatric clinical practice of severe mental disorder care in adults, according to the concept of a neurodevelopmental continuum.MethodsAn exploratory literature review on the topic in PubMed, including the terms: “copy number variants/CNVs” AND “neurodevelopmental delay/disorders, congenital anomalies/malformations, ADHD, autism/ASD, learning disabilities, epilepsy, Tourette, schizophrenia, bipolar, behaviour”.ResultsThe prevalence of carriers of pathogenic or likely pathogenic CNVs among the different NDD phenotypes investigated by microarray analysis ranged from 3-22.5%. The majority of studies in adult psychiatric populations examined schizophrenia. Intellectual disability, autism spectrum disorders, dysmorphic features and multiple NDD/psychiatric diagnoses were described as predictors of an increased diagnostic yield of microarray testing.ConclusionsWhile CNV testing is frequent in early-onset NDD; microarray analysis has not been established in psychiatric clinical practice despite the evidence of a high prevalence of findings in adult-onset NDD. The potential benefits in the detection of CNV are associated with physical comorbidities detection, understanding of pathogenesis of disease or genetic counseling. High-quality research designs are required before a routine clinical use.DisclosureNo significant relationships.

Genomewide alteration of histone H3K4 methylation underlies genetic vulnerability to psychopathology

Dysregulated histone methylation has emerged as a recurring theme in multiple neuropsychiatric disorders. However, it is yet unclear whether the altered histone methylation is associated with aetiologic mechanisms or an outcome of disease manifestation. In this study, we examined the genomewide association studies datasets of three major psychiatric disorders, schizophrenia (SCZ), bipolar disorder (BIP), and major depression disorder (MDD), which represents a total of 231,783 cases and 425,444 controls, to clarify the relationship. Our gene-set enrichment analysis results identified statistically significant association of genes involved in three histone methylation biological processes with the three adult-onset psychiatric disorders, which is mainly driven by the histone H3K4 methylation pathway (GO: 0051568). Further analysis of histone H3K4 methylation pathway genes revealed a widespread role of the genes in brain function and disease; 29 (52%) and 41 genes (73.2%) were associated with at least one brain-related trait or brain disorder, respectively. Spatiotemporal gene expression analysis suggests that these pathway genes play a critical role during the prenatal period and are consistent regulators in the cerebral cortex throughout an individual's life. AUTS2, DNMT1 and TET2 are genes of particular interest due to their pervasive role in various aspects of brain function. Our findings support a critical aetiologic role of H3K4 methylation genes shared across SCZ, BIP and MDD, providing new direction for the development of epigenetically-focussed drugs targeting common causal factors of these devastating disorders.

Associations Between Common Forms of Psychopathology and Fecundity: Evidence From a Prospective, Longitudinal Twin Study.

We examined associations between common psychiatric disorders and fecundity in a population-based cohort of 1252 twins prospectively assessed from adolescence into adulthood. Major depressive, anxiety, and alcohol use disorders were associated with lower likelihood of having children and having fewer children. Survival analyses yielded similar results accounting for timing/recurrence. Although both early- and adult-onset psychiatric disorders were associated with decreased fecundity, early-onset major depressive, anxiety (among boys), and alcohol use disorders (among girls) were associated with greater likelihood of having a child during adolescence. Among twin pairs discordant for psychiatric disorders, twins affected by anxiety and alcohol use, but not major depressive, disorders were less likely to have children than unaffected co-twins. However, unaffected twins with an affected co-twin were no more likely to have children than twins from unaffected twin pairs, inconsistent with the balancing selection hypothesis that increased fecundity in unaffected relatives accounts for persistence of psychiatric disorders.

Genome-wide association study of patients with a severe major depressive episode treated with electroconvulsive therapy

Although large genome-wide association studies (GWAS) of major depressive disorder (MDD) have identified many significant loci, the SNP-based heritability remains notably low, which might be due to etiological heterogeneity in existing samples. Here, we test the utility of targeting the severe end of the MDD spectrum through genome-wide SNP genotyping of 2725 cases who received electroconvulsive therapy (ECT) for a major depressive episode (MDE) and 4035 controls. A subset of cases (n = 1796) met a narrow case definition (MDE occurring in the context of MDD). Standard GWAS quality control procedures and imputation were conducted. SNP heritability and genetic correlations with other traits were estimated using linkage disequilibrium score regression. Results were compared with MDD cases of mild-moderate severity receiving internet-based cognitive behavioral therapy (iCBT) and summary results from the Psychiatric Genomics Consortium (PGC). The SNP-based heritability was estimated at 29–34% (SE: 6%) for the narrow case definition, considerably higher than the 6.5–8.0% estimate in the most recent PGC MDD study. Our severe MDE cases had smaller genetic correlations with neurodevelopmental disorders and neuroticism than PGC MDD cases but higher genetic risk scores for bipolar disorder than iCBT MDD cases. One genome-wide significant locus was identified (rs114583506, P = 5e−8) in an intron of HLA-B in the major histocompatibility locus on chr6. These results indicate that individuals receiving ECT for an MDE have higher burden of common variant risk loci than individuals with mild-moderate MDD. Furthermore, severe MDE shows stronger relations with other severe adult-onset psychiatric disorders but weaker relations with personality and stress-related traits than mild-moderate MDD. These findings suggest a different genetic architecture at the severest end of the spectrum, and support further study of the severest MDD cases as an extreme phenotype approach to understand the etiology of MDD.

Genes Within The Context of Development: Changes In Genetic Trait Architectures During Childhood and Adolescence

The extent to which genetic aetiologies are shared between traits and disorders naturally depends on the genetic composition of the two phenotypes. While psychiatric disorders are diagnostic entities, defined by diagnostic criteria including the age of onset, human behaviour changes continuously during development.Studying the genetic overlap between psychiatric illness and social-communication difficulties across multiple developmental stages, we identified, for example, distinct developmental profiles for childhood- versus adult-onset psychiatric disorders respectively. The genetic overlap between clinical ASD and social-communication difficulties during childhood, declined with progressing age of the trait, while the genetic overlap between clinical schizophrenia and social-communication problems was strongest for traits during later adolescence. Thus, the risk of developing these contrasting psychiatric conditions might be related to distinct sets of genes, both of which influence social communication skills, but exert their maximum influence during different periods of development. This suggests complex developmental modifications of the underlying genetic trait architecture.We have now developed a multivariate analysis framework in unrelated individuals to assess the developmental profile of genetic influences that contribute to phenotypic variation during childhood and adolescence. This analysis combines whole-genome genotyping information in unrelated individuals with structural equation modelling techniques (Genetic-relationship-matrix structural equation models, GSEM). Analogous to multivariate twin research, multivariate GSEM can include Cholesky decomposition models, common pathway models or independent pathway model, among many others. Using standard model fitting procedures, we could show that a Cholesky decomposition model, specifying two distinct genetic factors arising during childhood, fitted, for example, developmental changes in social communication abilities best. One genetic factor was common to social communication problems across development spanning 8 to 17 years (path coefficients: 0.20 to 0.54, based on standardised measures). The other factor accounted for independent phenotypic variation arising at 11 years and later ages (path coefficients: 0.20 to 0.44, based on standardised measures). Thus, genetic factors operating during mid-childhood only accounted for a limited proportion (~60%) of genetic variation at age 17 years. These incremental changes in genetic factors influencing social-communication difficulties during child and adolescent development are consistent with distinct developmental trait profiles in genetic overlap with psychiatric illness.An understanding of developmental variations in complex genetic trait architectures is therefore important for studies investigating the continuity of psychiatric disorders.

ULK4 Genetic Variants Have Pleiotropic Effect on Risk of Autism, Associated with Brain mRNA Expression and Antipsychotic Treatment Response

Background: ULK4 genetic variants have been implicated for adult-onset psychiatric disorders, and common variants are associated with hematologic and cardiologic disorders at genome-wide significance. This study aimed to examine the pleiotropic effect of ULK4 on the risk of autism, cis-association with mRNA and impact on antipsychotic treatment response in humans. Methods: The clinical genetic data comprised one cohort of autism case-parent triad sample in the Han Chinese and three cohorts of family-based samples in the European ancestry, from Autism Genetic Research Exchange, the Autism Genome Project and the Simons Foundation for Autism Research Initiative; mRNA expression in postmortem human prefrontal cortex across the lifespan and different brain regions of postmortem human brain and other tissues from two independent datasets were used for examining the cis-association with ULK4 variants. Antipsychotic treatment response data were from the Clinical Antipsychotic Trials in Intervention Effectiveness in patients with chronic schizophrenia. Transmission disequilibrium test was used to examine the genetic association with autism. General linear regression analysis was performed for cis-association with mRNA expression. The Cox proportion hazard model was used to analyze the primary outcome, the time to discontinued use of antipsychotics. Results: Multiple functional SNPs including rs2272007 in strong linkage disequilibrium at ULK4 were associated with autism in the Han Chinese sample (minimum p < 0.00071) which survived the Bonferroni correction for multiple testing. SNP rs2272007 and other SNPs were significantly associated with ULK4 expression in postmortem human prefrontal cortex in subjects across the lifespan and multiple brain areas in two independent datasets. In addition, two SNPs rs7651623 (Hazard Ratio, HR = 16.33; p = 5.00 × 10−4) and rs2030431 (HR = 17.25; p = 3.00 × 10−4) in strong LD were associated with the risk of discontinuing use of antipsychotic medications in the patients with schizophrenia. SNP rs2272007, perfect LD with rs7651623, was associated with treatment response in olanzapine only (HR = 4.22; p = 0.0034). Conclusion: We provide evidence at multiple layers for ULK4 common genetic variants associated with the risk of autism. This may have clinical implication for translational research and precision psychiatry

Evolution of structural abnormalities in the rat brain following in utero exposure to maternal immune activation: A longitudinal in vivo MRI study

Genetic and environmental risk factors for psychiatric disorders are suggested to disrupt the trajectory of brain maturation during adolescence, leading to the development of psychopathology in adulthood. Rodent models are powerful tools to dissect the specific effects of such risk factors on brain maturational profiles, particularly when combined with Magnetic Resonance Imaging (MRI; clinically comparable technology). We therefore investigated the effect of maternal immune activation (MIA), an epidemiological risk factor for adult-onset psychiatric disorders, on rat brain maturation using atlas and tensor-based morphometry analysis of longitudinal in vivo MR images. Exposure to MIA resulted in decreases in the volume of several cortical regions, the hippocampus, amygdala, striatum, nucleus accumbens and unexpectedly, the lateral ventricles, relative to controls. In contrast, the volumes of the thalamus, ventral mesencephalon, brain stem and major white matter tracts were larger, relative to controls. These volumetric changes were maximal between post-natal day 50 and 100 with no differences between the groups thereafter. These data are consistent with and extend prior studies of brain structure in MIA-exposed rodents. Apart from the ventricular findings, these data have robust face validity to clinical imaging findings reported in studies of individuals at high clinical risk for a psychiatric disorder. Further work is now required to address the relationship of these MRI changes to behavioral dysfunction and to establish thier cellular correlates.

Polygenic Risk of Schizophrenia and Cognition in a Population-Based Survey of Older Adults.

Cognitive impairment is a common feature of the major psychotic disorders, with deficits often present in at risk individuals and unaffected first-degree relatives. Previous studies have suggested that polygenic risk scores (PRS) for schizophrenia (SCZ) are associated with cognitive deficits, but there has been little examination of this association in longitudinal datasets, or comparison with other disorders. We used mixed models to study the association between PRS for 4 adult onset psychiatric disorders with cross-sectional cognitive performance and longitudinal cognitive decline in 8616 older adults from the Health and Retirement Study (HRS), followed for an average of 10 years. PRS were computed for SCZ, bipolar disorder (BD), Major Depressive Disorder (MDD), and Alzheimer's disease (ALZ). SCZ PRS associated with decreased cognitive function (z = -3.00, P = .001, ΔR (2) = 0.04%), which was largely driven by an association with impaired attention and orientation (z = -3.33, P = 4.3×10(-4), ΔR (2) = 0.08%). We found no effect of BD or MDD PRS on cognition, in contrast to a robust effect of the APOE4/TOMM40 locus (z = -5.05, P = 2.2×10(-7), ΔR (2) = 0.36%), which was primarily associated with impaired verbal memory (z = -5.15, P = 1.3×10(-7), ΔR (2) = 0.21%). APOE4/TOMM40 locus and the ALZ PRS, but not the PRS for SCZ, were associated with greater cognitive decline. In summary, using a large, representative sample of older adults, we found evidence for different degrees of association between polygenic risk for SCZ and genetic risk factors for ALZ on cognitive function and decline, highlighting potential differences in the pathophysiology of cognitive deficits seen in SCZ and ALZ.

Autistic-like traits in adult patients with mood disorders and schizophrenia.

Autism spectrum disorder often co-occurs with other psychiatric disorders. Although a high prevalence of autistic-like traits/symptoms has been identified in the pediatric psychiatric population of normal intelligence, there are no reports from adult psychiatric population. This study examined whether there is a greater prevalence of autistic-like traits/symptoms in patients with adult-onset psychiatric disorders such as major depressive disorder (MDD), bipolar disorder, or schizophrenia, and whether such an association is independent of symptom severity. The subjects were 290 adults of normal intelligence between 25 and 59 years of age (MDD, n=125; bipolar disorder, n=56; schizophrenia, n=44; healthy controls, n=65). Autistic-like traits/symptoms were measured using the Social Responsiveness Scale for Adults. Symptom severity was measured using the Positive and Negative Symptoms Scale, the Hamilton Depression Rating Scale, and/or the Young Mania Rating Scale. Almost half of the clinical subjects, except those with remitted MDD, exhibited autistic-like traits/symptoms at levels typical for sub-threshold or threshold autism spectrum disorder. Furthermore, the proportion of psychiatric patients that demonstrated high autistic-like traits/symptoms was significantly greater than that of healthy controls, and not different between that of remitted or unremitted subjects with bipolar disorder or schizophrenia. On the other hand, remitted subjects with MDD did not differ from healthy controls with regard to the prevalence or degree of high autistic-like traits/symptoms. A substantial proportion of adults with bipolar disorder and schizophrenia showed high autistic-like traits/symptoms independent of symptom severity, suggesting a shared pathophysiology among autism spectrum disorder and these psychiatric disorders. Conversely, autistic-like traits among subjects with MDD were associated with the depressive symptom severity. These findings suggest the importance of evaluating autistic-like traits/symptoms underlying adult-onset psychiatric disorders for the best-suited treatment. Further studies with a prospective design and larger samples are needed.

Research review: Polygenic methods and their application to psychiatric traits.

Despite evidence from twin and family studies for an important contribution of genetic factors to both childhood and adult onset psychiatric disorders, identifying robustly associated specific DNA variants has proved challenging. In the pregenomics era the genetic architecture (number, frequency and effect size of risk variants) of complex genetic disorders was unknown. Empirical evidence for the genetic architecture of psychiatric disorders is emerging from the genetic studies of the last 5 years. We review the methods investigating the polygenic nature of complex disorders. We provide mini-guides to genomic profile (or polygenic) risk scoring and to estimation of variance (or heritability) from common SNPs; a glossary of key terms is also provided. We review results of applications of the methods to psychiatric disorders and related traits and consider how these methods inform on missing heritability, hidden heritability and still-missing heritability. Genome-wide genotyping and sequencing studies are providing evidence that psychiatric disorders are truly polygenic, that is they have a genetic architecture of many genetic variants, including risk variants that are both common and rare in the population. Sample sizes published to date are mostly underpowered to detect effect sizes of the magnitude presented by nature, and these effect sizes may be constrained by the biological validity of the diagnostic constructs. Increasing the sample size for genome wide association studies of psychiatric disorders will lead to the identification of more associated genetic variants, as already found for schizophrenia. These loci provide the starting point of functional analyses that might eventually lead to new prevention and treatment options and to improved biological validity of diagnostic constructs. Polygenic analyses will contribute further to our understanding of complex genetic traits as sample sizes increase and as sample resources become richer in phenotypic descriptors, both in terms of clinical symptoms and of nongenetic risk factors.

Clinical and functional outcome of childhood attention-deficit/hyperactivity disorder 33 years later.

CONTEXT Prospective studies of childhood attention-deficit/hyperactivity disorder (ADHD) have not extended beyond early adulthood. OBJECTIVE To examine whether children diagnosed as having ADHD at a mean age of 8 years (probands) have worse educational, occupational, economic, social, and marital outcomes and higher rates of ongoing ADHD, antisocial personality disorder (ASPD), substance use disorders (SUDs), adult-onset psychiatric disorders, psychiatric hospitalizations, and incarcerations than non-ADHD comparison participants at a mean age of 41 years. DESIGN Prospective, 33-year follow-up study, with masked clinical assessments. SETTING Research clinic. PARTICIPANTS A total of 135 white men with ADHD in childhood, free of conduct disorder, and 136 men without childhood ADHD (65.2% and 76.4% of original cohort, respectively). MAIN OUTCOME MEASURES Occupational, economic, and educational attainment; marital history; occupational and social functioning; ongoing and lifetime psychiatric disorders; psychiatric hospitalizations; and incarcerations. RESULTS Probands had significantly worse educational, occupational, economic, and social outcomes; more divorces; and higher rates of ongoing ADHD (22.2% vs 5.1%, P&lt;.001), ASPD (16.3% vs 0%, P&lt;.001), and SUDs (14.1% vs 5.1%, P=.01) but not more mood or anxiety disorders (P=.36 and .33) than did comparison participants. Ongoing ADHD was weakly related to ongoing SUDs (ϕ=0.19, P=.04), as well as ASPD with SUDs (ϕ=0.20, P=.04). During their lifetime, probands had significantly more ASPD and SUDs but not mood or anxiety disorders and more psychiatric hospitalizations and incarcerations than comparison participants. Relative to comparisons, psychiatric disorders with onsets at 21 years or older were not significantly elevated in probands. Probands without ongoing psychiatric disorders had worse social, but not occupational, functioning. CONCLUSIONS The multiple disadvantages predicted by childhood ADHD well into adulthood began in adolescence, without increased onsets of new disorders after 20 years of age. Findings highlight the importance of extended monitoring and treatment of children with ADHD.

Preterm Birth and Psychiatric Disorders in Young Adult Life

Preterm birth, intrauterine growth restriction, and delivery-related hypoxia have been associated with schizophrenia. It is unclear whether these associations pertain to other adult-onset psychiatric disorders and whether these perinatal events are independent. To investigate the relationships among gestational age, nonoptimal fetal growth, Apgar score, and various psychiatric disorders in young adult life. Historical population-based cohort study. Identification of adult-onset psychiatric admissions using data from the National Board of Health and Welfare, Stockholm, Sweden. All live-born individuals registered in the nationwide Swedish Medical Birth Register between 1973 and 1985 and living in Sweden at age 16 years by December 2002 (n=1 301 522). Psychiatric hospitalization with nonaffective psychosis, bipolar affective disorder, depressive disorder, eating disorder, drug dependency, or alcohol dependency, diagnosed according to the International Classification of Diseases codes for 8 through 10. Cox proportional hazards regression models were used to estimate hazard ratios and 95% CIs. Preterm birth was significantly associated with increased risk of psychiatric hospitalization in adulthood (defined as ≥16 years of age) in a monotonic manner across a range of psychiatric disorders. Compared with term births (37-41 weeks), those born at 32 to 36 weeks' gestation were 1.6 (95% CI, 1.1-2.3) times more likely to have nonaffective psychosis, 1.3 (95% CI, 1.1-1.7) times more likely to have depressive disorder, and 2.7 (95% CI, 1.6-4.5) times more likely to have bipolar affective disorder. Those born at less than 32 weeks' gestation were 2.5 (95% CI, 1.0-6.0) times more likely to have nonaffective psychosis, 2.9 (95% CI, 1.8-4.6) times more likely to have depressive disorder, and 7.4 (95% CI, 2.7-20.6) times more likely to have bipolar affective disorder. The vulnerability for hospitalization with a range of psychiatric diagnoses may increase with younger gestational age. Similar associations were not observed for nonoptimal fetal growth and low Apgar score.

Prenatal Exposure to Lead, δ-Aminolevulinic Acid, and Schizophrenia: Further Evidence

BackgroundA previously conducted study of prenatal lead exposure and schizophrenia using δ-aminolevulinic acid, a biologic marker of Pb exposure, in archived maternal serum samples collected from subjects enrolled in the Childhood Health and Development Study (1959–1966) based in Oakland, California, suggested a possible association between prenatal Pb exposure and the development of schizophrenia in later life.ObjectivesIn the present study we extend these findings using samples collected from the New England cohort of the National Collaborative Perinatal Project (1959–1966). Using similar methods, in this study we found results that suggest a comparable association in this cohort.MethodsWe pooled matched sets of cases and controls from both the California and New England sites using a multilevel random-intercept logistic regression model, accounting for matching and site structure as well as adjusting for maternal age at delivery and maternal education.ResultsThe estimated odds ratio for schizophrenia associated with exposure corresponding to 15 μg/dL of blood Pb was 1.92 (95% confidence interval, 1.05–3.87; p = 0.03).ConclusionAlthough several limitations constrain generalizability, these results are consistent with previous findings and provide further evidence for the role of early environmental exposures in the development of adult-onset psychiatric disorders.