Polygenic Analyses Show Important Differences Between Major Depressive Disorder Symptoms Measured Using Various Instruments
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Polygenic Analyses Show Important Differences Between Major Depressive Disorder Symptoms Measured Using Various Instruments. / Huang, Lianyun; Tang, Sonja; Rietkerk, Jolien; Appadurai, Vivek; Krebs, Morten Dybdahl; Schork, Andrew J.; Werge, Thomas; Zuber, Verena; Kendler, Kenneth; Cai, Na.
In: Biological Psychiatry, 2024.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Polygenic Analyses Show Important Differences Between Major Depressive Disorder Symptoms Measured Using Various Instruments
AU - Huang, Lianyun
AU - Tang, Sonja
AU - Rietkerk, Jolien
AU - Appadurai, Vivek
AU - Krebs, Morten Dybdahl
AU - Schork, Andrew J.
AU - Werge, Thomas
AU - Zuber, Verena
AU - Kendler, Kenneth
AU - Cai, Na
N1 - Publisher Copyright: © 2023 Society of Biological Psychiatry
PY - 2024
Y1 - 2024
N2 - 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.
AB - 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.
KW - Depression
KW - Factor analysis
KW - Genetics
KW - GWAS
KW - Heterogeneity
KW - Symptoms
U2 - 10.1016/j.biopsych.2023.11.021
DO - 10.1016/j.biopsych.2023.11.021
M3 - Journal article
C2 - 38056704
AN - SCOPUS:85184248328
JO - Biological Psychiatry
JF - Biological Psychiatry
SN - 0006-3223
ER -
ID: 382988157