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

BACKGROUND: Symptoms of major depressive disorder (MDD) are commonly assessed using self-rating instruments like the Patient Health Questionnaire-9 (PHQ-9) (current symptoms) and the Composite International Diagnostic Interview Short-Form (CIDI-SF) (worst-episode symptoms). We performed a systematic comparison between them for their genetic architecture and utility in investigating MDD heterogeneity. METHODS: Using data from the UK Biobank (n = 41,948-109,417), we assessed the single nucleotide polymorphism heritability and genetic correlation (rg) of both sets of MDD symptoms. We further compared their rg with non-MDD traits and used Mendelian randomization to assess whether either set of symptoms has more genetic sharing with non-MDD traits. We also assessed how specific each set of symptoms is to MDD using the metric polygenic risk score pleiotropy. Finally, we used genomic structural equation modeling to identify factors that explain the genetic covariance between each set of symptoms. RESULTS: Corresponding symptoms reported through the PHQ-9 and CIDI-SF have low to moderate genetic correlations (rg = 0.43-0.87), and this cannot be fully attributed to different severity thresholds or the use of a skip structure in the CIDI-SF. Both Mendelian randomization and polygenic risk score pleiotropy analyses showed that PHQ-9 symptoms are more associated with traits that reflect general dysphoria, whereas the skip structure in the CIDI-SF allows for the identification of heterogeneity among likely MDD cases. Finally, the 2 sets of symptoms showed different factor structures in genomic structural equation modeling, reflective of their genetic differences. CONCLUSIONS: MDD symptoms assessed using the PHQ-9 and CIDI-SF are not interchangeable; the former better indexes general dysphoria, while the latter is more informative about within-MDD heterogeneity.

Polygenic analyses show important differences between MDD symptoms collected using PHQ9 and CIDI-SF.

Symptoms of Major Depressive Disorder (MDD) are commonly assessed using self-rating instruments like the Patient Health Questionnaire 9 (PHQ9, for current symptoms), and the Composite International Diagnostic Interview Short-Form (CIDI-SF, for lifetime worst-episode symptoms). Using data from the UKBiobank, we show that corresponding symptoms endorsed through PHQ9 and CIDI-SF have low to moderate genetic correlations (rG=0.43-0.87), and this cannot be fully attributed to different severity thresholds or the use of a skip-structure in CIDI-SF. Through a combination of Mendelian Randomization (MR) and polygenic prediction analyses, we find that PHQ9 symptoms are more associated with traits which reflect general dysphoria, while the skip-structure in CIDI-SF allows for the identification of heterogeneity among likely MDD cases. This has important implications on factor analyses performed on their respective genetic covariance matrices for the purpose of identification of genetic factors behind MDD symptom dimensions and heterogeneity.