-
Nature Medicine Jul 2023Depression is a common psychiatric disorder and a leading cause of disability worldwide. Here we conducted a genome-wide association study meta-analysis of six datasets,... (Meta-Analysis)
Meta-Analysis
Depression is a common psychiatric disorder and a leading cause of disability worldwide. Here we conducted a genome-wide association study meta-analysis of six datasets, including >1.3 million individuals (371,184 with depression) and identified 243 risk loci. Overall, 64 loci were new, including genes encoding glutamate and GABA receptors, which are targets for antidepressant drugs. Intersection with functional genomics data prioritized likely causal genes and revealed new enrichment of prenatal GABAergic neurons, astrocytes and oligodendrocyte lineages. We found depression to be highly polygenic, with ~11,700 variants explaining 90% of the single-nucleotide polymorphism heritability, estimating that >95% of risk variants for other psychiatric disorders (anxiety, schizophrenia, bipolar disorder and attention deficit hyperactivity disorder) were influencing depression risk when both concordant and discordant variants were considered, and nearly all depression risk variants influenced educational attainment. Additionally, depression genetic risk was associated with impaired complex cognition domains. We dissected the genetic and clinical heterogeneity, revealing distinct polygenic architectures across subgroups of depression and demonstrating significantly increased absolute risks for recurrence and psychiatric comorbidity among cases of depression with the highest polygenic burden, with considerable sex differences. The risks were up to 5- and 32-fold higher than cases with the lowest polygenic burden and the background population, respectively. These results deepen the understanding of the biology underlying depression, its disease progression and inform precision medicine approaches to treatment.
Topics: Male; Female; Humans; Genome-Wide Association Study; Depression; Bipolar Disorder; Schizophrenia; Attention Deficit Disorder with Hyperactivity; Polymorphism, Single Nucleotide; Genetic Predisposition to Disease
PubMed: 37464041
DOI: 10.1038/s41591-023-02352-1 -
Science (New York, N.Y.) Oct 2023Recent advances in single-cell transcriptomics have illuminated the diverse neuronal and glial cell types within the human brain. However, the regulatory programs...
Recent advances in single-cell transcriptomics have illuminated the diverse neuronal and glial cell types within the human brain. However, the regulatory programs governing cell identity and function remain unclear. Using a single-nucleus assay for transposase-accessible chromatin using sequencing (snATAC-seq), we explored open chromatin landscapes across 1.1 million cells in 42 brain regions from three adults. Integrating this data unveiled 107 distinct cell types and their specific utilization of 544,735 candidate cis-regulatory DNA elements (cCREs) in the human genome. Nearly a third of the cCREs demonstrated conservation and chromatin accessibility in the mouse brain cells. We reveal strong links between specific brain cell types and neuropsychiatric disorders including schizophrenia, bipolar disorder, Alzheimer's disease (AD), and major depression, and have developed deep learning models to predict the regulatory roles of noncoding risk variants in these disorders.
Topics: Animals; Humans; Mice; Brain; Chromatin; DNA; Neurons; Regulatory Sequences, Nucleic Acid; Atlases as Topic; Single-Cell Analysis
PubMed: 37824643
DOI: 10.1126/science.adf7044 -
Aging and Disease Jun 2023The metabolism of L-tryptophan (TRP) regulates homeostasis, immunity, and neuronal function. Altered TRP metabolism has been implicated in the pathophysiology of various... (Review)
Review
The metabolism of L-tryptophan (TRP) regulates homeostasis, immunity, and neuronal function. Altered TRP metabolism has been implicated in the pathophysiology of various diseases of the central nervous system. TRP is metabolized through two main pathways, the kynurenine pathway and the methoxyindole pathway. First, TRP is metabolized to kynurenine, then kynurenic acid, quinolinic acid, anthranilic acid, 3-hydroxykynurenine, and finally 3-hydroxyanthranilic acid along the kynurenine pathway. Second, TRP is metabolized to serotonin and melatonin along the methoxyindole pathway. In this review, we summarize the biological properties of key metabolites and their pathogenic functions in 12 disorders of the central nervous system: schizophrenia, bipolar disorder, major depressive disorder, spinal cord injury, traumatic brain injury, ischemic stroke, intracerebral hemorrhage, multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Furthermore, we summarize preclinical and clinical studies, mainly since 2015, that investigated the metabolic pathway of TRP, focusing on changes in biomarkers of these neurologic disorders, their pathogenic implications, and potential therapeutic strategies targeting this metabolic pathway. This critical, comprehensive, and up-to-date review helps identify promising directions for future preclinical, clinical, and translational research on neuropsychiatric disorders.
PubMed: 37191427
DOI: 10.14336/AD.2022.0916 -
Nature Dec 2023The basic plan of the retina is conserved across vertebrates, yet species differ profoundly in their visual needs. Retinal cell types may have evolved to accommodate... (Comparative Study)
Comparative Study
The basic plan of the retina is conserved across vertebrates, yet species differ profoundly in their visual needs. Retinal cell types may have evolved to accommodate these varied needs, but this has not been systematically studied. Here we generated and integrated single-cell transcriptomic atlases of the retina from 17 species: humans, two non-human primates, four rodents, three ungulates, opossum, ferret, tree shrew, a bird, a reptile, a teleost fish and a lamprey. We found high molecular conservation of the six retinal cell classes (photoreceptors, horizontal cells, bipolar cells, amacrine cells, retinal ganglion cells (RGCs) and Müller glia), with transcriptomic variation across species related to evolutionary distance. Major subclasses were also conserved, whereas variation among cell types within classes or subclasses was more pronounced. However, an integrative analysis revealed that numerous cell types are shared across species, based on conserved gene expression programmes that are likely to trace back to an early ancestral vertebrate. The degree of variation among cell types increased from the outer retina (photoreceptors) to the inner retina (RGCs), suggesting that evolution acts preferentially to shape the retinal output. Finally, we identified rodent orthologues of midget RGCs, which comprise more than 80% of RGCs in the human retina, subserve high-acuity vision, and were previously believed to be restricted to primates. By contrast, the mouse orthologues have large receptive fields and comprise around 2% of mouse RGCs. Projections of both primate and mouse orthologous types are overrepresented in the thalamus, which supplies the primary visual cortex. We suggest that midget RGCs are not primate innovations, but are descendants of evolutionarily ancient types that decreased in size and increased in number as primates evolved, thereby facilitating high visual acuity and increased cortical processing of visual information.
Topics: Animals; Humans; Neurons; Retina; Retinal Ganglion Cells; Single-Cell Gene Expression Analysis; Vertebrates; Vision, Ocular; Species Specificity; Biological Evolution; Amacrine Cells; Photoreceptor Cells; Ependymoglial Cells; Retinal Bipolar Cells; Visual Perception
PubMed: 38092908
DOI: 10.1038/s41586-023-06638-9 -
Psychiatria Danubina Oct 2023Bipolar disorder and Parkinson's disease are two distinct neurological conditions that share common features related to dopaminergic dysfunction. This article presents a... (Review)
Review
Bipolar disorder and Parkinson's disease are two distinct neurological conditions that share common features related to dopaminergic dysfunction. This article presents a comprehensive review of the existing literature to investigate the association between bipolar disorder and Parkinson's disease, focusing on the dopaminergic hypothesis and potential therapeutic options. The dopaminergic hypothesis suggests that both bipolar disorder and Parkinson's disease involve impairments in the nigrostriatal or mesolimbic dopaminergic pathways. Studies have demonstrated alterations in dopamine regulation during manic and depressive phases of bipolar disorder. Similarly, Parkinson's disease is characterized by the loss of dopaminergic neurons in the substantia nigra, resulting in motor symptoms. Recent analyses have highlighted a predisposition to Parkinson's disease in individuals with bipolar disorder. Longitudinal studies and meta-analyses have demonstrated an increased risk of developing Parkinson's disease in patients with bipolar disorder. However, differentiating idiopathic Parkinson's disease from parkinsonism induced by medications used in bipolar disorder can be challenging. Dopamine transporter (DAT) scans can aid in making a differential diagnosis. Treatment options for patients with both bipolar disorder and Parkinson's disease are limited. Neuroleptics, commonly used to manage psychotic symptoms in Parkinson's disease, may worsen motor symptoms and have limitations in bipolar disorder patients. Clozapine has shown efficacy in treating psychosis without worsening motor symptoms. Pimavanserin, an inverse agonist of the 5-HT2A receptor can offer new opportunities. However, its efficacy in bipolar disorder patients with Parkinson's disease remains unexplored. In conclusion, the association between bipolar disorder and Parkinson's disease is supported by the involvement of the dopaminergic system in both conditions. The identification of shared mechanisms opens new avenues for potential therapeutic interventions. Further research is needed to investigate the efficacy of pimavanserin and explore other treatment options for individuals with both bipolar disorder and Parkinson's disease.
Topics: Humans; Parkinson Disease; Bipolar Disorder; Drug Inverse Agonism; Piperidines; Dopamine
PubMed: 37800205
DOI: No ID Found -
Molecular Psychiatry Sep 2023There has been substantial progress in understanding the genetics of schizophrenia over the past 15 years. This has revealed a highly polygenic condition with the... (Review)
Review
There has been substantial progress in understanding the genetics of schizophrenia over the past 15 years. This has revealed a highly polygenic condition with the majority of the currently explained heritability coming from common alleles of small effect but with additional contributions from rare copy number and coding variants. Many specific genes and loci have been implicated that provide a firm basis upon which mechanistic research can proceed. These point to disturbances in neuronal, and particularly synaptic, functions that are not confined to a small number of brain regions and circuits. Genetic findings have also revealed the nature of schizophrenia's close relationship to other conditions, particularly bipolar disorder and childhood neurodevelopmental disorders, and provided an explanation for how common risk alleles persist in the population in the face of reduced fecundity. Current genomic approaches only potentially explain around 40% of heritability, but only a small proportion of this is attributable to robustly identified loci. The extreme polygenicity poses challenges for understanding biological mechanisms. The high degree of pleiotropy points to the need for more transdiagnostic research and the shortcomings of current diagnostic criteria as means of delineating biologically distinct strata. It also poses challenges for inferring causality in observational and experimental studies in both humans and model systems. Finally, the Eurocentric bias of genomic studies needs to be rectified to maximise benefits and ensure these are felt across diverse communities. Further advances are likely to come through the application of new and emerging technologies, such as whole-genome and long-read sequencing, to large and diverse samples. Substantive progress in biological understanding will require parallel advances in functional genomics and proteomics applied to the brain across developmental stages. For these efforts to succeed in identifying disease mechanisms and defining novel strata they will need to be combined with sufficiently granular phenotypic data.
Topics: Humans; Child; Schizophrenia; Bipolar Disorder; Genome; Genomics; Emotions; Genetic Predisposition to Disease; Genome-Wide Association Study
PubMed: 37853064
DOI: 10.1038/s41380-023-02293-8 -
Proceedings of the National Academy of... Oct 2023Voltage-gated sodium (Na) channels govern membrane excitability, thus setting the foundation for various physiological and neuronal processes. Na channels serve as the...
Voltage-gated sodium (Na) channels govern membrane excitability, thus setting the foundation for various physiological and neuronal processes. Na channels serve as the primary targets for several classes of widely used and investigational drugs, including local anesthetics, antiepileptic drugs, antiarrhythmics, and analgesics. In this study, we present cryogenic electron microscopy (cryo-EM) structures of human Na1.7 bound to two clinical drugs, riluzole (RLZ) and lamotrigine (LTG), at resolutions of 2.9 Å and 2.7 Å, respectively. A 3D EM reconstruction of ligand-free Na1.7 was also obtained at 2.1 Å resolution. RLZ resides in the central cavity of the pore domain and is coordinated by residues from repeats III and IV. Whereas one LTG molecule also binds to the central cavity, the other is found beneath the intracellular gate, known as site BIG. Therefore, LTG, similar to lacosamide and cannabidiol, blocks Na channels via a dual-pocket mechanism. These structures, complemented with docking and mutational analyses, also explain the structure-activity relationships of the LTG-related linear 6,6 series that have been developed for improved efficacy and subtype specificity on different Na channels. Our findings reveal the molecular basis for these drugs' mechanism of action and will aid the development of novel antiepileptic and pain-relieving drugs.
Topics: Humans; Anticonvulsants; Lamotrigine; Cannabidiol; Sodium; Voltage-Gated Sodium Channels
PubMed: 37782796
DOI: 10.1073/pnas.2309773120