To Örebro University

Background: Major depressive disorders (MDD) is a common disorder with lifetime prevalence of ∼20%. MDD is phenotypically and genetically heterogenous. Estimated heritability of the disorder ranged between 30% and 50%. Heterogeneity hinders the discovery of genetic risk factors as well as treatment optimization of MDD. Some previous studies demonstrated the heterogeneity of MDD by comparing heritability and genetic correlation of MDD subtypes based on sexes, age at onset, recurrence, vegetative symptoms (atypical MDD). However, the results are inconclusive, and we still lack a comprehensive evidence of MDD subgroups heterogeneity.

In our previous study (https://doi.org/10.1101/2021.03.05.21252911), we investigated major depression heterogeneity using genetic data in the UK Biobank cohort. The results indicated that major depression subtypes were divergent in their genetic architectures.

Here we aim to unravel heterogeneity in key clinical indicators of MDD by estimating heritability (h2), and genetic correlations (rg) using diagnostic data from the Swedish population.

Methods: Using the Swedish registers, we included ∼1.5 million individuals who were born in Sweden between 1977-1993. MDD cases (ICD-10 codes: F32, F33) were identified from the Swedish patients register. We defined 16 MDD clinical subgroups within 8 categories, severity (severe vs mild/moderate cases), anxiety comorbidity (MDD with vs without comorbid anxiety disorder), age at onset (early onset vs late onset), recurrence (recurrent vs single episode), suicidality (suicidal vs non-suicidal MDD), impairment (MDD with vs without impairment), disability (measured by MDD with vs without early retirement), and care unit (inpatient vs outpatient cases).

We used structural equation modelling to estimate the proportion of genetic contribution to the liability of MDD subgroups (i.e., heritability), and the variance due to genetic contribution shared between 2 traits (i.e., genetic correlation). We estimated three components, additive genetic (A), shared environment (C), and unique environment (E) by contrasting full siblings and maternal half siblings.

Results: Of the entire cohort, ∼88,000 MDD cases (∼5.9%) were identified. Estimated heritability of MDD was ∼40% which agreed with previous studies.

Overall, subgroups with more severe manifestation tend to be more heritable compared with the subgroups in the same categories. MDD with comorbid anxiety disorder, early onset, recurrent episodes, suicide, and early retirement had higher heritability than the counterpart subgroups. Estimated heritability ranged between 19.6% (for late onset MDD) and 51.5% (for MDD with early retirement).

All estimates for genetic correlation were lower than one which indicate non-identical genetic contribution of the subgroups within the same category. Three of the eight studied subgroup categories (suicidality, impairment, disability) showed genetic correlations (range 0.6-0.7) that significantly differ from one.

Discussion: Our study suggested that heterogeneity of MDD can be demonstrated by clinical subgroups. The tendency of divergence in heritability, and the genetic correlations are lower than one in many subgroup categories indicated that the genetic profile of those subgroups are partially distinct. Finally, our results suggested that some clinical indices including suicidality, impairment and disability, may index genetic heterogeneity of MDD better than others indices.