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Polygenic scores (PGSs) for psychiatric disorders are largely driven by shared genetic liability, not specific traits. Accounting for this transdiagnostic factor improves PGS specificity and can inform risk stratification for general psychopathology.

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Area of Science:

  • Psychiatry and Genetics
  • Behavioral Science

Background:

  • Polygenic scores (PGSs) estimate genetic liability for psychiatric disorders.
  • Limited disorder specificity of current PGSs hinders clinical and research applications.

Purpose of the Study:

  • To determine if psychiatric PGS-trait associations stem from transdiagnostic or disorder-specific genetic liability.
  • To investigate the utility of transdiagnostic (p) and disorder-specific (non-p) PGSs.

Main Methods:

  • Utilized a population-based cohort (Twins Early Development Study) of 6567 participants aged 25-28.
  • Assessed quantitative symptom scores and self-reported psychiatric diagnoses.
  • Compared associations of uncorrected PGSs, a transdiagnostic PGS (p), and residual disorder-specific PGSs (non-p).

Main Results:

  • The transdiagnostic PGS (p) showed comparable or stronger associations with most symptom outcomes than uncorrected PGSs.
  • Much of the genetic signal in uncorrected PGSs was linked to transdiagnostic liability, significantly attenuated when accounting for p.
  • Some disorder-specific (non-p) PGSs retained significant associations, indicating residual specificity for conditions like PTSD and anorexia nervosa.

Conclusions:

  • Psychiatric PGS associations with outcomes are predominantly driven by transdiagnostic genetic liability.
  • Accounting for shared genetic effects can enhance PGS specificity.
  • Transdiagnostic scores offer potential for risk stratification and interventions targeting general psychopathology.