American Journal of Medical Genetics Part B: Neuropsychiatric Genetics最新文献

The cover image is based on the article Genetics of Response to ECT, TMS, Ketamine and Esketamine by Clio E. Franklin et al., https://doi.org/10.1002/ajmg.b.33038.

The development of high throughput technologies has resulted in the collection of large quantities of genomic and transcriptomic data. However, identifying disease-associated genes or networks from these data has remained an ongoing challenge. In recent years, graph neural networks (GNNs) have emerged as a promising analytical tool, but it is not well understood which characteristics of these models result in improved performance. We conducted a systematic search and review of publications that used GNNs to identify disease-associated biological interactions. Information was extracted about model characteristics and performance with the goal of examining the relationship between these factors and performance. Data leakage was found in 31% of these models. For node level tasks, univariate positive associations were identified between model accuracy and use of hyper parameter optimization, data leakage via hyperparameter optimization, test set size, and total dataset size. Among graph level tasks, an increase in AUC was identified in association with testing method and a decrease with optimization reporting. Data leakage may pose an issue for GNN-based approaches; the adoption of best practice guidelines and consistent reporting of model design would be beneficial for future studies.

Schizophrenia is a neurodevelopmental psychiatric disorder characterized by symptoms of psychosis, thought disorder, and flattened affect. Immune mechanisms are associated with schizophrenia, though the precise nature of this relationship (causal, correlated, consequential) and the mechanisms involved are not fully understood. To elucidate these mechanisms, we conducted a transcriptome-wide Mendelian randomization study using gene expression exposures from 29 human cis-eQTL data sets encompassing 11 unique immune cell types, available from the eQTL catalog. These analyses highlighted 196 genes, including 67 located within the human leukocyte antigen (HLA) region. Enrichment analyses indicated an overrepresentation of immune genes, which was driven by the HLA genes. Stringent validation and replication steps retained 61 candidate genes, 27 of which were the sole causal signals at their respective loci, thereby representing strong candidate effector genes at known risk loci. We highlighted L3HYPDH as a potential novel schizophrenia risk gene and DPYD and MAPK3 as candidate drug repurposing targets. Furthermore, we performed follow-up analyses focused on one of the candidate effectors, interferon regulatory transcription factor 3 (IRF3), which coordinates interferon responses to viral infections. We found evidence of shared genetic etiology between schizophrenia and autoimmune diseases at the IRF3 locus, and a significant enrichment of IRF3 chromatin binding at known schizophrenia risk loci. Our findings highlight a novel schizophrenia risk gene, potential drug repurposing opportunities, and provide support for IRF3 as a schizophrenia hub gene, which may play critical roles in mediating schizophrenia-autoimmune comorbidities and the impact of infections on schizophrenia risk.

Investigations into the etiology and genetic basis of autism continue to drive much autism research, yet reports are emerging of this research not aligning with priorities of autistic people. Engagement of autistic people in the research process is a key way to take their perspectives on board. We investigated whether influential genetic autism research shows evidence of engagement with the autistic community via indicators in published article texts. Through text mining of the abstracts of articles mentioning the words "autism" or "autistic," we found minimal prevalence of progressive terminology associated with autism. We also devised a novel rating system to assess three hallmarks of autistic community engagement: presence of non-stigmatizing language, referencing community priorities, and the use of participatory methods. We reviewed 149 articles within leading autism and genetic journals. Minimal evidence of engagement with the autistic community was found within all three hallmarks. Genetics researchers focused on autism should embrace opportunities to engage with the autistic community to bring their work into closer alignment with their priorities, yielding scientific and moral benefits.

To investigate the role of miR-132-5p in the inflammatory response in epilepsy. Peripheral blood was collected from epileptic and healthy children, and the expression of LINC00665 and miR-132-5p was detected by q-PCR. Epilepsy cell models were constructed with microglia, transfected with miR-132-5p inhibitor and NC, and the expression of LINC00665 and miR-132-5p was detected by q-PCR, the expression of TNF-α, IL-1β, and IL-6 in the cell supernatant was detected by ELISA, and the protein levels of NLRP3 and MAPK3 were detected by WB. Finally, the targeting relationship between LINC00665 and miR-132-5p was verified by dual luciferase assay. The expression levels of both LINC00665 and miR-132-5p in the peripheral blood of children with epilepsy were significantly higher than those of healthy children. After transfection of epileptic cells with miR-132-5p inhibitor, the expression levels of LINC00665 and miR-132-5p were increased, and the expression levels of TNF-α, IL-1β, IL-6, NLRP3, and MAPK3 were decreased. Dual luciferase assay showed targeted binding of LINC00665 and miR-132-5p. LINC00665/miR-132-5p attenuates inflammatory responses in epileptic cells by targeting MAPK3.

Psychomotor development delays affect 1%-3% of children and encompass a wide range of motor, cognitive, and social impairments. The histone deacetylase 4 (HDAC4) gene, critical for neurodevelopmental pathways, has been associated with developmental delays, autism spectrum disorders, and cognitive impairments. Here, we report a case of a female patient with global psychomotor developmental delay, hypotonia, and feeding difficulties since infancy. By the age of seven, she developed epilepsy, later diagnosed as Lennox-Gastaut syndrome. Brain magnetic resonance imaging revealed reduced white matter and polymicrogyria-like cortical malformations, primarily in the fronto-basal regions. Whole-exome sequencing identified a novel de novo HDAC4 mutation (p.Gln1046AspfsTer29; c.3136_3137delCA), resulting in a frameshift and a premature stop codon. Additional phenotypic features included distinct craniofacial abnormalities and hypertrichosis. This report highlights the critical role of HDAC4 in psychomotor development and cognitive function, expands the phenotypic spectrum associated with HDAC4 mutations, and suggests a potential link to epilepsy and cortical malformations.

Prader-Willi Syndrome (PWS), a rare genetic disorder, affects development and behavior, frequently resulting in self-injury, aggression, hyperphagia, oppositional behavior, impulsivity, and over-activity, causing significant morbidity. Currently, limited therapeutic options are available to manage these neuropsychiatric manifestations. A randomized, placebo-controlled trial was conducted to assess the efficacy of guanfacine-extended release (GXR) in reducing aggression and self-injury in individuals with PWS. Subjects with a diagnosis of PWS, aged 6-35 years with moderate to severe aggressive and/or self-injurious behavior, as determined by the clinical global impression (CGI)-Severity scale, were included in an 8-week double-blind, placebo-controlled, fixed-flexible dose clinical trial of GXR, that was followed by an 8-week open-label extension phase. Validated behavioral instruments and physician assessments measured the efficacy of GXR treatment, its safety, and tolerability. GXR was effective in reducing aggression/agitation and hyperactivity/noncompliance, as measured by the Aberrant Behavior Checklist (ABC) scales (p = 0.03). Overall aberrant behavior scores significantly reduced in the GXR arm. Aggression, as measured by the modified overt aggression scale (MOAS) also showed a significant reduction. Skin-picking lesions, as measured by the self injury trauma (SIT) scale, decreased in response to GXR. No serious adverse events were experienced by any of the study participants. Fatigue/sedation was the only adverse event significantly associated with GXR. The GXR group demonstrated significant overall clinical improvement, as measured by the CGI-Improvement (CGI-I) scale (p < 0.01). Findings of this pragmatic trial strongly support the use of GXR for the treatment of aggression, skin picking, and hyperactivity in children, adolescents, and adults with PWS.