Dataset Information

Genetic Contribution to the Heterogeneity of Major Depressive Disorder: Evidence From a Sibling-Based Design Using Swedish National Registers.

ABSTRACT:

Objective

Major depressive disorder (MDD) is highly heterogeneous. Standard typology partly captures the disorder's symptomatic heterogeneity, although whether it adequately captures etiological heterogeneity remains elusive. The aim of this study was to investigate the genetic characterization of MDD heterogeneity.

Methods

Using Swedish patient register data on 1.5 million individuals, the authors identified 46,255 individuals with specialist-diagnosed MDD. Eighteen subgroups were identified based on nine comparison groups defined by clinical and psychosocial features, including severity, recurrence, comorbidities, suicidality, impairment, disability, care unit, and age at diagnosis. A sibling-based design and classic quantitative genetic models were applied to estimate heritability of MDD subgroups and genetic correlations between subgroups.

Results

Estimates of heritability ranged from 30.5% to 58.3% across subgroups. The disabled and youth-onset subgroups showed significantly higher heritability (55.1%-58.3%) than the overall MDD sample (45.3%, 95% CI=43.0-47.5), and the subgroups with single-episode MDD and without psychiatric comorbidity showed significantly lower estimates (30.5%-34.4%). Estimates of genetic correlations between the subgroups within comparison groups ranged from 0.33 to 0.90. Seven of nine genetic correlations were significantly smaller than 1, suggesting differences in underlying genetic architecture. These results were largely consistent with previous work using genomic data.

Conclusions

The findings of differential heritability and partially distinct genetic components in subgroups provide important insights into the genetic heterogeneity of MDD and a deeper etiological understanding of MDD clinical subgroups.

SUBMITTER: Nguyen TD

PROVIDER: S-EPMC10632940 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Publications

Genetic Contribution to the Heterogeneity of Major Depressive Disorder: Evidence From a Sibling-Based Design Using Swedish National Registers.

Nguyen Thuy-Dung TD Kowalec Kaarina K Pasman Joëlle J Larsson Henrik H Lichtenstein Paul P Dalman Christina C Sullivan Patrick F PF Kuja-Halkola Ralf R Lu Yi Y

The American journal of psychiatry 20230830 10

<h4>Objective</h4>Major depressive disorder (MDD) is highly heterogeneous. Standard typology partly captures the disorder's symptomatic heterogeneity, although whether it adequately captures etiological heterogeneity remains elusive. The aim of this study was to investigate the genetic characterization of MDD heterogeneity.<h4>Methods</h4>Using Swedish patient register data on 1.5 million individuals, the authors identified 46,255 individuals with specialist-diagnosed MDD. Eighteen subgroups wer ...[more]

PMID: 37644812

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Project description:BackgroundMajor depressive disorder (MDD) is a common psychiatric disorder associated with a high disease burden. This study gives a comprehensive overview of the prevalence, outcomes, treatment, and genetic epidemiology of MDD within and across the Scandinavian countries.MethodsThis study has aimed to assess and compare across Norway, Denmark, and Sweden 1) the prevalence and trajectories of MDD and comorbidity, 2) outcomes and treatment, and 3) heritability (Denmark and Sweden only). The analyses leveraged data on 272,944 MDD cases (and 6.2 million non-cases) from Norway, Sweden, and Denmark in specialist care in national longitudinal health registers covering 1975-2013. Relying on harmonized public data global comparisons of socioeconomic and health metrics were performed to assess to what extent findings are generalizable.FindingsMDD ranked among the most prevalent psychiatric disorders. For many cases, the disorder trajectory was severe, with varying proportions experiencing recurrence, developing comorbid disorders, requiring inpatient treatment, or dying of suicide. Important country differences in specialist care prevalence and treatment were observed. Heritability estimates were moderate (35-48%). In terms of socioeconomic and health indices, the Scandinavian nations were comparable to one another and grouped with other Western nations.InterpretationThe Scandinavian countries were similar with regards to MDD epidemiological measures, but we show that differences in health care organization need to be taken into consideration when comparing countries. This study demonstrates the utility of using comprehensive population-wide registry data, outlining possibilities for other applications. The findings will be of use to policy makers for developing better prevention and intervention strategies.FundingSwedish Research Council (Vetenskapsrådet, award D0886501 to PFS), US National Institutes of Mental HealthR01 MH123724 (to PFS), European Union's Horizon 2020 Research and Innovation Program (847776 and 964874, to OA) and European Research Council grant (grant agreement ID 101042183, to YL).

Project description:Background: Major Depressive Disorder (MDD) is a moderately heritable disorder with a high lifetime prevalence. At present, laboratory blood tests to support MDD diagnosis are not available. Methods: We used a classifier approach on blood gene expression profiles of a unique set of non-medicated subjects (MDD patients and controls) to select genes of which expression is predictive for disease status. To reveal blood gene expression changes related to MDD disease, we applied a powerful ex vivo stimulus to the blood, i.e. incubation with lipopolysaccharide (LPS; 10 ng/ml blood). Results: Based on LPS-stimulated blood gene expression using whole-genome microarrays in 42 subjects (primary cohort; 21 MDD patients (mean age 42.3 years), 21 healthy controls (mean age 41.9 years)), we identified a set of genes (CAPRIN1, CLEC4A, KRT23, MLC1, PLSCR1, PROK2, ZBTB16) that serves as a molecular signature of MDD. These findings were validated for the primary cohort using an independent quantitative PCR method (P = 0.007). The difference between depressive patients and controls was confirmed (P = 0.019) in a replication cohort of 13 patients with MDD (mean age 42.8 years) and 14 controls (mean age 45.6 years). The MDD-signature score comprised of expression levels of 7 genes could discriminate depressive patients from controls with sensitivity of 76.9% and specificity of 71.8%. Conclusions: We show for the first time that molecular analysis of stimulated blood cells can be used as an endophenotype for MDD diagnosis, which is a milestone in establishing biomarkers for neuropsychiatric disorders with moderate heritability in general. Our results may provide a new entry point for following and predicting treatment outcome, as well as prediction of severity and recurrence of MDD. In total, 33 MDD patients and 34 healthy controls were analyzed using basal gene expression in whole blood, and gene expression from whole blood that was stimulated with LPS for 5-6 h, using microarrays. Patients were arbitrarily selected from all patients to serve as primary cohort (nMDD = 21 (MDD01-MDD21); nControls = 21 (Con01-Con21)), or replication cohort (nMDD = 12 (MDD22-MDD35); nControls = 13 (Con22-Con37)) using microarrays. This submission does not include Samples CON21_LPS or CON30_LPS.

Dataset Information

Genetic Contribution to the Heterogeneity of Major Depressive Disorder: Evidence From a Sibling-Based Design Using Swedish National Registers.

Objective

Methods

Results

Conclusions

Publications

Genetic Contribution to the Heterogeneity of Major Depressive Disorder: Evidence From a Sibling-Based Design Using Swedish National Registers.

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