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Genetics of Psychiatric Disorders
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Genetics of Psychiatric Disorders

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 (31 August 2020) | Viewed by 36275

Special Issue Editors

Prof. Dr. Bryan Mowry

E-Mail Website
Guest Editor
1. Queensland Brain Institute, University of Queensland, Brisbane, QLD 4072, Australia
2. Queensland Centre for Mental Health Research, The Park-Centre for Mental Health, Wacol, QLD 4076, Australia
Interests: molecular genetics of schizophrenia and other psychiatric disorders; statistical genetics; functional genomics; gene expression
Prof. Dr. Lan Xiong

E-Mail Website
Guest Editor
Department of Neurology and Neurosurgery, Montreal Neurological Institute - Hospital, McGill University, Montréal, QC H3A 2B4, Canada
Interests: human genetics; neurogenomics; neurodevelopmental disorders; molecular genetics; complex traits
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Psychiatric disorders are the most puzzling illnesses in medicine and are associated with considerable morbidity and increased rates of mortality worldwide due to suicide and ill health (e.g., 10- to 15-year reduction in life expectancy for schizophrenia) and cost (due to health care, disability, and lost income). The human impact of a severe mental illness on the lives of the people afflicted and their families and communities is profound.

Despite highly variable clinical features and manifestations, most psychiatric disorders have demonstrated high heritability from the twin and family studies, such as bipolar disorder, schizophrenia, and autism, which have shown 60% or higher heritability. However, earlier-stage molecular genetic studies of psychiatric disorders were unable to uncover the significant genetic contribution based on small number of families or case-control cohorts.

New technologies and accesses to large databases and biospecimens have fundamentally changed how researchers investigate the genetic roots of psychiatric disorders. There has been remarkable progress in the past decade in elucidating the genetic underpinnings of psychiatric disorders with numerous significant findings. The evidence is now overwhelming that psychiatric disorders have a polygenic basis—that many genetic loci, mostly with small effect sizes, contribute to the disease risk.

In this Special Issue, we would like to invite reviews, perspectives, and research papers that will highlight the most recent and significant advances, as well as indicate the new research frontiers in this field. Particularly, we would like to encourage genetic studies with different designs and approaches, with larger sample sizes or new meta-analyses or integrative multiomics analyses to elucidate the gene pathways or brain networks involved in psychiatric disorders. We would also like to encourage genetic studies from more diverse human populations, as well as highly relevant functional genomics and well-represented animal models.

Prof. Dr. Bryan Mowry
Prof. Lan Xiong
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • psychiatric disorders
  • bipolar disorder
  • schizophrenia
  • autism
  • twin and family studies
  • heritability
  • cohort studies
  • gene pathways
  • meta-analyses
  • multiomics analyses
  • brain networks
  • animal models
  • functional genomics

Published Papers (7 papers)

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Research

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18 pages, 1119 KiB  
Article
Genetic Risk of Autism Spectrum Disorder in a Pakistani Population
by Madiha Khalid, Hashim Raza, Terri M. Driessen, Paul J. Lee, Leon Tejwani, Abdul Sami, Muhammad Nawaz, Shahid Mehmood Baig, Janghoo Lim and Ghazala Kaukab Raja
Genes 2020, 11(10), 1206; https://doi.org/10.3390/genes11101206 - 15 Oct 2020
Cited by 12 | Viewed by 4260
Abstract
Autism spectrum disorder (ASD) is a group of complex multifactorial neurodevelopmental and neuropsychiatric disorders in children characterized by impairment of communication and social interaction. Several genes with associated single nucleotide polymorphisms (SNPs) have been identified for ASD in different genetic association studies, meta-analyses, [...] Read more.
Autism spectrum disorder (ASD) is a group of complex multifactorial neurodevelopmental and neuropsychiatric disorders in children characterized by impairment of communication and social interaction. Several genes with associated single nucleotide polymorphisms (SNPs) have been identified for ASD in different genetic association studies, meta-analyses, and genome-wide association studies (GWAS). However, associations between different SNPs and ASD vary from population to population. Four SNPs in genes CNTNAP2, EIF4E, ATP2B2, CACNA1C, and SNP rs4307059 (which is found between CDH9 and CDH10 genes) have been identified and reported as candidate risk factors for ASD. The aim of the present study was, for the first time, to assess the association of SNPs in these genes with ASD in the Pakistani population. PCR-based genotyping was performed using allele-specific primers in 93 ASD and 93 control Pakistani individuals. All genetic associations, genotype frequencies, and allele frequencies were computed as odds’ ratios (ORs) using logistic regression with a threshold of p ≤ 0.01 to determine statistical significance. We found that the homozygous genotypes of mutant T alleles of CNTNAP2 and ATP2B2 were significantly associated with Pakistani ASD patients in unadjusted ORs (p < 0.01), but their significance score was lost in the adjusted model. Other SNPs such as rs4307059, rs17850950 of EIF4E, and rs1006737 of CACNA1C were not statistically significant. Based on this, we conclude that SNPs are not associated with, or are not the main cause of, autism in the Pakistani population, indicating the involvement of additional players, which need to be investigated in future studies in a large population size. One of the limitations of present study is its small sample size. However, this study, being the first on Pakistani ASD patients, may lay the foundations for future studies in larger samples. Full article
(This article belongs to the Special Issue Genetics of Psychiatric Disorders)
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12 pages, 246 KiB  
Article
Next Generation Sequencing of 134 Children with Autism Spectrum Disorder and Regression
by Jiani Yin, Chun-An Chun, Nikolay N. Zavadenko, Natalia L. Pechatnikova, Oxana Yu. Naumova, Harsha V. Doddapaneni, Jianhong Hu, Donna M. Muzny, Christian P. Schaaf and Elena L. Grigorenko
Genes 2020, 11(8), 853; https://doi.org/10.3390/genes11080853 - 25 Jul 2020
Cited by 14 | Viewed by 5772
Abstract
Approximately 30% of individuals with autism spectrum disorder (ASD) experience developmental regression, the etiology of which remains largely unknown. We performed a complete literature search and identified 47 genes that had been implicated in such cases. We sequenced these genes in a preselected [...] Read more.
Approximately 30% of individuals with autism spectrum disorder (ASD) experience developmental regression, the etiology of which remains largely unknown. We performed a complete literature search and identified 47 genes that had been implicated in such cases. We sequenced these genes in a preselected cohort of 134 individuals with regressive autism. In total, 16 variants in 12 genes with evidence supportive of pathogenicity were identified. They were classified as variants of uncertain significance based on ACMG standards and guidelines. Among these were recurring variants in GRIN2A and PLXNB2, variants in genes that were linked to syndromic forms of ASD (GRIN2A, MECP2, CDKL5, SCN1A,PCDH19, UBE3A, and SLC9A6), and variants in the form of oligogenic heterozygosity (EHMT1, SLC9A6, and MFSD8). Full article
(This article belongs to the Special Issue Genetics of Psychiatric Disorders)
17 pages, 2077 KiB  
Article
A Novel Cosegregating DCTN1 Splice Site Variant in a Family with Bipolar Disorder May Hold the Key to Understanding the Etiology
by André Hallen and Arthur J. L. Cooper
Genes 2020, 11(4), 446; https://doi.org/10.3390/genes11040446 - 18 Apr 2020
Cited by 1 | Viewed by 10129
Abstract
A novel cosegregating splice site variant in the Dynactin-1 (DCTN1) gene was discovered by Next Generation Sequencing (NGS) in a family with a history of bipolar disorder (BD) and major depressive diagnosis (MDD). Psychiatric illness in this family follows an autosomal [...] Read more.
A novel cosegregating splice site variant in the Dynactin-1 (DCTN1) gene was discovered by Next Generation Sequencing (NGS) in a family with a history of bipolar disorder (BD) and major depressive diagnosis (MDD). Psychiatric illness in this family follows an autosomal dominant pattern. DCTN1 codes for the largest dynactin subunit, namely p150Glued, which plays an essential role in retrograde axonal transport and in neuronal autophagy. A GT→TT transversion in the DCTN1 gene, uncovered in the present work, is predicted to disrupt the invariant canonical splice donor site IVS22 + 1G > T and result in intron retention and a premature termination codon (PTC). Thus, this splice site variant is predicted to trigger RNA nonsense-mediated decay (NMD) and/or result in a C-terminal truncated p150Glued protein (ct-p150Glued), thereby negatively impacting retrograde axonal transport and neuronal autophagy. BD prophylactic medications, and most antipsychotics and antidepressants, are known to enhance neuronal autophagy. This variant is analogous to the dominant-negative GLUED Gl1 mutation in Drosophila, which is responsible for a neurodegenerative phenotype. The newly identified variant may reflect an autosomal dominant cause of psychiatric pathology in this affected family. Factors that affect alternative splicing of the DCTN1 gene, leading to NMD and/or ct-p150Glued, may be of fundamental importance in contributing to our understanding of the etiology of BD as well as MDD. Full article
(This article belongs to the Special Issue Genetics of Psychiatric Disorders)
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16 pages, 2958 KiB  
Article
Meta-Analysis of Transcriptomic Data of Dorsolateral Prefrontal Cortex and of Peripheral Blood Mononuclear Cells Identifies Altered Pathways in Schizophrenia
by Maria Cristina Petralia, Rosella Ciurleo, Andrea Saraceno, Manuela Pennisi, Maria Sofia Basile, Paolo Fagone, Placido Bramanti, Ferdinando Nicoletti and Eugenio Cavalli
Genes 2020, 11(4), 390; https://doi.org/10.3390/genes11040390 - 3 Apr 2020
Cited by 14 | Viewed by 3120
Abstract
Schizophrenia (SCZ) is a psychiatric disorder characterized by both positive and negative symptoms, including cognitive dysfunction, decline in motivation, delusion and hallucinations. Antipsychotic agents are currently the standard of care treatment for SCZ. However, only about one-third of SCZ patients respond to antipsychotic [...] Read more.
Schizophrenia (SCZ) is a psychiatric disorder characterized by both positive and negative symptoms, including cognitive dysfunction, decline in motivation, delusion and hallucinations. Antipsychotic agents are currently the standard of care treatment for SCZ. However, only about one-third of SCZ patients respond to antipsychotic medications. In the current study, we have performed a meta-analysis of publicly available whole-genome expression datasets on Brodmann area 46 of the brain dorsolateral prefrontal cortex in order to prioritize potential pathways underlying SCZ pathology. Moreover, we have evaluated whether the differentially expressed genes in SCZ belong to specific subsets of cell types. Finally, a cross-tissue comparison at both the gene and functional level was performed by analyzing the transcriptomic pattern of peripheral blood mononuclear cells of SCZ patients. Our study identified a robust disease-specific set of dysfunctional biological pathways characterizing SCZ patients that could in the future be exploited as potential therapeutic targets. Full article
(This article belongs to the Special Issue Genetics of Psychiatric Disorders)
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14 pages, 819 KiB  
Article
Differential Dorsolateral Prefrontal Cortex Proteomic Profiles of Suicide Victims with Mood Disorders
by Alejandra Cabello-Arreola, Ada Man-Choi Ho, Aysegul Ozerdem, Alfredo B. Cuellar-Barboza, Mehmet U. Kucuker, Carrie J. Heppelmann, M. Cristine Charlesworth, Deniz Ceylan, Craig A. Stockmeier, Grazyna Rajkowska, Mark A. Frye, Doo-Sup Choi and Marin Veldic
Genes 2020, 11(3), 256; https://doi.org/10.3390/genes11030256 - 27 Feb 2020
Cited by 9 | Viewed by 3216
Abstract
Suicide is a major public health concern; nevertheless, its neurobiology remains unknown. An area of interest in suicide research is the dorsolateral prefrontal cortex (DLPFC). We aimed to identify altered proteins and potential biological pathways in the DLPFC of individuals who died by [...] Read more.
Suicide is a major public health concern; nevertheless, its neurobiology remains unknown. An area of interest in suicide research is the dorsolateral prefrontal cortex (DLPFC). We aimed to identify altered proteins and potential biological pathways in the DLPFC of individuals who died by suicide employing mass spectrometry-based untargeted proteomics. Postmortem DLPFC from age-matched male suicide mood disorder cases (n = 5) and non-suicide mood disorder cases (n = 5) were compared. The proteins that differed between groups at false discovery rate (FDR) adjusted p-values (Benjamini–Hochberg–Yekutieli) <0.3 and Log2 fold change (FC) >|0.4| were considered statistically significant and were subjected to pathway analysis by Qiagen Ingenuity software. Thirty-three of the 5162 detected proteins showed significantly altered expression levels in the suicide cases and two of them after adjustment for body mass index. The top differentially expressed protein was potassium voltage-gated channel subfamily Q member 3 (KCNQ3) (Log2FC = −0.481, p = 2.10 × 10−09, FDR = 5.93 × 10−06), which also showed a trend to downregulation in Western blot (p = 0.045, Bonferroni adjusted p = 0.090). The most notably enriched pathway was the GABA receptor signaling pathway (p < 0.001). Here, we report a reduction trend of KCNQ3 levels in the DLPFC of male suicide victims with mood disorders. Further studies with a larger sample size and equal sex representation are needed. Full article
(This article belongs to the Special Issue Genetics of Psychiatric Disorders)
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14 pages, 1688 KiB  
Article
Coding and Non-Coding RNA Abnormalities in Bipolar Disorder
by Jurjen J. Luykx, Fabrizio Giuliani, Giuliano Giuliani and Jan Veldink
Genes 2019, 10(11), 946; https://doi.org/10.3390/genes10110946 - 19 Nov 2019
Cited by 22 | Viewed by 3502
Abstract
The molecular mechanisms underlying bipolar disorder (BPD) have remained largely unknown. Postmortem brain tissue studies comparing BPD patients with healthy controls have produced a heterogeneous array of potentially implicated protein-coding RNAs. We hypothesized that dysregulation of not only coding, but multiple classes of [...] Read more.
The molecular mechanisms underlying bipolar disorder (BPD) have remained largely unknown. Postmortem brain tissue studies comparing BPD patients with healthy controls have produced a heterogeneous array of potentially implicated protein-coding RNAs. We hypothesized that dysregulation of not only coding, but multiple classes of RNA (coding RNA, long non-coding (lnc) RNA, circular (circ) RNA, and/or alternative splicing) underlie the pathogenesis of BPD. Using non-polyadenylated libraries we performed RNA sequencing in postmortem human medial frontal gyrus tissue from BPD patients and healthy controls. Twenty genes, some of which not previously implicated in BPD, were differentially expressed (DE). PCR validation and replication confirmed the implication of these DE genes. Functional in silico analyses identified enrichment of angiogenesis, vascular system development and histone H3-K4 demethylation. In addition, ten lncRNA transcripts were differentially expressed. Furthermore, an overall increased number of alternative splicing events in BPD was detected, as well as an increase in the number of genes carrying alternative splicing events. Finally, a large reservoir of circRNAs populating brain tissue not affected by BPD is described, while in BPD altered levels of two circular transcripts, cNEBL and cEPHA3, are reported. cEPHA3, hitherto unlinked to BPD, is implicated in developmental processes in the central nervous system. Although we did not perform replication analyses of non-coding RNA findings, our findings hint that RNA dysregulation in BPD is not limited to coding regions, opening avenues for future pharmacological investigations and biomarker research. Full article
(This article belongs to the Special Issue Genetics of Psychiatric Disorders)
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Review

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21 pages, 1239 KiB  
Review
5HTTLPR Genetic Variant and Major Depressive Disorder: A Review
by Caroline Fratelli, Jhon Siqueira, Calliandra Silva, Eduardo Ferreira and Izabel Silva
Genes 2020, 11(11), 1260; https://doi.org/10.3390/genes11111260 - 26 Oct 2020
Cited by 16 | Viewed by 5506
Abstract
Major Depressive Disorder (MDD) is a disease that involves biological, psychological, and social interactions. Studies have shown the importance of genetics contribution to MDD development. The SCL6A4 protein (5HTTLPR) functions transporting serotonin, a neurotransmitter linked to mood and emotion, to the synaptic cleft. [...] Read more.
Major Depressive Disorder (MDD) is a disease that involves biological, psychological, and social interactions. Studies have shown the importance of genetics contribution to MDD development. The SCL6A4 protein (5HTTLPR) functions transporting serotonin, a neurotransmitter linked to mood and emotion, to the synaptic cleft. Hence, this study seeks, through a literature review, a better comprehension of the 5HTTLPR genetic variant association with MDD. For this purpose, a search was performed on the Virtual Health Library Portal for articles that related 5HTTLPR to MDD. Most of the articles found were conducted in the American continent, with one (1) study implemented in Brazil. 5HTTLPR associations were found regarding changes in the nervous system, pharmacology, and risk factors seen in MDD patients. When verifying the allelic distribution, the S allele had a higher frequency in most of the studies analyzed. Despite not finding a commonality in the different studies, the tremendous genetic variation found demonstrates the MDD complexity. For this reason, further studies in diverse populations should be conducted to assist in the understanding and treatment of the disease. Full article
(This article belongs to the Special Issue Genetics of Psychiatric Disorders)
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