Mitchell2022 - What have we learned from psychiatric genetics, The view from 2022

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Key takeaways

  • Rare de novo mutations like CNVs are non-specific and may be associated with schizophrenia, bipolar, autism, intellectual disability
  • The presence of two X chromosomes in females has created a greater genomic robustness, they are less sensitive to genetic variation on the X chromosome.
    • This is probably why there is more variation in traits among males

Mental disorders are associated with reduced (evolutionary) fitness, so why do they persist? No single variant has a moderate or strong effect on risk, and only a sufficient number among the thousands of genetic variants underlying human behavior results in a mental disorder. This is called polygenic mutation-selection balance.

Take-home messages:

  • There is Equipotentiality in the genetics of psychiatric disorders. Many disorders can have the same genetic origin.
  • Severe and early-onset cases may have de novo mutations
  • There is a balance between mutation and selection: polygenic mutation-selection balance
  • Overall burden is key
  • Typically, what is inherited is not a disorder but a more general risk for psychopathology

In summary, mutations in any of hundreds of different genes, involved in all kinds of molecular and cellular processes, and modified strongly by genetic background, can indirectly and non-specifically lead to altered trajectories of brain development that sometimes result in atypical outcomes that can manifest in diverse modes of psychopathology.