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

The National Institute of Health (NIH) Undiagnosed Diseases Program (UDP) is an NIH project with the goal of providing both a comprehensive diagnosis and a better understanding of the many mechanisms of disease for patients with rare and undiagnosed conditions. Patients accepted to the program receive a careful review of their medical records and a tailored inpatient evaluation at the NIH Clinical Center in Bethesda, MD. For the pediatric population, systematic neurodevelopmental phenotypic evaluations are included. Here we report neurodevelopmental phenotyping data on pediatric participants enrolled in the NIH UDP from 2009 to 2019, with genetic findings reported through 2025. Results for 219 pediatric participants included a high rate of intellectual disability, with 27% of the sample in the severe-to-profound range. The phenotype often included multisystemic involvement, with motor impairments as well as vision and hearing concerns. For the 46% for whom a genetic diagnosis was made, there was greater impairment, including more severe intellectual disability and more frequent motor impairments as well as minimal verbal status. This study documented that severe neurodevelopmental impairments are frequently present in the unique pediatric undiagnosed patients enrolled in NIH UDP; the diagnosis of a genetic condition was associated with greater impairment.

We investigate the role of m6A RNA methylation in regulating transcription factor EB (TFEB) and its contribution to mitochondrial autophagy (mitophagy) dysfunction in amyotrophic lateral sclerosis (ALS). ALS cell models were used to analyse mitophagy markers and TFEB expression under METTL3 and TFEB modulation, using RT-qPCR, Western blot, MeRIP, RIP, and immunofluorescence. Elevated m6A methylation and reduced TFEB expression were observed in hSOD1-G93A models. METTL3 overexpression suppressed TFEB expression, leading to impaired mitophagy, while METTL3 knockdown alleviated these effects. MeRIP assays confirmed increased m6A modifications on TFEB mRNA, and RIP assays demonstrated direct interaction between METTL3 and TFEB mRNA. Notably, TFEB overexpression rescued mitophagy dysfunction, whereas TFEB knockdown exacerbated the impairment. METTL3-mediated m6A methylation inhibits mitophagy by downregulating TFEB expression, revealing the m6A-TFEB pathway as a promising therapeutic target for ALS.

Mental disorders are a significant global public health concern, affecting nearly one in eight individuals worldwide. This review investigates the multifaceted etiology of mental disorders—specifically major depressive disorder (MDD), schizophrenia (SCZ), and bipolar disorder (BD)—through genetic, neurobiological, and environmental perspectives, with a particular emphasis on the role of trace elements (TrEs). TrEs such as zinc, magnesium, copper, iron, and selenium are essential micronutrients that influence several central nervous system functions, including enzymatic activity, neurotransmitter synthesis, and synaptic plasticity. Both deficiencies and excesses of these elements have been linked to psychiatric disorders. This study explores the associations between TrEs, psychiatric symptoms, and biological pathways due to the Research Domain Criteria (RDoC) framework. We discuss clinical evidence and genetic studies to evaluate possible correlations between TrEs and key RDoC endophenotypes. By elucidating these connections, this review focuses on the potential and current limitations of TrEs in mental health.

International collaborations between high-income countries (HICs) and low- and middle-income countries (LMICs) have become increasingly essential in advancing global health, particularly within psychiatric research. These partnerships not only accelerate scientific discovery and enhance public health, but they also bring to light significant challenges in equity and fairness. Specifically, research partnerships often suffer from imbalances, such as “helicopter” research approaches or the exploitation and marginalization of LMIC researchers. Here, we present a consensus report by members of the International Society for Psychiatric Genetics, outlining key considerations and strategies for planning, implementing, and disseminating equitable collaborative research. Throughout the collaboration process, we identified both challenges and opportunities and provided recommendations to maximize the benefits of these partnerships. Among our considerations, we emphasize that Equitable Collaboration must begin with comprehensive stakeholder engagement, fostering a participatory environment that includes local communities, governments, and institutions from both HICs and LMICs. Among the potential challenges we identify are differences in ethical research and data-sharing frameworks across countries, inequalities in research resources and infrastructure, and reduced visibility of research conducted in LMICs. These factors can significantly impact research outcomes and their applicability. In conclusion, while global collaboration in psychiatric genetics presents complex challenges, it also offers substantial opportunities for impactful research and improved global mental health.

The missense SNP NC_000004.12:g.102267552C>T (also known as SLC39A8.p.(Ala391Thr), rs13107325) in SLC39A8 encodes a zinc transporter. This SNP has been linked to schizophrenia and is the likely causal variant for one of the genome-wide association loci associated with the disorder. Using regression analyses, we tested whether the schizophrenia-risk allele at p.(Ala391Thr) was associated with schizophrenia-related phenotypes, including positive, negative, and disorganized symptoms, cognitive ability, educational attainment, and age of psychosis onset, within three schizophrenia cohorts (combined N = 1232) and, with equivalent phenotypes, in a sample of population controls (UK Biobank, N = 355,069). We also used the population controls to test for associations with rare protein-truncating and deleterious missense variants within SLC39A8. Within the schizophrenia cohorts, after correction for multiple testing, p.(Ala391Thr) was not significantly associated with any schizophrenia-related phenotypes. In the unaffected participants from the UK Biobank, the schizophrenia-risk allele at p.(Ala391Thr) was associated with significantly poorer cognitive ability and fluid intelligence, a lower probability of obtaining GCSEs or a degree-level qualification, and fewer years in education. There was no association between p.(Ala391Thr) and self-reported psychotic experiences in this cohort. Rare variants in SLC39A8 were nominally associated with poorer cognitive ability, but these associations did not survive correction for multiple testing. The schizophrenia-risk allele was associated with poorer cognitive ability, but not psychotic experiences, in a volunteer sample drawn from the general population. We found no evidence that p.(Ala391Thr) was associated with symptom severity in schizophrenia. To understand the impact of rare variants in SLC39A8 on cognitive impairment, larger independent samples are required.

Treatment-resistant mood disorders are often managed with intensive interventions that include electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), ketamine, and esketamine, but the role of genetics in clinical response to those interventions is yet to be clearly determined. Here, we review the current literature on the genetics of response to these treatment modalities. To date, the limited number of studies done to investigate genetic predictors of treatment response have primarily focused on single variants in candidate genes, and none of these have been consistently reproducible. The majority of candidate gene studies examine the effect of variants in the COMT and BDNF genes on treatment response. There are a limited number of genome-wide association studies (GWAS) looking at treatment response, though they are almost all underpowered, with only one study including a sample size > 1000. As a result, there have been few single nucleotide polymorphisms (SNPs) found to be associated with treatment response at a statistically significant level, all in genes other than COMT and BDNF. The challenge is now to generate data from a large group of patients undergoing these therapies in order to more robustly assess the genetic factors affecting treatment response. This will not only help establish genetic predictors of response, but also potentially develop differential predictors of response to available treatments, which could provide clinicians with critical information to aid in deciding which treatment modality to recommend for treatment-resistant depression. We are currently pursuing such a strategy in our 50-site worldwide Gen-ECT-ic consortium.