Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap

TLDR

Neuropsychiatric disease risk is driven by a complex, polygenic, pleiotropic genetic architecture, yet the mechanisms by which variants cause brain dysfunction remain poorly understood. The study profiled brain transcriptomes from patients with autism, schizophrenia, bipolar disorder, depression, and alcoholism versus matched controls to quantify molecular phenotypes. Shared and distinct gene‑expression changes were found across disorders, with the extent of overlap mirroring polygenic similarity, indicating a causal genetic influence and revealing convergent and specific molecular pathways.

Abstract

The predisposition to neuropsychiatric disease involves a complex, polygenic, and pleiotropic genetic architecture. However, little is known about how genetic variants impart brain dysfunction or pathology. We used transcriptomic profiling as a quantitative readout of molecular brain-based phenotypes across five major psychiatric disorders-autism, schizophrenia, bipolar disorder, depression, and alcoholism-compared with matched controls. We identified patterns of shared and distinct gene-expression perturbations across these conditions. The degree of sharing of transcriptional dysregulation is related to polygenic (single-nucleotide polymorphism-based) overlap across disorders, suggesting a substantial causal genetic component. This comprehensive systems-level view of the neurobiological architecture of major neuropsychiatric illness demonstrates pathways of molecular convergence and specificity.