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Rare copy number variation in treatment-resistant major depressive disorder.

ABSTRACT: While antidepressant treatment response appears to be partially heritable, no consistent genetic associations have been identified. Large, rare copy number variants (CNVs) play a role in other neuropsychiatric diseases, so we assessed their association with treatment-resistant depression (TRD).We analyzed data from two genome-wide association studies comprising 1263 Caucasian patients with major depressive disorder. One was drawn from a large health system by applying natural language processing to electronic health records (i2b2 cohort). The second consisted of a multicenter study of sequential antidepressant treatments, Sequenced Treatment Alternatives to Relieve Depression. The Birdsuite package was used to identify rare deletions and duplications. Individuals without symptomatic remission, despite two antidepressant treatment trials, were contrasted with those who remitted with a first treatment trial.CNV data were derived for 778 subjects in the i2b2 cohort, including 300 subjects (37%) with TRD, and 485 subjects in Sequenced Treatment Alternatives to Relieve Depression cohort, including 152 (31%) with TRD. CNV burden analyses identified modest enrichment of duplications in cases (empirical p = .04 for duplications of 100-200 kilobase) and a particular deletion region spanning gene PABPC4L (empirical p = .02, 6 cases: 0 controls). Pathway analysis suggested enrichment of CNVs intersecting genes regulating actin cytoskeleton. However, none of these associations survived genome-wide correction.Contribution of rare CNVs to TRD appears to be modest, individually or in aggregate. The electronic health record-based methodology demonstrated here should facilitate collection of larger TRD cohorts necessary to further characterize these effects.

SUBMITTER: O'Dushlaine C

PROVIDER: S-EPMC4104153 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Rare copy number variation in treatment-resistant major depressive disorder.

O'Dushlaine Colm C Ripke Stephan S Ruderfer Douglas M DM Hamilton Steven P SP Fava Maurizio M Iosifescu Dan V DV Kohane Isaac S IS Churchill Susanne E SE Castro Victor M VM Clements Caitlin C CC Blumenthal Sarah R SR Murphy Shawn N SN Smoller Jordan W JW Perlis Roy H RH

Biological psychiatry 20140119 7

<h4>Background</h4>While antidepressant treatment response appears to be partially heritable, no consistent genetic associations have been identified. Large, rare copy number variants (CNVs) play a role in other neuropsychiatric diseases, so we assessed their association with treatment-resistant depression (TRD).<h4>Methods</h4>We analyzed data from two genome-wide association studies comprising 1263 Caucasian patients with major depressive disorder. One was drawn from a large health system by a ...[more]

PMID: 24529801

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Project description:BackgroundTreatment-resistant depression (TRD) refers to patients with major depressive disorder who do not remit after 2 or more antidepressant trials. TRD is common and highly debilitating, but its neurobiological basis remains poorly understood. Recent neuroimaging studies have revealed cortical connectivity gradients that dissociate primary sensorimotor areas from higher-order associative cortices. This fundamental topography determines cortical information flow and is affected by psychiatric disorders. We examined how TRD impacts gradient-based hierarchical cortical organization.MethodsIn this secondary study, we analyzed resting-state functional magnetic resonance imaging data from a mindfulness-based intervention enrolling 56 patients with TRD and 28 healthy control subjects. Using gradient extraction tools, baseline measures of cortical gradient dispersion within and between functional brain networks were derived, compared across groups, and associated with graph theoretical measures of network topology. In patients, correlation analyses were used to associate measures of cortical gradient dispersion with clinical measures of anxiety, depression, and mindfulness at baseline and following the intervention.ResultsCortical gradient dispersion was reduced within major intrinsic brain networks in patients with TRD. Reduced cortical gradient dispersion correlated with increased network degree assessed through graph theory-based measures of network topology. Lower dispersion among default mode, control, and limbic network nodes related to baseline levels of trait anxiety, depression, and mindfulness. Patients' baseline limbic network dispersion predicted trait anxiety scores 24 weeks after the intervention.ConclusionsOur findings provide preliminary support for widespread alterations in cortical gradient architecture in TRD, implicating a significant role for transmodal and limbic networks in mediating depression, anxiety, and lower mindfulness in patients with TRD.

Dataset Information

Rare copy number variation in treatment-resistant major depressive disorder.

Publications

Rare copy number variation in treatment-resistant major depressive disorder.

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