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Genomics of Neuropsychiatric Disorders

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A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (15 August 2022) | Viewed by 35832

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Dr. Derek Morris

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Guest Editor

Discipline of Biochemistry, National University of Ireland Galway, Galway, Ireland
Interests: neuropsychiatry; schizophrenia; cognition; genes; GWAS; next-generation sequencing

Special Issue Information

Common neuropsychiatric disorders such as schizophrenia, bipolar disorder, and autism spectrum disorder (ASD) have high heritabilities >0.8, indicating a strong genetic component to their etiology. Mortality is increased for these disorders but their biggest impact on societies and economies is due to the often chronic illness and significant disability that they cause. They have some commons symptoms; psychosis in schizophrenia and bipolar disorder, cognitive impairment in schizophrenia and ASD, indicating some shared biology despite different developmental trajectories. The systematic application of genome-wide association studies (GWAS) and next-generation sequencing (NGS) technologies to large population-based and family-based sample collections, coordinated by collaborative research consortia, has resulted in hundreds of new genetic findings for these disorders. This is uncovering the role of common and rare genetic variants in the etiology of these disorders and shining a light on their molecular mechanisms down to the individual types of cells that are affected in the brain. This Special Issue will bring together a set of reviews and research articles that explore how the application of genomics data science to genetic and phenotypic data from studies of neuropsychiatric disorders is providing novel insights into the biology of these illnesses.

Dr. Derek Morris
Guest Editor

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Keywords

Schizophrenia
Bipolar disorder
Autism spectrum disorder
Cognition
Neuroimaging
Genome-wide association studies
Exome sequencing
De novo mutations
Transcriptomics
Epigenomics
Single-cell analysis

Published Papers (10 papers)

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Research

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15 pages, 316 KiB

Open AccessArticle

Interactions between Environmental Factors and Glutathione S-Transferase (GST) Genes with Respect to Detectable Blood Aluminum Concentrations in Jamaican Children

by Mohammad H. Rahbar, Maureen Samms-Vaughan, Yuansong Zhao, Sepideh Saroukhani, Jan Bressler, Manouchehr Hessabi, Megan L. Grove, Sydonnie Shakespeare-Pellington and Katherine A. Loveland

Genes 2022, 13(10), 1907; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13101907 - 20 Oct 2022

Viewed by 1223

Abstract

Aluminum (Al) is a metallic toxicant at high concentrations following natural or unnatural exposures. Dietary intake is considered as the main source of aluminum exposure in children. We used data from 366 typically developing (TD) children (ages 2–8 years) who participated as controls in an age- and sex-matched case–control study in Jamaica. We investigated additive and interactive associations among environmental factors and children’s genotypes for glutathione S-transferase (GST) genes (GSTT1, GSTM1, GSTP1), in relation to having a detectable blood aluminum concentration (BAlC) of >5.0 μg/L, using multivariable logistic regression models. Findings from interactive models revealed that the odds of having a detectable BAlC was significantly higher among children who ate string beans (p ≤ 0.01), whereas about 40% lower odds of having a detectable BAlC was observed in children with higher parental education level, (p = 0.02). A significant interaction between consumption of saltwater fish and GSTP1 in relation to having a detectable BAlC using either co-dominant or dominant genetic models (overall interaction p = 0.02 for both models) indicated that consumption of saltwater fish was associated with higher odds of having a detectable BAlC only among children with the GSTP1 Ile105Val Ile/Ile genotype using either co-dominant or dominant models [OR (95% CI) = 2.73 (1.07, 6.96), p = 0.04; and OR (95% CI) = 2.74 (1.08, 6.99), p = 0.03]. Since this is the first study from Jamaica that reports such findings, replication in other populations is warranted. Full article

(This article belongs to the Special Issue Genomics of Neuropsychiatric Disorders)

26 pages, 4875 KiB

Open AccessArticle

In Vitro Analysis of Biological Activity of Circulating Cell-Free DNA Isolated from Blood Plasma of Schizophrenic Patients and Healthy Controls

by Elizaveta S. Ershova, Galina V. Shmarina, Lev N. Porokhovnik, Natalia V. Zakharova, George P. Kostyuk, Pavel E. Umriukhin, Sergey I. Kutsev, Vasilina A. Sergeeva, Natalia N. Veiko and Svetlana V. Kostyuk

Genes 2022, 13(3), 551; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13030551 - 20 Mar 2022

Cited by 8 | Viewed by 3075

Abstract

Schizophrenia is associated with low-grade systemic inflammation. Circulating cell-free DNA (c-cfDNA) belongs to the DAMP class. The major research question was: can the c-cfDNA of schizophrenic patients (sz-cfDNA) stimulate the DNA sensor genes, which control the innate immunity? We investigated the in vitro response of ten human skin fibroblast (HSF) lines to five DNA probes containing different amounts of a GC-rich marker (the ribosomal repeat) and a DNA oxidation marker (8-oxodG) including sz-cfDNA and healthy control c-cfDNA (hc-cfDNA) probes. After 1 h, 3 h, and 24 h of incubation, the expression of 6 protein genes responsible for cfDNA transport into the cell (EEA1 and HMGB1) and the recognition of cytosolic DNA (TLR9, AIM2, STING and RIG-I) was analyzed at the transcriptional (RT-qPCR) and protein level (flow cytometry and fluorescence microscopy). Additionally, we analyzed changes in the RNA amount of 32 genes (RT-qPCR), which had been previously associated with different cellular responses to cell-free DNA with different characteristics. Adding sz-cfDNA and hc-cfDNA to the HSF medium in equal amounts (50 ng/mL) blocked endocytosis and stimulated TLR9 and STING gene expression while blocking RIG-I and AIM2 expression. Sz-cfDNA and hc-cfDNA, compared to gDNA, demonstrated much stronger stimulated transcription of genes that control cell proliferation, cytokine synthesis, apoptosis, autophagy, and mitochondrial biogenesis. No significant difference was observed in the response of the cells to sz-cfDNA and hc-cfDNA. Sz-cfDNA and hc-cfDNA showed similarly high biological activity towards HSFs, stimulating the gene activity of TLR9 and STING DNA sensor proteins and blocking the activity of the AIM2 protein gene. Since the sz-cfDNA content in the patients’ blood is several times higher than the hc-cfDNA content, sz-cfDNA may upregulate pro-inflammatory cytokines in schizophrenia. Full article

(This article belongs to the Special Issue Genomics of Neuropsychiatric Disorders)

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15 pages, 621 KiB

Open AccessArticle

Major Depressive Disorder and Lifestyle: Correlated Genetic Effects in Extended Twin Pedigrees

by Floris Huider, Yuri Milaneschi, Matthijs D. van der Zee, Eco J. C. de Geus, Quinta Helmer, Brenda W. J. H. Penninx and Dorret I. Boomsma

Genes 2021, 12(10), 1509; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12101509 - 26 Sep 2021

Cited by 11 | Viewed by 3232

Abstract

In recent years, evidence has accumulated with regard to the ubiquity of pleiotropy across the genome, and shared genetic etiology is thought to play a large role in the widespread comorbidity among psychiatric disorders and risk factors. Recent methods investigate pleiotropy by estimating genetic correlation from genome-wide association summary statistics. More comprehensive estimates can be derived from the known relatedness between genetic relatives. Analysis of extended twin pedigree data allows for the estimation of genetic correlation for additive and non-additive genetic effects, as well as a shared household effect. Here we conduct a series of bivariate genetic analyses in extended twin pedigree data on lifetime major depressive disorder (MDD) and three indicators of lifestyle, namely smoking behavior, physical inactivity, and obesity, decomposing phenotypic variance and covariance into genetic and environmental components. We analyze lifetime MDD and lifestyle data in a large multigenerational dataset of 19,496 individuals by variance component analysis in the ‘Mendel’ software. We find genetic correlations for MDD and smoking behavior (r_G = 0.249), physical inactivity (r_G = 0.161), body-mass index (r_G = 0.081), and obesity (r_G = 0.155), which were primarily driven by additive genetic effects. These outcomes provide evidence in favor of a shared genetic etiology between MDD and the lifestyle factors. Full article

(This article belongs to the Special Issue Genomics of Neuropsychiatric Disorders)

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15 pages, 884 KiB

Open AccessArticle

Meta-Analysis of Brain Gene Expression Data from Mouse Model Studies of Maternal Immune Activation Using Poly(I:C)

by Aodán Laighneach, Lieve Desbonnet, John P. Kelly, Gary Donohoe and Derek W. Morris

Genes 2021, 12(9), 1363; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12091363 - 30 Aug 2021

Cited by 4 | Viewed by 3024

Abstract

Maternal immune activation (MIA) is a known risk factor for schizophrenia (SCZ) and autism spectrum disorder (ASD) and is often modelled in animal studies in order to study the effect of prenatal infection on brain function including behaviour and gene expression. Although the effect of MIA on gene expression are highly heterogeneous, combining data from multiple gene expression studies in a robust method may shed light on the true underlying biological effects caused by MIA and this could inform studies of SCZ and ASD. This study combined four RNA-seq and microarray datasets in an overlap analysis and ranked meta-analysis in order to investigate genes, pathways and cell types dysregulated in the MIA mouse models. Genes linked to SCZ and ASD and crucial in neurodevelopmental processes including neural tube folding, regulation of cellular stress and neuronal/glial cell differentiation were among the most consistently dysregulated in these ranked analyses. Gene ontologies including K+ ion channel function, neuron and glial cell differentiation, synaptic structure, axonal outgrowth, cilia function and lipid metabolism were also strongly implicated. Single-cell analysis identified excitatory and inhibitory cell types in the cortex, hippocampus and striatum that may be affected by MIA and are also enriched for genes associated with SCZ, ASD and cognitive phenotypes. This points to the cellular location of molecular mechanisms that may be consistent between the MIA model and neurodevelopmental disease, improving our understanding of its utility to study prenatal infection as an environmental stressor. Full article

(This article belongs to the Special Issue Genomics of Neuropsychiatric Disorders)

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10 pages, 529 KiB

Open AccessEditor’s ChoiceArticle

Sensory Reactivity Phenotype in Phelan–McDermid Syndrome Is Distinct from Idiopathic ASD

by Teresa Tavassoli, Christina Layton, Tess Levy, Mikaela Rowe, Julia George-Jones, Jessica Zweifach, Stacey Lurie, Joseph D. Buxbaum, Alexander Kolevzon and Paige M. Siper

Genes 2021, 12(7), 977; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12070977 - 26 Jun 2021

Cited by 14 | Viewed by 2690

Abstract

Phelan–McDermid syndrome (PMS) is one of the most common genetic forms of autism spectrum disorder (ASD). While sensory reactivity symptoms are widely reported in idiopathic ASD (iASD), few studies have examined sensory symptoms in PMS. The current study delineates the sensory reactivity phenotype and examines genotype–phenotype interactions in a large sample of children with PMS. Sensory reactivity was measured in a group of 52 children with PMS, 132 children with iASD, and 54 typically developing (TD) children using the Sensory Assessment for Neurodevelopmental Disorders (SAND). The SAND is a clinician-administered observation and corresponding caregiver interview that captures sensory symptoms based on the DSM-5 criteria for ASD. Children with PMS demonstrated significantly greater hyporeactivity symptoms and fewer hyperreactivity and seeking symptoms compared to children with iASD and TD controls. There were no differences between those with Class I deletions or sequence variants and those with larger Class II deletions, suggesting that haploinsufficiency of SHANK3 is the main driver of the sensory phenotype seen in PMS. The syndrome-specific sensory phenotype identified in this study is distinct from other monogenic forms of ASD and offers insight into the potential role of SHANK3 deficiency in sensory reactivity. Understanding sensory reactivity abnormalities in PMS, in the context of known glutamatergic dysregulation, may inform future clinical trials in the syndrome. Full article

(This article belongs to the Special Issue Genomics of Neuropsychiatric Disorders)

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12 pages, 1981 KiB

Open AccessArticle

Family-Based Genome-Wide Association Study of Autism Spectrum Disorder in Middle Eastern Families

by Yasser Al-Sarraj, Eman Al-Dous, Rowaida Z. Taha, Dina Ahram, Fouad Alshaban, Mohammed Tolfat, Hatem El-Shanti and Omar M.E. Albagha

Genes 2021, 12(5), 761; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12050761 - 18 May 2021

Cited by 6 | Viewed by 3170

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disease characterized by abnormalities in language and social communication with substantial clinical heterogeneity. Genetic factors play an important role in ASD with heritability estimated between 70% to 80%. Genome-wide association studies (GWAS) have identified multiple loci associated with ASD. However, most studies were performed on European populations and little is known about the genetic architecture of ASD in Middle Eastern populations. Here, we report the first GWAS of ASD in the Middle eastern population of Qatar. We analyzed 171 families with ASD, using linear mixed models adjusting for relatedness and other confounders. Results showed that common single nucleotide polymorphisms (SNP) in seven loci are associated with ASD (p < 1 × 10⁻⁵). Although the identified loci did not reach genome-wide significance, many of the top associated SNPs are located within or near genes that have been implicated in ASD or related neurodevelopmental disorders. These include GORASP2, GABBR2, ANKS6, THSD4, ERCC6L, ARHGEF6, and HDAC8. Additionally, three of the top associated SNPs were significantly associated with gene expression. We also found evidence of association signals in two previously reported ASD-susceptibility loci (rs10099100 and rs4299400). Our results warrant further functional studies and replication to provide further insights into the genetic architecture of ASD. Full article

(This article belongs to the Special Issue Genomics of Neuropsychiatric Disorders)

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16 pages, 2092 KiB

Open AccessArticle

Dissection of the Genetic Association between Anorexia Nervosa and Obsessive–Compulsive Disorder at the Network and Cellular Levels

by Weichen Song, Weidi Wang, Shunying Yu and Guan Ning Lin

Genes 2021, 12(4), 491; https://doi.org/10.3390/genes12040491 - 27 Mar 2021

Cited by 4 | Viewed by 3105

Abstract

Anorexia nervosa (AN) and obsessive–compulsive disorder (OCD) exhibit a high co-morbidity rate, similar symptoms, and a shared genetic basis. However, an understanding of the specific underlying mechanisms of these commonalities is currently limited. Here, we collected Genome-Wide Association Analysis results for AN and OCD, and obtained genes hit by the top SNPs as the risk genes. We then carried out an integrative coexpression network analysis to explore the convergence and divergence of AN and OCD risk genes. At first, we observed that the AN risk genes were enriched in coexpression modules that involved extracellular matrix functions and highly are expressed in the postnatal brain, limbic system, and non-neuronal cell types, while the OCD risk genes were enriched in modules of synapse function, the prenatal brain, cortex layers, and neurons. Next, by comparing the expressions from the eating disorder and OCD postmortem patient brain tissues, we observed both disorders have similar prefrontal cortex expression alterations influencing the synapse transmission, suggesting that the two diseases could have similar functional pathways. We found that the AN and OCD risk genes had distinct functional and spatiotemporal enrichment patterns but carried similar expression alterations as a disease mechanism, which may be one of the key reasons they had similar but not identical clinical phenotypes. Full article

(This article belongs to the Special Issue Genomics of Neuropsychiatric Disorders)

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11 pages, 1088 KiB

Open AccessArticle

Sensory Reactivity Symptoms Are a Core Feature of ADNP Syndrome Irrespective of Autism Diagnosis

by Paige M. Siper, Christina Layton, Tess Levy, Stacey Lurie, Nurit Benrey, Jessica Zweifach, Mikaela Rowe, Lara Tang, Sylvia Guillory, Danielle Halpern, Ivy Giserman-Kiss, Maria Del Pilar Trelles, Jennifer H. Foss-Feig, Silvia De Rubeis, Teresa Tavassoli, Joseph D. Buxbaum and Alexander Kolevzon

Genes 2021, 12(3), 351; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12030351 - 27 Feb 2021

Cited by 13 | Viewed by 5179

Abstract

Background: Activity dependent neuroprotective protein (ADNP) syndrome is one of the most common single-gene causes of autism spectrum disorder (ASD) and intellectual disability, however, the phenotypes remain poorly described. Here we examine the sensory reactivity phenotype in children and adolescents with ADNP syndrome. Methods: Twenty-two individuals with ADNP syndrome received comprehensive clinical evaluations including standardized observations, caregiver interviews, and questionnaires to assess sensory reactivity symptoms. Relationships between sensory symptoms and age, sex, ASD, IQ, and adaptive behavior were examined. Genotype-phenotype correlations with the recurrent p.Tyr719* variant were also explored. Results: Sensory reactivity symptoms were observed and reported in all participants. A syndrome-specific phenotype was identified, characterized by high levels of sensory seeking across tactile, auditory, and visual domains. Tactile hyporeactivity, characterized by pain insensitivity, was reported in the majority of participants. Sensory symptoms were identified across individuals regardless of age, sex, IQ, adaptive ability, genetic variant, and most importantly, ASD status. No significant differences were identified between participants with and without the recurrent p.Tyr719* variant on any sensory measure. Conclusions: Sensory reactivity symptoms are a common clinical feature of ADNP syndrome. Quantifying sensory reactivity using existing standardized measures will enhance understanding of sensory reactivity in individuals with ADNP syndrome and will aid in clinical care. The sensory domain may also represent a promising target for treatment in clinical trials. Full article

(This article belongs to the Special Issue Genomics of Neuropsychiatric Disorders)

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Review

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10 pages, 1061 KiB

Open AccessReview

Autism and ADHD in the Era of Big Data; An Overview of Digital Resources for Patient, Genetic and Clinical Trials Information

by Faris M. Abomelha, Hesham AlDhalaan, Mohammad Ghaziuddin, Nada A. Al-Tassan and Bashayer R. Al-Mubarak

Genes 2022, 13(9), 1551; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13091551 - 28 Aug 2022

Viewed by 2584

Abstract

Even in the era of information “prosperity” in the form of databases and registries that compile a wealth of data, information about ASD and ADHD remains scattered and disconnected. These data systems are powerful tools that can inform decision-making and policy creation, as well as advancing and disseminating knowledge. Here, we review three types of data systems (patient registries, clinical trial registries and genetic databases) that are concerned with ASD or ADHD and discuss their features, advantages and limitations. We noticed the lack of ethnic diversity in the data, as the majority of their content is curated from European and (to a lesser extent) Asian populations. Acutely aware of this knowledge gap, we introduce here the framework of the Neurodevelopmental Disorders Database (NDDB). This registry was designed to serve as a model for the national repository for collecting data from Saudi Arabia on neurodevelopmental disorders, particularly ASD and ADHD, across diverse domains. Full article

(This article belongs to the Special Issue Genomics of Neuropsychiatric Disorders)

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19 pages, 604 KiB

Open AccessReview

Major Depressive Disorder: Existing Hypotheses about Pathophysiological Mechanisms and New Genetic Findings

by Muhammad Kamran, Farhana Bibi, Asim. ur. Rehman and Derek W. Morris

Genes 2022, 13(4), 646; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13040646 - 06 Apr 2022

Cited by 15 | Viewed by 7269

Abstract

Major depressive disorder (MDD) is a common mental disorder generally characterized by symptoms associated with mood, pleasure and effectiveness in daily life activities. MDD is ranked as a major contributor to worldwide disability. The complex pathogenesis of MDD is not yet understood, and this is a major cause of failure to develop new therapies and MDD recurrence. Here we summarize the literature on existing hypotheses about the pathophysiological mechanisms of MDD. We describe the different approaches undertaken to understand the molecular mechanism of MDD using genetic data. Hundreds of loci have now been identified by large genome-wide association studies (GWAS). We describe these studies and how they have provided information on the biological processes, cell types, tissues and druggable targets that are enriched for MDD risk genes. We detail our understanding of the genetic correlations and causal relationships between MDD and many psychiatric and non-psychiatric disorders and traits. We highlight the challenges associated with genetic studies, including the complexity of MDD genetics in diverse populations and the need for a study of rare variants and new studies of gene-environment interactions. Full article

(This article belongs to the Special Issue Genomics of Neuropsychiatric Disorders)

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