Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap

Predisposition to neuropsychiatric disease involves a complex, polygenic (involvement of many genes), pleiotropic (the same gene contributing to two or more seemingly unrelated traits) genetic architecture (characteristics of genetic variation that are responsible for heritable phenotypic variability; genetic architecture depends on the number of genetic variants affecting a trait and their frequencies in the population, effect-size, and interactions with each other and the environment).

Genome-wide association studies (GWAS) have been quite successful at identifying genetic risk factors for major psychiatric disorders. However, despite discovering many single-nucleotide variants (SNVs) in dozens of genes, it remains unknown how these genetic variants interact with environmental and epigenetic risk factors in the brain to impart risk for clinically distinct psychiatric disorders. Authors [see attached article] reasoned that brain transcriptome-profiling –– a quantitative, genome-wide molecular phenotype –– would allow them to determine whether disease-related signatures are shared across major neuropsychiatric disorders with distinct symptoms and whether these patterns reflect genetic risk.

Authors first analyzed published gene-expression microarray studies of the cerebral cortex across five major neuropsychiatric disorders in 700 cerebral cortex samples from subjects having: autism (N = 50 samples), schizophrenia (N = 159), bipolar disorder (N = 94), major depressive disorder (N = 87), alcohol addictive disorder (N = 17), and matched controls (N = 293). Inflammatory bowel disease (N = 197) was included as a non-neural comparison. Authors identified patterns of shared, as well as distinct, gene-expression perturbations across these five neural conditions. The degree of sharing of transcriptional dysregulation was found to be related to polygenic (SNV–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 that should be explored further.

[Giving all that we are learning these days about “brain-gut-microbiome” interactions, however, one might question the validity of using inflammatory bowel disease as the “non-psychiatric comparison”.]

Science 9 Feb 2o18; 359: 693–697

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