RT Journal Article
SR Electronic
T1 Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 040022
DO 10.1101/040022
A1 Michael J. Gandal
A1 Jillian R. Haney
A1 Neelroop N. Parikshak
A1 Virpi Leppa
A1 Steve Horvath
A1 Geschwind H. Daniel
YR 2016
UL http://biorxiv.org/content/early/2016/02/18/040022.abstract
AB 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 Summary Autism, schizophrenia, and bipolar disorder share global gene expression patterns, characterized by astrocyte activation and disrupted synaptic processes.