scholarly journals Higher polygenic risk scores for schizophrenia may be suggestive of treatment non-response in major depressive disorder

2020 ◽  
Author(s):  
Giuseppe Fanelli ◽  
Francesco Benedetti ◽  
Siegfried Kasper ◽  
Alexander Kautzky ◽  
Joseph Zohar ◽  
...  
Keyword(s):  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Association Studies ◽  
Poor Response ◽  
Point Of View ◽  
Risk Scores ◽  
Genome Wide Association Studies ◽  
Major Depressive ◽  
Polygenic Risk ◽  
Resistant Depression

AbstractBackgroundUp to 60% of patients with major depressive disorder (MDD) do not respond to the first treatment with antidepressants. Response to antidepressants is a polygenic trait, although its underpinning genetics has not been fully clarified. This study aimed to investigate if Polygenic Risk Scores (PRSs) for major psychiatric disorders and neuroticism were associated with non-response or resistance to antidepressants in MDD.MethodsPRSs for bipolar disorder, MDD, neuroticism, and schizophrenia (SCZ) were computed in 1148 MDD patients recruited by the European Group for the Study of Resistant Depression. Summary statistics from largest meta-analyses of genome-wide association studies were used as base data. Patients were classified as responders, non-responders to one treatment, non-responders to two or more treatments (treatment-resistant depression or TRD). Regression analyses were adjusted for population stratification and recruitment sites.ResultsPRSs did not predict either non-response or TRD after Bonferroni correction. However, SCZ-PRS was nominally associated with non-response (p=0.003). Patients in the highest SCZ-PRS quintile were more likely to be non-responders than those in the lowest quintile (OR=2.23, 95% CI=1.21-4.10, p=0.02). Patients in the lowest SCZ-PRS quintile showed higher response rates when they did not receive augmentation with second-generation antipsychotics (SGAs), while those in the highest SCZ-PRS quintile had a poor response independently from the treatment strategy (p=0.009).ConclusionsA higher genetic liability to SCZ may reduce responsiveness to pharmacological treatment in MDD. From a clinical point of view, our results suggest that MDD patients with low SCZ-PRS do not benefit from augmentation with SGAs.

scholarly journals Polygenic interactions with environmental adversity in the aetiology of major depressive disorder

2015 ◽  
Vol 46 (4) ◽  
pp. 759-770 ◽  
Author(s):  
N. Mullins ◽  
R. A. Power ◽  
H. L. Fisher ◽  
K. B. Hanscombe ◽  
J. Euesden ◽  
...  
Keyword(s):  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Environmental Risk ◽  
Complex Traits ◽  
Risk Scores ◽  
Environment Interaction ◽  
Inverse Association ◽  
Major Depressive ◽  
Polygenic Risk ◽  
Gene Environment

BackgroundMajor depressive disorder (MDD) is a common and disabling condition with well-established heritability and environmental risk factors. Gene–environment interaction studies in MDD have typically investigated candidate genes, though the disorder is known to be highly polygenic. This study aims to test for interaction between polygenic risk and stressful life events (SLEs) or childhood trauma (CT) in the aetiology of MDD.MethodThe RADIANT UK sample consists of 1605 MDD cases and 1064 controls with SLE data, and a subset of 240 cases and 272 controls with CT data. Polygenic risk scores (PRS) were constructed using results from a mega-analysis on MDD by the Psychiatric Genomics Consortium. PRS and environmental factors were tested for association with case/control status and for interaction between them.ResultsPRS significantly predicted depression, explaining 1.1% of variance in phenotype (p= 1.9 × 10−6). SLEs and CT were also associated with MDD status (p= 2.19 × 10−4andp= 5.12 × 10−20, respectively). No interactions were found between PRS and SLEs. Significant PRSxCT interactions were found (p= 0.002), but showed an inverse association with MDD status, as cases who experienced more severe CT tended to have a lower PRS than other cases or controls. This relationship between PRS and CT was not observed in independent replication samples.ConclusionsCT is a strong risk factor for MDD but may have greater effect in individuals with lower genetic liability for the disorder. Including environmental risk along with genetics is important in studying the aetiology of MDD and PRS provide a useful approach to investigating gene–environment interactions in complex traits.

scholarly journals Relationship between the LHPP Gene Polymorphism and Resting-State Brain Activity in Major Depressive Disorder

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Lingling Cui ◽  
Xiaohong Gong ◽  
Yanqing Tang ◽  
Lingtao Kong ◽  
Miao Chang ◽  
...  
Keyword(s):  
Major Depressive Disorder ◽  
Prefrontal Cortex ◽  
Depressive Disorder ◽  
Resting State ◽  
Brain Activity ◽  
Association Studies ◽  
Neural System ◽  
Middle Temporal Gyrus ◽  
Genome Wide Association Studies ◽  
Major Depressive

A single-nucleotide polymorphism at the LHPP gene (rs35936514) has been reported in genome-wide association studies to be associated with major depressive disorder (MDD). However, the neural system effects of rs35936514 that mediate the association are unknown. The present work explores whether the LHPP rs35936514 polymorphism moderates brain regional activity in MDD. A total of 160 subjects were studied: a CC group homozygous for the C allele (23 individuals with MDD and 57 controls) and a T-carrier group carrying the high risk T allele (CT/TT genotypes; 22 MDD and 58 controls). All participants underwent resting-state functional magnetic resonance imaging (rs-fMRI) scanning. Brain activity was assessed using the amplitudes of low-frequency fluctuations (ALFF). MDD patients showed a significant increased ALFF in the left middle temporal gyrus and occipital cortex. The T-carrier group showed increased ALFF in the left superior temporal gyrus. Significant diagnosis × genotype interaction was noted in the bilateral lingual gyri, bilateral dorsal lateral prefrontal cortex (dlPFC), and left medial prefrontal cortex (mPFC) (P<0.05, corrected). Results demonstrated that MDD patients with LHPP rs35936514 CT/TT genotype may influence the regional brain activity. These findings implicate the effects of the rs35936514 variation on the neural system in MDD.

scholarly journals Dissection of major depressive disorder using polygenic risk scores for schizophrenia in two independent cohorts

2016 ◽  
Vol 6 (11) ◽  
pp. e938-e938 ◽  
Author(s):  
H C Whalley ◽  
M J Adams ◽  
L S Hall ◽  
T-K Clarke ◽  
A M Fernandez-Pujals ◽  
...  
Keyword(s):  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Risk Scores ◽  
Major Depressive ◽  
Polygenic Risk

Discriminating bipolar depression from major depressive disorder with polygenic risk scores

2020 ◽  
pp. 1-8 ◽  
Author(s):  
David T. Liebers ◽  
Mehdi Pirooznia ◽  
Andrea Ganna ◽  
Fernando S. Goes ◽  
Keyword(s):  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Clinical Features ◽  
Clinical Symptoms ◽  
Bipolar Depression ◽  
Risk Scores ◽  
Characteristic Analysis ◽  
Major Depressive ◽  
Polygenic Risk ◽  
Increased Risk

Abstract Background Although accurate differentiation between bipolar disorder (BD) and unipolar major depressive disorder (MDD) has important prognostic and therapeutic implications, the distinction is often challenging based on clinical grounds alone. In this study, we tested whether psychiatric polygenic risk scores (PRSs) improve clinically based classification models of BD v. MDD diagnosis. Methods Our sample included 843 BD and 930 MDD subjects similarly genotyped and phenotyped using the same standardized interview. We performed multivariate modeling and receiver operating characteristic analysis, testing the incremental effect of PRSs on a baseline model with clinical symptoms and features known to associate with BD compared with MDD status. Results We found a strong association between a BD diagnosis and PRSs drawn from BD (R2 = 3.5%, p = 4.94 × 10−12) and schizophrenia (R2 = 3.2%, p = 5.71 × 10−11) genome-wide association meta-analyses. Individuals with top decile BD PRS had a significantly increased risk for BD v. MDD compared with those in the lowest decile (odds ratio 3.39, confidence interval 2.19–5.25). PRSs discriminated BD v. MDD to a degree comparable with many individual symptoms and clinical features previously shown to associate with BD. When compared with the full composite model with all symptoms and clinical features PRSs provided modestly improved discriminatory ability (ΔC = 0.011, p = 6.48 × 10−4). Conclusions Our study demonstrates that psychiatric PRSs provide modest independent discrimination between BD and MDD cases, suggesting that PRSs could ultimately have utility in subjects at the extremes of the distribution and/or subjects for whom clinical symptoms are poorly measured or yet to manifest.

The current state of play on the molecular genetics of depression

2012 ◽  
Vol 43 (4) ◽  
pp. 673-687 ◽  
Author(s):  
S. Cohen-Woods ◽  
I. W. Craig ◽  
P. McGuffin
Keyword(s):  
Major Depressive Disorder ◽  
High Risk ◽  
Depressive Disorder ◽  
Association Studies ◽  
Genetic Research ◽  
Small Samples ◽  
Shared Environment ◽  
Genome Wide Association Studies ◽  
Major Depressive ◽  
Comprehensive Overview

BackgroundIt has been well established that both genes and non-shared environment contribute substantially to the underlying aetiology of major depressive disorder (MDD). A comprehensive overview of genetic research in MDD is presented.MethodPapers were retrieved from PubMed up to December 2011, using many keywords including: depression, major depressive disorder, genetics, rare variants, gene–environment, whole genome, epigenetics, and specific candidate genes and variants. These were combined in a variety of permutations.ResultsLinkage studies have yielded some promising chromosomal regions in MDD. However, there is a continued lack of consistency in association studies, in both candidate gene and genome-wide association studies (GWAS). Numerous factors may account for variable results including the use of different diagnostic approaches, small samples in early studies, population stratification, epigenetic phenomena, copy number variation (CNV), rare variation, and phenotypic and allelic heterogeneity. The conflicting results are also probably, in part, a consequence of environmental factors not being considered or controlled for.ConclusionsEach research group has to identify what issues their sample may best address. We suggest that, where possible, more emphasis should be placed on the environment in molecular behavioural genetics to identify individuals at environmental high risk in addition to genetic high risk. Sequencing should be used to identify rare and alternative variation that may act as a risk factor, and a systems biology approach including gene–gene interactions and pathway analyses would be advantageous. GWAS may require even larger samples with reliably defined (sub)phenotypes.

scholarly journals Polygenic risk scores for major depressive disorder and neuroticism as predictors of antidepressant response: meta-analysis of three treatment cohorts

2018 ◽  
Author(s):  
Joey Ward ◽  
Nicholas Graham ◽  
Rona Strawbridge ◽  
Amy Ferguson ◽  
Gregory Jenkins ◽  
...  
Keyword(s):  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Meta Analysis ◽  
Antidepressant Medication ◽  
Research Network ◽  
Risk Scores ◽  
Antidepressant Response ◽  
Major Depressive ◽  
Polygenic Risk ◽  
Therapeutic Drugs

AbstractThere are currently no reliable approaches for correctly identifying which patients with major depressive disorder (MDD) will respond well to antidepressant therapy. However, recent genetic advances suggest that Polygenic Risk Scores (PRS) could allow MDD patients to be stratified for antidepressant response. We used PRS for MDD and PRS for neuroticism as putative predictors of antidepressant response within three treatment cohorts: The Genome-based Therapeutic Drugs for Depression (GENDEP) cohort, and 2 sub-cohorts from the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomics Study PRGN-AMPS (total patient number = 783). Results across cohorts were combined via meta-analysis within a random effects model. Overall, PRS for MDD and neuroticism did not significantly predict antidepressant response but there was a consistent direction of effect, whereby greater genetic loading for both MDD (best MDD result, p < 5*10-5 MDD-PRS at 4 weeks, β = -0.019, S.E = 0.008, p = 0.01) and neuroticism (best neuroticism result, p < 0.1 neuroticism-PRS at 8 weeks, β = -0.017, S.E = 0.008, p = 0.03) were associated with less favourable response. We conclude that the PRS approach may offer some promise for treatment stratification in MDD and should now be assessed within larger clinical cohorts.

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