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Commentary| Volume 80, ISSUE 2, P92-93, July 15, 2016

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Beyond the Diagnosis: A Path Toward Understanding Behavior Through the Lens of Rare Genetics

  • Daniel Moreno-De-Luca
    Correspondence
    Address correspondence to: Daniel Moreno-De-Luca, M.D., M.Sc., Department of Psychiatry, Yale University, 300 George Street, Suite 901, New Haven, CT 06510; .
    Affiliations
    Department of Psychiatry, Yale University, New Haven, Connecticut
    Search for articles by this author
      This is an exciting time for psychiatry. We have long known that many of the disorders we treat, such as autism and schizophrenia, have a strong genetic component, as evidenced by their high heritability, and progress in the past several years has begun to shed light on the specific genetic underpinnings of these conditions. Insights have come from common and rare genetics alike, exemplified by polygenic risk scores, copy number variants (CNVs), and single nucleotide variants (SNVs). With these discoveries, an interesting phenomenon reflecting simultaneously the clinical heterogeneity and overlap of these conditions has continued to emerge—all for one, and one for all: multiple different genetic variants increase risk for the same psychiatric condition, and, conversely, a given genetic variant has been associated with multiple psychiatric diagnoses (
      • Moreno-De-Luca A.
      • Myers S.M.
      • Challman T.D.
      • Moreno-De-Luca D.
      • Evans D.W.
      • Ledbetter D.H.
      Developmental brain dysfunction: revival and expansion of old concepts based on new genetic evidence.
      ). Reconciling these numerous streams of genetic evidence poses a challenge that can be tackled in various ways. Although considerable focus has been placed on reducing the clinical heterogeneity by studying discrete isolated psychiatric diagnoses to better understand their underlying biology, a different genotype-first approach (
      • Stessman H.A.
      • Bernier R.
      • Eichler E.E.
      A genotype-first approach to defining the subtypes of a complex disease.
      ) focusing instead on reducing the genetic heterogeneity to elucidate the clinical and behavioral consequences of specific genetic risk factors has likewise proven to be a successful route. This has provided us the opportunity to identify at-risk individuals early in their development, understand the consequences of these genetic changes over time, and understand their relationship with different psychiatric disorders.
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