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Molecular mentality

How studying transcription in the brain could advance the biology of psychiatry

A Science study of gene expression signatures in psychiatric disease patients is the field’s largest transcriptomic readout to date, moving it closer toward molecular characterization of mental disorders. By helping map targets and pathways, the findings could pave the way for therapies and contribute to new ways of defining a range of CNS diseases.

A growing caucus of researchers has been calling for new ways to define psychiatric diseases like autism, schizophrenia and depression, departing from traditional DSM definitions, which don’t capture mechanistically distinct subtypes of disease, and are largely based on behavioral readouts.

But finding molecular targets and biomarkers has lagged far behind areas like cancer, which have capitalized on advances in sequencing, imaging and in situ assay technologies to enable more precise subsectioning of patient populations.

Clues about molecular underpinnings for psychiatric disease have largely come from common DNA risk alleles identified in large genome-wide association studies (GWAS) and rare disease-associated alleles found in smaller patient-focused studies.

The problem is how to make sense of individual risk alleles in complex disorders that are likely to involve multiple genes with variable penetrance across the population.

Individual genetic hits usually explain only a small fraction of disease risk, making it challenging

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