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Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap.

  • Author(s): Gandal, Michael J
  • Haney, Jillian R
  • Parikshak, Neelroop N
  • Leppa, Virpi
  • Ramaswami, Gokul
  • Hartl, Chris
  • Schork, Andrew J
  • Appadurai, Vivek
  • Buil, Alfonso
  • Buil, Alfonso
  • Werge, Thomas M
  • Liu, Chunyu
  • White, Kevin P
  • CommonMind Consortium
  • PsychENCODE Consortium
  • iPSYCH-BROAD Working Group
  • Horvath, Steve
  • Geschwind, Daniel H
  • et al.
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.

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