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Genetics of Neuropsychiatric Disorders
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Genetics of Neuropsychiatric Disorders

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

Deadline for manuscript submissions: closed (25 October 2025) | Viewed by 6195

Special Issue Editors

Dr. Melloni Cook

E-Mail Website
Guest Editor
Department of Psychology, University of Memphis, Memphis, TN 38152, USA
Interests: genetics of complex traits; behavioral genetics; anxiety; stress; learning and memory; stress/ethanol interactions
Dr. Kristin Hamre

E-Mail Website
Guest Editor
Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA
Interests: genetics of substance abuse particularly following developmental exposure; genetics of behavioral traits; interaction of sex and genetics

Special Issue Information

Dear Colleagues,

Neuropsychiatric disorders are pervasive and can be debilitating. Further, individuals with these disorders often have delayed diagnoses or present comorbid disorders. Treatment options remain limited, are often associated with undesirable side effects, and have significant nonresponse rates. As many of these disorders involve a genetic component, identifying and characterizing genetic influences on these disorders may help in discovering biomarkers for early/better detection, characterizing causal variants, pinpointing novel pathways as targets for the development of therapeutics, and determining whether comorbid disorders have common underlying mechanisms. Thanks to conceptual, technical, and bioinformatic advances, we are better positioned to understand these complex disorders.

In the Special Issue of Genes, we will highlight recent discoveries in the genetics of neuropsychiatric disorders, including major depressive disorder, schizophrenia, post-traumatic stress disorder, anxiety disorders, addiction, stress-related disorders, and their related phenotypes. We welcome review and original articles in the following areas: behavioral neuroscience, gene expression analyses, epigenetics, optogenetics, and miRNA expression, among others. Works employing animal models, clinical populations, or human tissues are welcome.

Dr. Melloni Cook
Dr. Kristin Hamre
Guest Editors

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Keywords

  • major depressive disorder
  • schizophrenia
  • post-traumatic stress disorder
  • addiction
  • alcohol
  • drugs
  • anxiety disorder
  • stress-related disorders
  • genes
  • epigenetics
  • mRNA
  • optogenetics
  • miRNA
  • causal variant

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Published Papers (6 papers)

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20 pages, 9291 KB  
Article
Atad1 Is a Potential Candidate Gene for Prepulse Inhibition
by Akhilesh K. Bajpai, Timothy G. Freels, Lu Lu and Melloni N. Cook
Genes 2025, 16(10), 1139; https://doi.org/10.3390/genes16101139 - 26 Sep 2025
Viewed by 407
Abstract
Background/Objectives: Prepulse inhibition (PPI) is a robust, reproducible phenotype associated with schizophrenia and other psychiatric disorders. This study was carried out to identify gene(s) influencing PPI. Methods: We performed Quantitative Trait Locus (QTL) analysis of PPI in 59 strains from [...] Read more.
Background/Objectives: Prepulse inhibition (PPI) is a robust, reproducible phenotype associated with schizophrenia and other psychiatric disorders. This study was carried out to identify gene(s) influencing PPI. Methods: We performed Quantitative Trait Locus (QTL) analysis of PPI in 59 strains from the BXD recombinant inbred (BXD RI) mouse family and used a 2-LOD region for candidate gene identification. Genes significantly correlated with the candidate gene were identified based on genetic, partial, and literature correlation, and were further studied through gene enrichment and protein–protein interaction analyses. Phenome-wide association study (PheWAS) and differential expression analyses of the candidate gene were performed using human data. Results: We identified one significant (GN Trait 11428) and two suggestive male-specific QTLs (GN Traits 11426 and 11427) on Chromosome 19 between 27 and 36 Mb with peak LRS values of 19.2 (−logP = 4.2), 14.4 (−logP = 3.1), and 13.3 (−logP = 2.9), respectively. Atad1, ATPase family, AAA domain containing 1 was identified as the strongest candidate for the male-specific PPI loci. Atad1 expression in BXDs is strongly cis-modulated in the nucleus accumbens (NAc, LRS = 26.5 (−logP = 5.7). Many of the Atad1-correlated genes in the NAc were enriched in neurotransmission-related categories. Protein–protein interaction analysis suggested that ATAD1 functions through its direct partners, GRIA2 and ASNA1. PheWAS revealed significant associations between Atad1 and psychiatric traits, including schizophrenia. Analysis of a human RNA-seq dataset revealed differential expression of Atad1 between schizophrenia patients and the control group. Conclusions: Collectively, our analyses support Atad1 as a potential candidate gene for PPI and suggest that this gene should be further investigated for its involvement in psychiatric disorders. Full article
(This article belongs to the Special Issue Genetics of Neuropsychiatric Disorders)
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14 pages, 291 KB  
Article
Association Study of the Heat Shock Protein 90 Alpha (HSP90AA1) Gene Polymorphisms with Schizophrenia in a Polish Population
by Malgorzata Kowalczyk, Aleksander J. Owczarek, Krzysztof Kucia, Maja Hasterok, Renata Suchanek-Raif, Monika Paul-Samojedny, Weronika Lakomy and Jan Kowalski
Genes 2025, 16(9), 1092; https://doi.org/10.3390/genes16091092 - 16 Sep 2025
Viewed by 600
Abstract
Background/Objectives: Schizophrenia (SCZ) is a highly heritable mental disorder with a complex polygenic genetic architecture. The heat shock protein 90 alpha (HSP90α), encoded by the HSP90AA1 gene, is a molecular chaperone that is required for the proper folding and activity of many of [...] Read more.
Background/Objectives: Schizophrenia (SCZ) is a highly heritable mental disorder with a complex polygenic genetic architecture. The heat shock protein 90 alpha (HSP90α), encoded by the HSP90AA1 gene, is a molecular chaperone that is required for the proper folding and activity of many of the client proteins that are involved in numerous essential cellular pathways. In addition to its general chaperone activity, HSP90α plays a role in other neuronal contexts and was found to have an altered expression in SCZ, which makes HSP90AA1 an attractive gene for association studies. The aim of this study was to determine whether the HSP90AA1 polymorphisms (rs8005905, rs10873531, rs11621560, rs4947 and rs2298877) are involved in the risk of developing SCZ and its clinical picture in a Polish Caucasian population. Methods: A total of 1088 unrelated subjects (409 patients and 679 healthy controls) were included in the study. The SNPs were genotyped using a TaqMan 5′-exonuclease allelic discrimination assay. The results of the Positive and Negative Syndrome Scale (PANSS) were presented in the five-dimensional model. Results: None of the SNPs were associated with a predisposition to developing SCZ in either the single-marker or haplotype analysis including the results of gender-stratified analyses. However, the genotypes of rs11621560, rs4947 and rs2298877 SNPs were associated with the emotional distress (EMO) dimension score. Conclusions: The results of the present study indicate that HSP90AA1 variants may have an impact on the psychopathology of SCZ, although larger studies are needed to clarify these findings. Full article
(This article belongs to the Special Issue Genetics of Neuropsychiatric Disorders)
14 pages, 846 KB  
Article
Multi-SNP Haplotypes in Circadian PER3 Gene Are Associated with Mood and Sleep Disorders in University Students
by Francesca Goodell and Krista K. Ingram
Genes 2025, 16(9), 1047; https://doi.org/10.3390/genes16091047 - 5 Sep 2025
Viewed by 840
Abstract
Background: Mood disorders, including anxiety, depression, and seasonal affective disorder (SAD), are often comorbid and can be exacerbated by the misalignment of an individual’s circadian rhythm with their social timing. Single-nucleotide polymorphisms (SNPs) in circadian clock genes have been associated with both [...] Read more.
Background: Mood disorders, including anxiety, depression, and seasonal affective disorder (SAD), are often comorbid and can be exacerbated by the misalignment of an individual’s circadian rhythm with their social timing. Single-nucleotide polymorphisms (SNPs) in circadian clock genes have been associated with both internalizing disorders and sleep disturbances, and some clock polymorphisms, including those in the Period3 (PER3) gene, likely function via delaying or advancing circadian period and affecting sleep–wake patterns. Methods: Here, we explore associations of multiple SNP haplotypes in the PER3 gene with anxiety, depression, internalizing disorder (ID), chronotype, and sleep disturbance in young adults (n = 1109 individuals). Results: We report novel, sex-specific associations of single PER3 SNPs with mood and sleep disorders and highlight strong multi-SNP haplotype associations, revealing a greater risk of mood and sleep disorders in university students with specific PER3 haplotypes. Conclusions: Our results suggest that the additive effects of multiple risk variants amplify the prevalence of mood disorders and sleep disruptions in young adults. Understanding how polymorphisms within circadian genes interact to alter clock function, sleep-wake behavior and downstream physiological changes in the brain may help explain the comorbidity of mood and sleep syndromes and provide future therapeutic targets to combat these debilitating disorders. Full article
(This article belongs to the Special Issue Genetics of Neuropsychiatric Disorders)
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24 pages, 2331 KB  
Article
Auditory Event-Related Potentials in Two Rat Models of Attention-Deficit Hyperactivity Disorder: Evidence of Automatic Attention Deficits in Spontaneously Hypertensive Rats but Not in Latrophilin-3 Knockout Rats
by Logan M. Brewer, Jankiben Patel, Frank Andrasik, Jeffrey J. Sable, Michael T. Williams, Charles V. Vorhees and Helen J. K. Sable
Genes 2025, 16(6), 672; https://doi.org/10.3390/genes16060672 - 30 May 2025
Viewed by 872
Abstract
Background/Objectives: Variations of the latrophilin-3 (Lphn3) gene have been associated with attention-deficit hyperactivity disorder (ADHD). To explore the functional influence of this gene, Lphn3 knockout (KO) rats were generated and have thus far demonstrated deficits in ADHD-relevant phenotypes, including working memory, [...] Read more.
Background/Objectives: Variations of the latrophilin-3 (Lphn3) gene have been associated with attention-deficit hyperactivity disorder (ADHD). To explore the functional influence of this gene, Lphn3 knockout (KO) rats were generated and have thus far demonstrated deficits in ADHD-relevant phenotypes, including working memory, impulsivity, and hyperactivity. However, inattention remains unexplored. Methods: We assessed automatic attention in Lphn3 KO (n = 19) and their control line (wildtype/WT, n = 20) through use of the following auditory event-related potentials (ERPs): P1, N1, P2, and N2. We also extended this exploratory study by comparing these same ERPs in spontaneously hypertensive rats (SHRs, n = 16), the most commonly studied animal model of ADHD, to their control line (Wistar–Kyoto/WKY, n = 20). Electroencephalograms (EEG) were recorded using subdermal needle electrodes at frontocentral sites while freely moving rats were presented with five-tone trains (50 ms tones, 400 ms tone onset asynchronies) with varying short (1 s) and long (5 s) inter-train intervals. Peak amplitudes and latencies were analyzed using GLM-mixed ANOVAs to assess differences across genotypes (KO vs. WTs) and strains (SHRs vs. WKYs). Results: The KOs did not demonstrate any significant differences in peak amplitudes relative to the WT controls, suggesting that the null expression of Lphn3 does not result in the development of inefficiencies in automatic attention. However, the SHRs exhibited significantly reduced peak P1 (and peak-to-peak P1–N1) values relative to the WKYs. These attenuations likely reflect inefficiencies in bottom-up arousal networks that are necessary for efficient automatic processing. Conclusions: Distinct findings between these animal models likely reflect differing alterations in dopamine and noradrenaline neurotransmission that may underlie ADHD-relevant phenotypes. Full article
(This article belongs to the Special Issue Genetics of Neuropsychiatric Disorders)
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16 pages, 2809 KB  
Article
Neuromolecular Basis of Impaired Conditioned Taste Aversion Acquisition in Valproate-Induced Rat Model of Autism Spectrum Disorder
by Tapasya Pal, Savannah Harvey, Allen S. Levine, Pawel K. Olszewski and Anica Klockars
Genes 2025, 16(2), 203; https://doi.org/10.3390/genes16020203 - 7 Feb 2025
Viewed by 1785
Abstract
Background/Objectives: Autism spectrum disorder (ASD), defined by social, behavioral, and cognitive anomalies, is also associated with dysregulated appetite. ASD individuals, often described as “picky eaters”, exhibit restricted dietary preferences and a pronounced avoidance of novel foods. This suggests that the perceived safety of [...] Read more.
Background/Objectives: Autism spectrum disorder (ASD), defined by social, behavioral, and cognitive anomalies, is also associated with dysregulated appetite. ASD individuals, often described as “picky eaters”, exhibit restricted dietary preferences and a pronounced avoidance of novel foods. This suggests that the perceived safety of specific tastants may be a crucial determinant of dietary acceptance in ASD. Here, we explore the hypothesis that conditioned taste aversion (CTA), a learned avoidance of foods whose intake promotes sickness, is exacerbated in ASD. Methods: We assessed the magnitude of a lithium chloride (LiCl)-induced CTA in the valproic acid (VPA) rat model of autism versus in healthy control rats. We also examined the effect of a standard 3 mEq LiCl dose on transcript and neuronal activation changes in brain circuits mediating feeding behavior and associative learning. Results: Surprisingly, we found that while 3 mEq LiCl induced CTA in healthy controls, even the 6 mEq dose was ineffective in generating aversion in VPA rats. LiCl at 3 mEq affected c-Fos immunoreactivity in the hypothalamus and amygdala in controls, whereas in VPA rats it did not produce any c-Fos changes. Gene expression analysis of feeding-related genes (AgRP, NPY, OXT) and those involved in regulating stress and anxiety (DOR and MC3R) were differentially regulated in the VPA rats. Interestingly, transcripts for COMT1, AgRP, OXT, and MC3R were downregulated in saline-treated VPA rats compared to saline-treated controls. Conclusions: We conclude that VPA rats show blunted CTA responsiveness, which is reflected by a differential impact of LiCl on circuits that promote the acquisition of CTA in healthy versus autistic individuals. Full article
(This article belongs to the Special Issue Genetics of Neuropsychiatric Disorders)
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8 pages, 1197 KB  
Case Report
A Case of Infantile Epileptic Spasms Syndrome with the SPTBN1 Mutation and Review of βII-Spectrin Variants
by Han Na Jang, Juyeon Ryu, Seung Soo Kim and Jin-Hwa Moon
Genes 2025, 16(8), 904; https://doi.org/10.3390/genes16080904 - 29 Jul 2025
Viewed by 923
Abstract
Background: Spectrin proteins are critical cytoskeleton components that maintain cellular structure and mediate intracellular transport. Pathogenic variants in SPTBN1, encoding βII-spectrin, have been associated with various neurodevelopmental disorders, including developmental delay, intellectual disability, autism spectrum disorder, and epilepsy. Here we report [...] Read more.
Background: Spectrin proteins are critical cytoskeleton components that maintain cellular structure and mediate intracellular transport. Pathogenic variants in SPTBN1, encoding βII-spectrin, have been associated with various neurodevelopmental disorders, including developmental delay, intellectual disability, autism spectrum disorder, and epilepsy. Here we report a Korean infant with infantile epileptic spasms syndrome (IESS) and an SPTBN1 mutation and provide a review of this mutation. Methods: The genomic data of the patient were analyzed by whole exome sequencing. A comprehensive literature review was conducted to identify and analyze all reported SPTBN1 variants, resulting in a dataset of 60 unique mutations associated with neurodevelopmental phenotypes. Case Presentation: A 10-month-old Korean female presented with IESS associated with a de novo heterozygous SPTBN1 mutation (c.785A>T; p.Asp262Val). The patient exhibited global developmental delay, microcephaly, hypotonia, spasticity, and MRI findings of diffuse cerebral atrophy and corpus callosum hypoplasia. Electroencephalography revealed hypsarrhythmia, confirming the diagnosis of IESS. Seizures persisted despite initial treatment with vigabatrin and steroids. Genetic analysis identified a likely pathogenic variant within the calponin homology 2 (CH2) domain of SPTBN1. Conclusions: This is the first report of an association between IESS and an SPTBN1 CH2 domain mutation in a Korean infant. This finding expands the clinical spectrum of SPTBN1-related disorders and suggests domain-specific effects may critically influence phenotypic severity. Further functional studies are warranted to elucidate the pathogenic mechanisms of domain-specific variants. Full article
(This article belongs to the Special Issue Genetics of Neuropsychiatric Disorders)
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