Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap
Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap
Abstract Recent large-scale studies have identified multiple genetic risk factors for mental illness and indicate a complex, polygenic, and pleiotropic genetic architecture for neuropsychiatric disease. However, little is known about how genetic variants yield brain dysfunction or pathology. We use transcriptomic profiling as an unbiased, quantitative readout of molecular phenotypes across 5 major psychiatric disorders, including autism (ASD), schizophrenia (SCZ), bipolar disorder (BD), depression (MDD), and alcoholism (AAD), compared with carefully matched controls. We identify a clear pattern of shared and distinct gene-expression perturbations across these conditions, identifying neuronal gene co-expression modules downregulated across ASD, SCZ, and BD, and astrocyte related modules most prominently upregulated in ASD and SCZ. Remarkably, the degree of sharing of transcriptional dysregulation was strongly related to polygenic (SNP-based) overlap across disorders, indicating a significant genetic component. These findings provide a systems-level view of the neurobiological architecture of major neuropsychiatric illness and demonstrate pathways of molecular convergence and specificity. One Sentence SummaryAutism, schizophrenia, and bipolar disorder share global gene expression patterns, characterized by astrocyte activation and disrupted synaptic processes.
Parikshak Neelroop N.、Leppa Virpi、Haney Jillian R.、Daniel Geschwind H.、Gandal Michael J.、Horvath Steve
Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California||Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California Los Angeles||Department of Human Genetics, David Geffen School of Medicine, University of CaliforniaProgram in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California||Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California Los Angeles||Department of Human Genetics, David Geffen School of Medicine, University of CaliforniaProgram in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California||Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California Los Angeles||Department of Human Genetics, David Geffen School of Medicine, University of CaliforniaProgram in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California||Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California Los Angeles||Department of Human Genetics, David Geffen School of Medicine, University of CaliforniaProgram in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California||Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California Los Angeles||Department of Human Genetics, David Geffen School of Medicine, University of California||Department of Psychiatry, Semel Institute, David Geffen School of Medicine, University of California Los AngelesDepartment of Human Genetics, David Geffen School of Medicine, University of California
神经病学、精神病学基础医学分子生物学
Parikshak Neelroop N.,Leppa Virpi,Haney Jillian R.,Daniel Geschwind H.,Gandal Michael J.,Horvath Steve.Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap[EB/OL].(2025-03-28)[2025-05-24].https://www.biorxiv.org/content/10.1101/040022.点此复制
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