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Intermediate phenotypes and genetic mechanisms of psychiatric disorders

Abstract

Genes are major contributors to many psychiatric diseases, but their mechanisms of action have long seemed elusive. The intermediate phenotype concept represents a strategy for characterizing the neural systems affected by risk gene variants to elucidate quantitative, mechanistic aspects of brain function implicated in psychiatric disease. Using imaging genetics as an example, we illustrate recent advances, challenges and implications of linking genes to structural and functional variation in brain systems related to cognition and emotion.

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Figure 1: The complex path from genes to behavioural and disease phenotype: mediation through brain circuitry.
Figure 2: Intermediate phenotypes as tools for gene discovery versus neural mechanism characterization.
Figure 3: COMT Val(108/158)Met polymorphism and its effect on prefrontal function.
Figure 4: Effects of COMT Val(108/158)Met on prefrontal cortex activity linked to extracellular dopamine.
Figure 5: Effects of COMT Val(108/158)Met on midbrain–prefrontal interactions and 22q11.2 syndrome.

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Acknowledgements

This work was supported by the National Institute of Mental Health's Intramural Research Program. We thank C. Rainey for help with figure preparation.

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DATABASES

OMIM

22q11.2 syndrome

autism

attention deficit hyperactivity disorder

major depression

schizophrenia

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Unit for Systems Neuroscience in Psychiatry

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Meyer-Lindenberg, A., Weinberger, D. Intermediate phenotypes and genetic mechanisms of psychiatric disorders. Nat Rev Neurosci 7, 818–827 (2006). https://doi.org/10.1038/nrn1993

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