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Genetic effects influencing risk for major depressive disorder in China and Europe.

ABSTRACT: Major depressive disorder (MDD) is a common, complex psychiatric disorder and a leading cause of disability worldwide. Despite twin studies indicating its modest heritability (~30-40%), extensive heterogeneity and a complex genetic architecture have complicated efforts to detect associated genetic risk variants. We combined single-nucleotide polymorphism (SNP) summary statistics from the CONVERGE and PGC studies of MDD, representing 10?502 Chinese (5282 cases and 5220 controls) and 18?663 European (9447 cases and 9215 controls) subjects. We determined the fraction of SNPs displaying consistent directions of effect, assessed the significance of polygenic risk scores and estimated the genetic correlation of MDD across ancestries. Subsequent trans-ancestry meta-analyses combined SNP-level evidence of association. Sign tests and polygenic score profiling weakly support an overlap of SNP effects between East Asian and European populations. We estimated the trans-ancestry genetic correlation of lifetime MDD as 0.33; female-only and recurrent MDD yielded estimates of 0.40 and 0.41, respectively. Common variants downstream of GPHN achieved genome-wide significance by Bayesian trans-ancestry meta-analysis (rs9323497; log10 Bayes Factor=8.08) but failed to replicate in an independent European sample (P=0.911). Gene-set enrichment analyses indicate enrichment of genes involved in neuronal development and axonal trafficking. We successfully demonstrate a partially shared polygenic basis of MDD in East Asian and European populations. Taken together, these findings support a complex etiology for MDD and possible population differences in predisposing genetic factors, with important implications for future genetic studies.

SUBMITTER: Bigdeli TB

PROVIDER: S-EPMC5404611 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Genetic effects influencing risk for major depressive disorder in China and Europe.

Bigdeli T B TB Ripke S S Peterson R E RE Trzaskowski M M Bacanu S-A SA Abdellaoui A A Andlauer T F M TF Beekman A T F AT Berger K K Blackwood D H R DH Boomsma D I DI Breen G G Buttenschøn H N HN Byrne E M EM Cichon S S Clarke T-K TK Couvy-Duchesne B B Craddock N N de Geus E J C EJ Degenhardt F F Dunn E C EC Edwards A C AC Fanous A H AH Forstner A J AJ Frank J J Gill M M Gordon S D SD Grabe H J HJ Hamilton S P SP Hardiman O O Hayward C C Heath A C AC Henders A K AK Herms S S Hickie I B IB Hoffmann P P Homuth G G Hottenga J-J JJ Ising M M Jansen R R Kloiber S S Knowles J A JA Lang M M Li Q S QS Lucae S S MacIntyre D J DJ Madden P A F PA Martin N G NG McGrath P J PJ McGuffin P P McIntosh A M AM Medland S E SE Mehta D D Middeldorp C M CM Milaneschi Y Y Montgomery G W GW Mors O O Müller-Myhsok B B Nauck M M Nyholt D R DR Nöthen M M MM Owen M J MJ Penninx B W J H BW Pergadia M L ML Perlis R H RH Peyrot W J WJ Porteous D J DJ Potash J B JB Rice J P JP Rietschel M M Riley B P BP Rivera M M Schoevers R R Schulze T G TG Shi J J Shyn S I SI Smit J H JH Smoller J W JW Streit F F Strohmaier J J Teumer A A Treutlein J J Van der Auwera S S van Grootheest G G van Hemert A M AM Völzke H H Webb B T BT Weissman M M MM Wellmann J J Willemsen G G Witt S H SH Levinson D F DF Lewis C M CM Wray N R NR Flint J J Sullivan P F PF Kendler K S KS

Translational psychiatry 20170328 3

Major depressive disorder (MDD) is a common, complex psychiatric disorder and a leading cause of disability worldwide. Despite twin studies indicating its modest heritability (~30-40%), extensive heterogeneity and a complex genetic architecture have complicated efforts to detect associated genetic risk variants. We combined single-nucleotide polymorphism (SNP) summary statistics from the CONVERGE and PGC studies of MDD, representing 10 502 Chinese (5282 cases and 5220 controls) and 18 663 Europe ...[more]

PMID: 28350396

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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.

Dataset Information

Genetic effects influencing risk for major depressive disorder in China and Europe.

Publications

Genetic effects influencing risk for major depressive disorder in China and Europe.

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