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Polygenic Analyses Show Important Differences Between Major Depressive Disorder Symptoms Measured Using Various

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Major depressive disorder (MDD) symptom assessments using the Patient Health Questionnaire-9 (PHQ-9) and Composite International Diagnostic Interview Short-Form (CIDI-SF) are not interchangeable. PHQ-9 measures general dysphoria, while CIDI-SF reveals MDD heterogeneity.

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Area of Science:

  • Psychiatry
  • Genetics
  • Epidemiology

Background:

  • Major depressive disorder (MDD) symptom assessment commonly uses self-rating instruments like the Patient Health Questionnaire-9 (PHQ-9) for current symptoms and the Composite International Diagnostic Interview Short-Form (CIDI-SF) for worst-episode symptoms.
  • A systematic comparison of the genetic architecture and utility of these instruments in investigating MDD heterogeneity is warranted.

Purpose of the Study:

  • To systematically compare the genetic architecture of MDD symptoms assessed by PHQ-9 and CIDI-SF.
  • To investigate the utility of PHQ-9 and CIDI-SF in understanding MDD heterogeneity.
  • To determine if PHQ-9 and CIDI-SF symptom sets are interchangeable for genetic studies.

Main Methods:

  • Utilized UK Biobank data (n=41,948-109,417) to assess single nucleotide polymorphism heritability and genetic correlation (rg) for PHQ-9 and CIDI-SF MDD symptoms.
  • Employed Mendelian randomization and polygenic risk score pleiotropy analyses to compare genetic sharing with non-MDD traits.
  • Applied genomic structural equation modeling to identify factors explaining genetic covariance between symptom sets.

Main Results:

  • PHQ-9 and CIDI-SF symptom sets exhibited low to moderate genetic correlations (rg=0.43-0.87), not solely due to severity thresholds or CIDI-SF skip structure.
  • Mendelian randomization and pleiotropy analyses indicated PHQ-9 symptoms associate more with general dysphoria traits.
  • CIDI-SF's skip structure identified heterogeneity among likely MDD cases, with distinct factor structures observed via genomic structural equation modeling.

Conclusions:

  • MDD symptom assessments via PHQ-9 and CIDI-SF are not interchangeable.
  • PHQ-9 is a better index of general dysphoria.
  • CIDI-SF provides more insight into within-MDD heterogeneity.