Genetic influences on eight psychiatric disorders based on family data of 4 408 646 full and half-siblings, and genetic data of 333 748 cases and controls

AbstractBackgroundMost studies underline the contribution of heritable factors for psychiatric disorders. However, heritability estimates depend on the population under study, diagnostic instruments, and study designs that each has its inherent assumptions, strengths, and biases. We aim to test the homogeneity in heritability estimates between two powerful, and state of the art study designs for eight psychiatric disorders.MethodsWe assessed heritability based on data of Swedish siblings (N = 4 408 646 full and maternal half-siblings), and based on summary data of eight samples with measured genotypes (N = 125 533 cases and 208 215 controls). All data were based on standard diagnostic criteria. Eight psychiatric disorders were studied: (1) alcohol dependence (AD), (2) anorexia nervosa, (3) attention deficit/hyperactivity disorder (ADHD), (4) autism spectrum disorder, (5) bipolar disorder, (6) major depressive disorder, (7) obsessive-compulsive disorder (OCD), and (8) schizophrenia.ResultsHeritability estimates from sibling data varied from 0.30 for Major Depression to 0.80 for ADHD. The estimates based on the measured genotypes were lower, ranging from 0.10 for AD to 0.28 for OCD, but were significant, and correlated positively (0.19) with national sibling-based estimates. When removing OCD from the data the correlation increased to 0.50.ConclusionsGiven the unique character of each study design, the convergent findings for these eight psychiatric conditions suggest that heritability estimates are robust across different methods. The findings also highlight large differences in genetic and environmental influences between psychiatric disorders, providing future directions for etiological psychiatric research.

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Comprehensive exploration of the genetic contribution of the dopaminergic and serotonergic pathways to psychiatric disorders

Translational Psychiatry ◽

10.1038/s41398-021-01771-3 ◽

2022 ◽

Vol 12 (1) ◽

Author(s):

Judit Cabana-Domínguez ◽

Bàrbara Torrico ◽

Andreas Reif ◽

Noèlia Fernàndez-Castillo ◽

Bru Cormand

Keyword(s):

Psychiatric Disorders ◽

Meta Analysis ◽

Autism Spectrum ◽

Genetic Contribution ◽

Obsessive Compulsive ◽

Gene Set ◽

Compulsive Disorder ◽

Kegg Pathways ◽

Gene Sets ◽

Psychiatric Conditions

AbstractPsychiatric disorders are highly prevalent and display considerable clinical and genetic overlap. Dopaminergic and serotonergic neurotransmission have been shown to play an important role in many psychiatric disorders. Here we aim to assess the genetic contribution of these systems to eight psychiatric disorders (attention-deficit hyperactivity disorder (ADHD), anorexia nervosa (ANO), autism spectrum disorder (ASD), bipolar disorder (BIP), major depression (MD), obsessive-compulsive disorder (OCD), schizophrenia (SCZ) and Tourette’s syndrome (TS)) using publicly available GWAS analyses performed by the Psychiatric Genomics Consortium that include more than 160,000 cases and 275,000 controls. To do so, we elaborated four different gene sets: two ‘wide’ selections for dopamine (DA) and for serotonin (SERT) using the Gene Ontology and KEGG pathways tools, and two’core’ selections for the same systems, manually curated. At the gene level, we found 67 genes from the DA and/or SERT gene sets significantly associated with one of the studied disorders, and 12 of them were associated with two different disorders. Gene-set analysis revealed significant associations for ADHD and ASD with the wide DA gene set, for BIP with the wide SERT gene set, and for MD with the core SERT set. Interestingly, interrogation of a cross-disorder GWAS meta-analysis of the eight psychiatric conditions displayed association with the wide DA gene set. To our knowledge, this is the first systematic examination of genes encoding proteins essential to the function of these two neurotransmitter systems in these disorders. Our results support a pleiotropic contribution of the dopaminergic and serotonergic systems in several psychiatric conditions.

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Genome wide meta-analysis identifies genomic relationships, novel loci, and pleiotropic mechanisms across eight psychiatric disorders

10.1101/528117 ◽

2019 ◽

Cited By ~ 9

Author(s):

◽

Phil H. Lee ◽

Verneri Anttila ◽

Hyejung Won ◽

Yen-Chen A. Feng ◽

...

Keyword(s):

Psychiatric Disorders ◽

Meta Analysis ◽

Autism Spectrum ◽

Pleiotropic Effects ◽

Obsessive Compulsive ◽

Compulsive Disorder ◽

Hyperactivity Disorder ◽

Genome Wide ◽

Genomic Relationships ◽

The Brain

SummaryGenetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed a meta-analysis of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders identifying three groups of inter-related disorders. We detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning in the second trimester prenatally, and play prominent roles in a suite of neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.

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Methylphenidate-induced Obsessive Compulsive Disorder in Attention Deficit Hyperactivity Disorder

The Journal of Medical Sciences ◽

10.5005/jp-journals-10045-0028 ◽

2016 ◽

Vol 2 (1) ◽

pp. 21-22

Author(s):

Sharath Vishwaraj

Keyword(s):

Attention Deficit Hyperactivity Disorder ◽

Complete Remission ◽

Psychiatric Disorders ◽

Obsessive Compulsive Disorder ◽

Attention Deficit ◽

Specific Treatment ◽

Obsessive Compulsive ◽

Compulsive Disorder ◽

Hyperactivity Disorder ◽

Childhood Psychiatric Disorders

ABSTRACT Introduction Attention deficit hyperactivity disorder (ADHD) is one of the most common childhood psychiatric disorders. It is most often treated with methylphenidate (MPH). A 6-year-old male with ADHD was started on MPH. He developed severe obsessive-compulsive disorder (OCD), which lasted for 1 day and was self-limiting. There was complete remission on stopping MPH, without any specific treatment for OCD. How to cite this article Bavle A, Vishwaraj S. Methylphenidate- induced Obsessive Compulsive Disorder in Attention Deficit Hyperactivity Disorder. J Med Sci 2016;2(1):21-22.

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Multilevel neural gradients reflect transdiagnostic effects of major psychiatric conditions on cortical morphology

10.1101/2021.10.29.466434 ◽

2021 ◽

Author(s):

Bo-yong Park ◽

Valeria Kebets ◽

Sara Lariviere ◽

Meike D. Hettwer ◽

Casey Paquola ◽

...

Keyword(s):

Multiple Scales ◽

Principal Component ◽

Autism Spectrum ◽

Neural Pathways ◽

Obsessive Compulsive ◽

Brain Organization ◽

Compulsive Disorder ◽

Working Groups ◽

Psychiatric Conditions ◽

Cortical Morphology

It is increasingly recognized that multiple psychiatric conditions are underpinned by shared neural pathways, affecting similar brain systems. Here, we assessed i) shared dimensions of alterations in cortical morphology across six major psychiatric conditions (autism spectrum disorder, attention deficit/hyperactivity disorder, major depression, obsessive-compulsive disorder, bipolar disorder, schizophrenia) and ii) carried out a multiscale neural contextualization, by cross-referencing shared anomalies against cortical myeloarchitecture and cytoarchitecture, as well as connectome and neurotransmitter organization. Pooling disease-related effects on MRI-based cortical thickness measures across six ENIGMA working groups, including a total of 28,546 participants (12,876 patients and 15,670 controls), we computed a shared disease dimension on cortical morphology using principal component analysis that described a sensory-fugal pattern with paralimbic regions showing the most consistent abnormalities across conditions. The shared disease dimension was closely related to cortical gradients of microstructure and intrinsic connectivity, as well as neurotransmitter systems, specifically serotonin and dopamine. Our findings embed the shared effects of major psychiatric conditions on brain structure in multiple scales of brain organization and may provide novel insights into neural mechanisms into transdiagnostic vulnerability.

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A-90 Personality Tests in Neuropsychological Assessment: Determining the Presence of Psychotic and Obsessive Compulsive Disorders in 3 Individuals with Autism Spectrum Disorder

Archives of Clinical Neuropsychology ◽

10.1093/arclin/acab062.108 ◽

2021 ◽

Vol 36 (6) ◽

pp. 1137-1137

Author(s):

Kathleen Torsney

Keyword(s):

Autism Spectrum Disorder ◽

Psychiatric Disorders ◽

Case Studies ◽

Correct Diagnosis ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Future Research ◽

Obsessive Compulsive ◽

Personality Tests ◽

Compulsive Disorder

Abstract Objective The assessment of personality and psychopathology in an individual who has symptoms of autism spectrum disorder (ASD) can be a challenging task due to the overlap of characteristic behaviors associated with ASD and markers of psychopathology. Through the examination of key factors in 3 case studies of neuropsychological assessments, this poster outlines steps to facilitate the correct diagnosis of psychiatric disorders in persons with autism spectrum disorder. Method This poster explores 3 case studies in which an individual exhibited signs of a psychiatric disorder as well as ASD. The author describes how the personality tests such as the MMPI-2 and MMPI-RF were administered and interpreted and how case history and test taking behavior affected the understanding of the results. Results The poster highlights critical factors in differentiating psychiatric disorders and symptoms that are part of the ASD. For example, in all 3 case studies, the individuals had significant difficulty with the computerized version of the test and needed to take it with paper and pencil. The author also outlines examples where the symptoms are manifestations of the ASD, such as perseveration and rigid thinking and when they are attributable to an obsessive–compulsive disorder. Further, the author differentiates signs of psychosis in a person with ASD from the typical tangential and circumstantial speech associated with ASD. Conclusion The author offers suggestions for administering personality tests to persons with ASD, for interpreting the results of the tests, and for conducting future research to facilitate the differentiation between symptoms consistent with ASD and with psychopathology.

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Functional MRI in Psychiatric Disorders

Functional MRI ◽

10.1093/med/9780190297763.003.0006 ◽

2018 ◽

pp. 91-118

Author(s):

Jie Lisa Ji ◽

Alan Anticevic

Keyword(s):

Magnetic Resonance Imaging ◽

Bipolar Disorder ◽

Psychiatric Disorders ◽

Large Scale ◽

Neural Substrates ◽

Behavioral Symptoms ◽

Neural Systems ◽

Obsessive Compulsive ◽

Compulsive Disorder ◽

Psychiatric Conditions

sSince its introduction to clinical research, functional magnetic resonance imaging (fMRI) has had a pivotal role in understanding the systems-level neural substrates of psychiatric disorders. fMRI is a powerful tool for the field of psychiatry because it is well suited to studying large-scale neural systems and distributed neuropathology, which are thought to underlie many of the behavioral symptoms in psychiatric conditions. This chapter highlights key fMRI findings in four major types of psychiatric disorders: schizophrenia, mood disorders (including major depressive disorder and bipolar disorder), obsessive-compulsive disorder, and posttraumatic stress disorder.

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Current Treatments for Pediatric Psychiatric Disorders

10.1093/med/9780190681425.003.0068 ◽

2017 ◽

Author(s):

M. Pilar Trelles ◽

Paige M. Siper ◽

Dorothy E. Grice

Keyword(s):

Psychiatric Disorders ◽

Psychiatric Symptoms ◽

Developmental Trajectories ◽

Psychosocial Interventions ◽

Autism Spectrum ◽

Tic Disorders ◽

Compulsive Disorder ◽

Empirically Supported ◽

Psychiatric Conditions ◽

Chronic Course

Many psychiatric disorders of childhood have a chronic course. As such, they impact multiple developmental epochs and negatively influence developmental trajectories. While early identification and intervention may minimize, or even prevent, symptoms being carried into adulthood, the availability of evidence-based treatments is sparse in children and adolescents compared to adult populations. Establishing effective interventions for psychiatric symptoms presenting in childhood is critical given the chronic course of most psychiatric disorders. This chapter describes psychopharmacological and psychosocial interventions used for the treatment of childhood psychiatric conditions, with an emphasis on empirically supported treatments. Both symptom- and diagnosis-specific approaches are described as well as the use of combined interventions for the following childhood psychiatric conditions: autism spectrum disorder (ASD), intellectual disability (ID), attention-deficit/hyperactivity disorder (ADHD), anxiety, depression, obsessive compulsive disorder (OCD), chronic tic disorders, eating disorders, and conduct problems.

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Glutamatergic Agents in the Treatment of Compulsivity and Impulsivity in Child and Adolescent Psychiatry: a Systematic Review of the Literature

Zeitschrift für Kinder- und Jugendpsychiatrie und Psychotherapie ◽

10.1024/1422-4917/a000546 ◽

2018 ◽

Vol 46 (3) ◽

pp. 246-263 ◽

Cited By ~ 4

Author(s):

Konstantin Mechler ◽

Alexander Häge ◽

Nina Schweinfurth ◽

Jeffrey C. Glennon ◽

Rick M. Dijkhuizen ◽

...

Keyword(s):

Glutamate Release ◽

Treatment Strategies ◽

Autism Spectrum ◽

Child And Adolescent Psychiatry ◽

The European Union ◽

Obsessive Compulsive ◽

Compulsive Disorder ◽

Hyperactivity Disorder ◽

Spectrum Disorders ◽

Viable Treatment

Abstract. Objective: Research has implicated glutamatergic projections between the various frontal subregions in the pathogenesis of compulsivity and impulsivity. Reducing striatal glutamate release, or antagonising the action of glutamate at its receptors, may therefore represent viable treatment strategies. Several glutamatergic agents with regulatory approval for other indications are available and may be of potential benefit in the treatment of compulsivity/impulsivity in psychiatric disorders in paediatric patients. Method: This review was performed according to PRISMA guidelines and evaluates available scientific literature concerning the use of glutamatergic agents in these patients, in order to determine their reported effectiveness/efficacy and tolerability/safety. Results: Out of a total of 1,426 publications, 21 trials examining six glutamatergic substances in patients with obsessive-compulsive disorder, autism spectrum disorders, and attention deficit/hyperactivity disorder were included. Conclusions: Trial designs as well as results were heterogeneous and thus comparability was limited. Available data support the hypothesis that glutamatergic agents are of potential value in the treatment of compulsivity/impulsivity in children and adolescents. Based on the data reviewed, memantine and N-acetylcysteine suggest the best risk-benefit profile for future trials. Riluzole should primarily be further investigated in adults. Clinical research of this nature is a key element of the TACTICS Consortium project funded by the European Union (FP7).

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Subcortical brain volume, regional cortical thickness and cortical surface area across attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD)

10.1101/673012 ◽

2019 ◽

Cited By ~ 4

Author(s):

Premika S.W. Boedhoe ◽

Daan van Rooij ◽

Martine Hoogman ◽

Jos W.R. Twisk ◽

Lianne Schmaal ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Attention Deficit Hyperactivity Disorder ◽

Surface Area ◽

Cortical Thickness ◽

Attention Deficit ◽

Age Groups ◽

Autism Spectrum ◽

Obsessive Compulsive ◽

Compulsive Disorder ◽

Hyperactivity Disorder

ABSTRACTObjectiveAttention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) are common neurodevelopmental disorders that frequently co-occur. We aimed to directly compare all three disorders. The ENIGMA consortium is ideally positioned to investigate structural brain alterations across these disorders.MethodsStructural T1-weighted whole-brain MRI of controls (n=5,827) and patients with ADHD (n=2,271), ASD (n=1,777), and OCD (n=2,323) from 151 cohorts worldwide were analyzed using standardized processing protocols. We examined subcortical volume, cortical thickness and surface area differences within a mega-analytical framework, pooling measures extracted from each cohort. Analyses were performed separately for children, adolescents, and adults using linear mixed-effects models adjusting for age, sex and site (and ICV for subcortical and surface area measures).ResultsWe found no shared alterations among all three disorders, while shared alterations between any two disorders did not survive multiple comparisons correction. Children with ADHD compared to those with OCD had smaller hippocampal volumes, possibly influenced by IQ. Children and adolescents with ADHD also had smaller ICV than controls and those with OCD or ASD. Adults with ASD showed thicker frontal cortices compared to adult controls and other clinical groups. No OCD-specific alterations across different age-groups and surface area alterations among all disorders in childhood and adulthood were observed.ConclusionOur findings suggest robust but subtle alterations across different age-groups among ADHD, ASD, and OCD. ADHD-specific ICV and hippocampal alterations in children and adolescents, and ASD-specific cortical thickness alterations in the frontal cortex in adults support previous work emphasizing neurodevelopmental alterations in these disorders.

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Brain structural abnormalities in six major psychiatric disorders: shared variation and network perspectives

F1000Research ◽

10.12688/f1000research.51475.1 ◽

2021 ◽

Vol 10 ◽

pp. 356

Author(s):

Euclides José de Mendonça Filho ◽

Márcio Bonesso Alves ◽

Patricia Pelufo Silveira

Keyword(s):

Network Analysis ◽

Psychiatric Disorders ◽

Regional Distribution ◽

Principal Component ◽

Autism Spectrum ◽

Brain Abnormalities ◽

Obsessive Compulsive ◽

Compulsive Disorder ◽

Component Loading ◽

Shared Variation

Common brain abnormalities are a possible explanation for comorbidities in psychiatric disorders. Challenges in understanding these conditions are likely due to the paucity of studies able to analyze the extent and regional distribution of shared morphometric abnormalities between disorders. Recently, Opeal et al. presented an elegant rationale to investigate shared and specific morphometric measures of cortical thickness and subcortical gray matter volume between healthy individuals and subjects across six major psychiatric disorders. Although their approach has the potential to systematically portrait shared brain alterations, the chosen principal component analysis solution may not address the central question of the observed shared versus specific brain alterations due to misspecification of the number of components. Given how this misspecification can lead to different conclusions, we reanalyzed Opel et al. data to thoroughly determine the number of factors to be considered, explore the alternative solution, and visualize the patterns of shared brain matter correlations using network analysis. Our approach suggests that a unidimensional solution was appropriate in this situation. The unidimensional solution indicated that brain alterations in autism spectrum disorder (ASD) had a significant negative component loading, suggesting that brain abnormalities found in ASD carry more similarities with major depressive disorder (MDD), bipolar disorder (BD), schizophrenia (SCZ), and obsessive-compulsive disorder (OCD) than demonstrated by the original work. Network analysis indicated that SCZ had the highest strength, BD the highest closeness, and BD and MDD had the highest betweenness in the network. This work highlights how different component solutions can lead to different conclusions, with important implications for the understanding of overlapped patterns of symptoms among six major psychiatric diseases. The network approach is complementary in indicating central markers of specific psychopathology domains. Investigations using shared-variation and network perspectives are promising for the study of pathophysiological patterns of common brain alterations.

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