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Additive genetic contribution to symptom dimensions in major depressive disorder.

ABSTRACT: Major depressive disorder (MDD) is a phenotypically heterogeneous disorder with a complex genetic architecture. In this study, genomic-relatedness-matrix restricted maximum-likelihood analysis (GREML) was used to investigate the extent to which variance in depression symptoms/symptom dimensions can be explained by variation in common single nucleotide polymorphisms (SNPs) in a sample of individuals with MDD (N = 1,558) who participated in the National Institute of Mental Health Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. A principal components analysis of items from the Hamilton Rating Scale for Depression (HRSD) obtained prior to treatment revealed 4 depression symptom components: (a) appetite, (b) core depression symptoms (e.g., depressed mood, anhedonia), (c) insomnia, and (d) anxiety. These symptom dimensions were associated with SNP-based heritability (hSNP2) estimates of 30%, 14%, 30%, and 5%, respectively. Results indicated that the genetic contribution of common SNPs to depression symptom dimensions were not uniform. Appetite and insomnia symptoms in MDD had a relatively strong genetic contribution whereas the genetic contribution was relatively small for core depression and anxiety symptoms. While in need of replication, these results suggest that future gene discovery efforts may strongly benefit from parsing depression into its constituent parts. (PsycINFO Database Record

SUBMITTER: Pearson R

PROVIDER: S-EPMC4852390 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Additive genetic contribution to symptom dimensions in major depressive disorder.

Pearson Rahel R Palmer Rohan H C RH Brick Leslie A LA McGeary John E JE Knopik Valerie S VS Beevers Christopher G CG

Journal of abnormal psychology 20160501 4

Major depressive disorder (MDD) is a phenotypically heterogeneous disorder with a complex genetic architecture. In this study, genomic-relatedness-matrix restricted maximum-likelihood analysis (GREML) was used to investigate the extent to which variance in depression symptoms/symptom dimensions can be explained by variation in common single nucleotide polymorphisms (SNPs) in a sample of individuals with MDD (N = 1,558) who participated in the National Institute of Mental Health Sequenced Treatme ...[more]

PMID: 27124715

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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.

Project description:Imaging techniques are a potentially powerful method of identifying phenotypes that are associated with, or are indicative of, a vulnerability to developing major depressive disorder (MDD). Here we identify seven promising MDD-associated traits identified by magnetic resonance imaging (MRI) or positron emission tomography (PET). We evaluate whether these traits are state-independent, heritable endophenotypes, or state-dependent phenotypes that may be useful markers of treatment efficacy. In MDD, increased activity of the amygdala in response to negative stimuli appears to be a mood-congruent phenomenon, and is likely moderated by the 5-HT transporter gene (SLC6A4) promoter polymorphism (5-HTTLPR). Hippocampal volume loss is characteristic of elderly or chronically-ill samples and may be impacted by the val66met brain-derived neurotrophic factor (BDNF) gene variant and the 5-HTTLPR SLC6A4 polymorphism. White matter pathology is salient in elderly MDD cohorts but is associated with cerebrovascular disease, and is unlikely to be a useful marker of a latent MDD diathesis. Increased blood flow or metabolism of the subgenual anterior cingulate cortex (sgACC), together with gray matter volume loss in this region, is a well-replicated finding in MDD. An attenuation of the usual pattern of fronto-limbic connectivity, particularly a decreased temporal correlation in amygdala-anterior cingulate cortex (ACC) activity, is another MDD-associated trait. Concerning neuroreceptor PET imaging, decreased 5-HT(1A) binding potential in the raphe, medial temporal lobe, and medial prefrontal cortex (mPFC) has been strongly associated with MDD, and may be impacted by a functional single nucleotide polymorphism in the promoter region of the 5-HT(1A) gene (HTR1A: -1019 C/G; rs6295). Potentially indicative of inter-study variation in MDD etiology or mood state, both increased and decreased binding potential of the 5-HT transporter has been reported. Challenges facing the field include the problem of phenotypic and etiological heterogeneity, technological limitations, the confounding effects of medication, and non-disease related inter-individual variation in brain morphology and function. Further advances are likely as epigenetic, copy-number variant, gene-gene interaction, and genome-wide association (GWA) approaches are brought to bear on imaging data.

Project description:Background: Sleep disturbances, such as early wakening, are frequently observed in patients with major depressive disorder (MDD). The suprachiasmatic nuclei (SCN), which controls circadian rhythm, is innervated by the raphe nucleus, a region where Tryptophan hydroxylase-2 (TPH-2) gene is primarily expressed. Although TPH-2 is often implicated in the pathophysiology of depression, few studies have applied a genetic and imaging technique to investigate the mechanism of early wakening symptom in MDD. We hypothesized that TPH-2 variants could influence the function of SCN in MDD patients with early wakening symptom. Methods: One hundred and eighty five MDD patients (62 patients without early wakening and 123 patients with early wakening) and 64 healthy controls participated in this study. Blood samples were collected and genotyping of rs4290270, rs4570625, rs11178998, rs7305115, rs41317118, and rs17110747 were performed by next-generation sequencing (NGS) technology. Logistic regression model was employed for genetic data analysis using the PLINK software. Based on the allele type, rs4290270, which was significant in the early wakening MDD group, participants were categorized into two groups (A allele and T carrier). All patients underwent whole brain resting-state functional magnetic resonance imaging (rs-fMRI) scanning and a voxel-wise functional connectivity comparison was performed between the groups. Results: rs4290270 was significantly linked to MDD patients who exhibited early wakening symptom. The functional connectivities of the right SCN with the right fusiform gyrus and right middle frontal gyrus were increased in the T carrier group compared to the A allele group. In addition, the functional connectivities of the left SCN with the right lingual gyrus and left calcarine sulcus were decreased in the T carrier group compared to the A allele group. Conclusion: These findings suggested that the TPH-2 gene variant, rs4290270, affected the circadian regulating function of SCN. The altered functional connectivities, observed between the SCN and right fusiform gyrus, right middle frontal gyrus, the right lingual gyrus and left calcarine sulcus, could highlight the neural mechanism by which SCN induces sleep-related circadian disruption in T carrier MDD patients. Hence, rs4290270 could potentially serve as a reliable biomarker to identify MDD patients with early wakening symptom.

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Additive genetic contribution to symptom dimensions in major depressive disorder.

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Additive genetic contribution to symptom dimensions in major depressive disorder.

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