Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap

By Michael Jeffrey Gandal, J. Haney, Neelroop Parikshak, Virpi Leppa, Gokul Ramaswami, C. Hartl, A. Schork, Vivek Appadurai, A. Buil, T. Werge and 4 more. Science, 2018

1,009 citations recorded by the source corpus.

Genes overlap across psychiatric disease Many genome-wide studies have examined genes associated with a range of neuropsychiatric disorders. However, the degree to which the genetic underpinnings of these diseases differ or overlap is unknown. Gandal et al. performed meta-analyses of transcriptomic studies covering five major psychiatric disorders and compared cases and controls to identify coexpressed gene modules. From this, they found that some psychiatric disorders share global gene expression patterns. This overlap in polygenic traits in neuropsychiatric disorders may allow for better diagnosis and treatment. Science, this issue p. 693 Neuropsychiatric disease patients have both shared and distinct gene expression pattern changes in the brain compared with controls. 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.

Subfields: Biophysics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/cb5b301ef027f52b4cad525396f7946fd18fff35

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Citations in the corpus

Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder (2018, neutral): “85, ref (1); Spearman ⍴ of log2FC, all P’s<10−16).”
Predictive Processing: A Canonical Cortical Computation (2018, background): “In addition, there is a common gene expression network that is dysregulated in the two conditions (Gandal et al., 2018), possibly in opposite directions (Crespi et al., 2010).”
The Lancet Commission on global mental health and sustainable development. (2018, background): “67 The implications for reenvisaging diagnoses are unclear; some genomic research has led to delineation of possible causal pathways (eg, potential role of the complement system in schizophrenia), but individual, small genetic effects might not readily allow insights into complex pathways purely…”
Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism (2019, result): “In contrast to post-mortem findings in adult ASD brains (Gandal et al., 2018; 22 Voineagu et al., 2011), no enrichment was observed in microglia.”
All for one and one for all: Mental disorders in one dimension (2018, background): “Cross-disorder comparisons are producing confirming evidence that different disorders may share some of the same illness-associated genetic variation (70, 71), which may be related to shared global gene expression patterns across different disorders (72).”