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. 2016 Apr;21(4):516-22.
doi: 10.1038/mp.2015.86. Epub 2015 Jun 30.

Polygenic Dissection of Major Depression Clinical Heterogeneity

Free PMC article

Polygenic Dissection of Major Depression Clinical Heterogeneity

Y Milaneschi et al. Mol Psychiatry. .
Free PMC article


The molecular mechanisms underlying major depressive disorder (MDD) are largely unknown. Limited success of previous genetics studies may be attributable to heterogeneity of MDD, aggregating biologically different subtypes. We examined the polygenic features of MDD and two common clinical subtypes (typical and atypical) defined by symptom profiles in a large sample of adults with established diagnoses. Data were from 1530 patients of the Netherlands Study of Depression and Anxiety (NESDA) and 1700 controls mainly from the Netherlands Twin Register (NTR). Diagnoses of MDD and its subtypes were based on DSM-IV symptoms. Genetic overlap of MDD and subtypes with psychiatric (MDD, bipolar disorder, schizophrenia) and metabolic (body mass index (BMI), C-reactive protein, triglycerides) traits was evaluated via genomic profile risk scores (GPRS) generated from meta-analysis results of large international consortia. Single nucleotide polymorphism (SNP)-heritability of MDD and subtypes was also estimated. MDD was associated with psychiatric GPRS, while no association was found for GPRS of metabolic traits. MDD subtypes had differential polygenic signatures: typical was strongly associated with schizophrenia GPRS (odds ratio (OR)=1.54, P=7.8e-9), while atypical was additionally associated with BMI (OR=1.29, P=2.7e-4) and triglycerides (OR=1.21, P=0.006) GPRS. Similar results were found when only the highly discriminatory symptoms of appetite/weight were used to define subtypes. SNP-heritability was 32% for MDD, 38% and 43% for subtypes with, respectively, decreased (typical) and increased (atypical) appetite/weight. In conclusion, MDD subtypes are characterized by partially distinct polygenic liabilities and may represent more homogeneous phenotypes. Disentangling MDD heterogeneity may help the psychiatric field moving forward in the search for molecular roots of depression.

Conflict of interest statement

Potential Conflicts of Interest: The authors do not have any conflict of interest in the publication of the manuscript.


Figure 1
Figure 1
Associations of GPRS for psychiatric and metabolic traits with MDD and subtypes (severe typical and severe atypical). Results (Odds Ratios and 95% Confidence Intervals) from binary (MDD: 1,530 cases) and multinomial (subtypes: 228 severe typical, 251 severe atypical) logistic regressions (reference: 1,700 controls) adjusted for year of birth, gender and three ancestry-informative principal components
Figure 2
Figure 2
Proportions of variance explained on the liability scale for MDD and subtypes (severe typical and severe atypical) by the GPRS for psychiatric and metabolic traits. Explained variance based on R2 coefficient proposed by Lee at al.(39); prevalences for linear transformation into liability scale: MDD K=0.18, severe typical K=0.035, severe atypical K=0.038

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