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Wringing Biological Insight From Polygenic Signals

      Despite widespread recognition of the high aggregate prevalence of psychiatric disorders, their enormous contribution to global disease burden, and vast unmet treatment needs, therapeutic discovery has languished. What psychiatry lacks is an understanding of disease mechanisms, without which the nomination of biomarkers and therapeutic targets remains guesswork. Attempts over decades to derive pathogenic mechanisms by attaining insight into the healthy and disordered functioning of the human brain have foundered. The reasons are well known, including brain complexity, inaccessibility of relevant human brain tissue in life, evolutionary divergences that limit the utility of laboratory animals as disease models, and the heterogeneity and comorbidity of psychiatric disorders (
      • Hyman S.E.
      Revolution stalled.
      ). A ray of hope comes from psychiatric genetics, which is providing molecular clues to pathogenesis in the form of hundreds of genome-wide significant loci associated with psychiatric disorders (
      • Visscher P.M.
      • Wray N.R.
      • Zhang Q.
      • Sklar P.
      • McCarthy M.I.
      • Brown M.A.
      • Yang J.
      10 years of GWAS discovery: Biology, function, and translation.
      ,
      Schizophrenia Working Group of the Psychiatric Genomics Consortium
      Biological insights from 108 schizophrenia-associated genetic loci.
      ), a smaller number of rare protein-altering variants, and aggregate risk measures such as polygenic risk scores. If emerging genetic information can be rigorously and effectively integrated with neurobiology, clinical investigation, and other disciplines, we will gain actionable insights into disease mechanisms. Success will not come easily, however, given the complexity of the emerging genetic picture. Greater investment and more effective communication across disciplines are needed to build the solid empirical and methodological foundations required to transform genetic information into biological insight.
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