Enriched pathways for major depressive disorder identified from a genome-wide association study

AbstractBackgroundCircadian rhythms are fundamental to health and are particularly important for mental wellbeing. Disrupted rhythms of rest and activity are recognised as risk factors for major depressive disorder and bipolar disorder.MethodsWe conducted a genome-wide association study (GWAS) of low relative amplitude (RA), an objective measure of circadian rhythmicity derived from the accelerometer data of 71 500 UK Biobank participants. Polygenic risk scores (PRS) for low RA were used to investigate potential associations with psychiatric phenotypes.OutcomesTwo independent genetic loci were associated with low RA, within genomic regions for Neurofascin (NFASC) and Solute Carrier Family 25 Member 17 (SLC25A17). A secondary GWAS of RA as a continuous measure identified a locus within Meis Homeobox 1 (MEIS1). There were no significant genetic correlations between low RA and any of the psychiatric phenotypes assessed. However, PRS for low RA was significantly associated with mood instability across multiple PRS thresholds (at PRS threshold 0·05: OR=1·02, 95% CI=1·01-1·02, p=9·6×10−5), and with major depressive disorder (at PRS threshold 0·1: OR=1·03, 95% CI=1·01-1·05, p=0·025) and neuroticism (at PRS threshold 0·5: Beta=0·02, 95% CI=0·007-0·04, p=0·021).InterpretationOverall, our findings contribute new knowledge on the complex genetic architecture of circadian rhythmicity and suggest a putative biological link between disrupted circadian function and mood disorder phenotypes, particularly mood instability, but also major depressive disorder and neuroticism.

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Genome-wide association study of recurrent major depressive disorder in two European case–control cohorts

Molecular Psychiatry ◽

10.1038/mp.2008.131 ◽

2008 ◽

Vol 15 (6) ◽

pp. 589-601 ◽

Cited By ~ 171

Author(s):

P Muglia ◽

F Tozzi ◽

N W Galwey ◽

C Francks ◽

R Upmanyu ◽

...

Keyword(s):

Major Depressive Disorder ◽

Depressive Disorder ◽

Association Study ◽

Genome Wide Association Study ◽

Case Control ◽

Genome Wide Association ◽

Major Depressive ◽

Genome Wide ◽

Recurrent Major Depressive Disorder

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Genome-Wide Significance for PCLO as a Gene for Major Depressive Disorder

Twin Research and Human Genetics ◽

10.1017/thg.2017.30 ◽

2017 ◽

Vol 20 (4) ◽

pp. 267-270 ◽

Cited By ~ 14

Author(s):

Hamdi Mbarek ◽

Yuri Milaneschi ◽

Jouke-Jan Hottenga ◽

Lannie Ligthart ◽

Eco J. C. de Geus ◽

...

Keyword(s):

Major Depressive Disorder ◽

Depressive Disorder ◽

Genome Wide Association Study ◽

Major Depressive ◽

Significance Level ◽

Functional Studies ◽

Genome Wide ◽

A Genome ◽

Genome Wide Significance

In 2009, the first genome-wide association study (GWAS) for major depressive disorder (MDD) highlighted an association with PCLO locus on chromosome 7, although not reaching genome-wide significance level. In the present study, we revisited the original GWAS after increasing the overall sample size and the number of interrogated SNPs. In an analysis comparing 1,942 cases with lifetime diagnosis of MDD and 4,565 controls, PCLO showed a genome-wide significant association with MDD at SNP (rs2715157, p = 2.91 × 10−8) and gene-based (p = 1.48 × 10−7) level. Our results confirm the potential role of the PCLO gene in MDD, which is worth further replication and functional studies.

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Using genetic drug-target networks to develop new drug hypotheses for major depressive disorder

10.1101/304113 ◽

2018 ◽

Author(s):

Héléna A Gaspar ◽

Zachary Gerring ◽

Christopher Hübel ◽

Christel M Middeldorp ◽

Eske M Derks ◽

...

Keyword(s):

Major Depressive Disorder ◽

Depressive Disorder ◽

Drug Target ◽

Model Systems ◽

Genome Wide Association ◽

Multiple Testing Correction ◽

Major Depressive ◽

Expression Levels ◽

Genome Wide ◽

A Genome

AbstractThe major depressive disorder (MDD) working group of the Psychiatric Genomics Consortium (PGC) has published a genome-wide association study (GWAS) for MDD in 130,664 cases, identifying 44 risk variants. We used these results to investigate potential drug targets and repurposing opportunities. We built easily interpretable bipartite drug-target networks integrating interactions between drugs and their targets, genome-wide association statistics and genetically predicted expression levels in different tissues, using our online tool Drug Targetor (drugtargetor.com). We also investigated drug-target relationships and drug effects on gene expression that could be impacting MDD. MAGMA was used to perform pathway analyses and S-PrediXcan to investigate the directionality of tissue-specific expression levels in patients vs. controls. Outside the major histocompatibility complex (MHC) region, 25 druggable genes were significantly associated with MDD after multiple testing correction, and 19 were suggestively significant. Several drug classes were significantly enriched, including monoamine reuptake inhibitors, sex hormones, antipsychotics and antihistamines, indicating an effect on MDD and potential repurposing opportunities. These findings require validation in model systems and clinical examination, but also show that GWAS may become a rich source of new therapeutic hypotheses for MDD and other psychiatric disorders that need new – and better – treatment options.

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Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depressive disorder

10.1101/167577 ◽

2017 ◽

Cited By ~ 19

Author(s):

Naomi R Wray ◽

Stephan Ripke ◽

Manuel Mattheisen ◽

Maciej Trzaskowski ◽

Enda M Byrne ◽

...

Keyword(s):

Major Depressive Disorder ◽

Depressive Disorder ◽

Educational Attainment ◽

Body Mass ◽

Genetic Risk ◽

Genome Wide Association ◽

Continuous Measure ◽

Major Depressive ◽

Genome Wide ◽

A Genome

Major depressive disorder (MDD) is a notably complex illness with a lifetime prevalence of 14%.1 It is often chronic or recurrent and is thus accompanied by considerable morbidity, excess mortality, substantial costs, and heightened risk of suicide.2-7 MDD is a major cause of disability worldwide.8 We conducted a genome-wide association (GWA) meta-analysis in 130,664 MDD cases and 330,470 controls, and identified 44 independent loci that met criteria for statistical significance. We present extensive analyses of these results which provide new insights into the nature of MDD. The genetic findings were associated with clinical features of MDD, and implicated prefrontal and anterior cingulate cortex in the pathophysiology of MDD (regions exhibiting anatomical differences between MDD cases and controls). Genes that are targets of antidepressant medications were strongly enriched for MDD association signals (P=8.5×10−10), suggesting the relevance of these findings for improved pharmacotherapy of MDD. Sets of genes involved in gene splicing and in creating isoforms were also enriched for smaller MDD GWA P-values, and these gene sets have also been implicated in schizophrenia and autism. Genetic risk for MDD was correlated with that for many adult and childhood onset psychiatric disorders. Our analyses suggested important relations of genetic risk for MDD with educational attainment, body mass, and schizophrenia: the genetic basis of lower educational attainment and higher body mass were putatively causal for MDD whereas MDD and schizophrenia reflected a partly shared biological etiology. All humans carry lesser or greater numbers of genetic risk factors for MDD, and a continuous measure of risk underlies the observed clinical phenotype. MDD is not a distinct entity that neatly demarcates normalcy from pathology but rather a useful clinical construct associated with a range of adverse outcomes and the end result of a complex process of intertwined genetic and environmental effects. These findings help refine and define the fundamental basis of MDD.

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