RESTING STATE FUNCTIONAL DYNAMICS IN MAJOR DEPRESSIVE DISORDER AND RELATIONSHIP WITH POLYGENIC RISK LOADING: EVIDENCE FROM UK BIOBANK

2019 ◽  
Vol 29 ◽  
pp. S907-S908
Author(s):  
Xueyi Shen ◽  
Simon Cox ◽  
Jude Gibson ◽  
Mark Adams ◽  
David Howard ◽  
...  
Keyword(s):  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Resting State ◽  
Uk Biobank ◽  
Major Depressive ◽  
Polygenic Risk ◽  
Functional Dynamics

scholarly journals Dissection of Major Depressive Disorder using polygenic risk scores for Schizophrenia in two independent cohort

2016 ◽  
Author(s):  
HC Whalley ◽  
MJ Adams ◽  
LS Hall ◽  
T-K Clarke ◽  
AM Fernandez-Pujals ◽  
...  
Keyword(s):  
Major Depressive Disorder ◽  
Psychological Distress ◽  
Depressive Disorder ◽  
Genetic Risk ◽  
Large Population ◽  
Case Control ◽  
Risk Scores ◽  
Uk Biobank ◽  
Major Depressive ◽  
Polygenic Risk

AbstractMajor depressive disorder (MDD) is known for its substantial clinical and suspected causal heterogeneity. It is characterised by low mood, psychomotor slowing, and increased levels of the personality trait neuroticism; factors which are also associated with schizophrenia (SCZ). It is possible that some cases of MDD may have a substantial genetic loading for SCZ. A sign of the presence of SCZ-like MDD sub-groups would be indicated by an interaction between MDD status and polygenic risk of SCZ on cognitive, personality and mood measures. In the current study, we hypothesised that higher SCZ-polygenic risk would define larger MDD case-control differences in cognitive ability, and smaller differences in distress and neuroticism. Polygenic risk scores (PGRS) for SCZ and their association with cognitive variables, neuroticism, mood, and psychological distress were estimated in a large population-based cohort (Generation Scotland: Scottish Family Health Study, GS:SFHS). Individuals were divided into those with, and without, depression (n=2587 & n=16,764 respectively) to test whether there was an interaction between MDD status and schizophrenia risk. Replication was sought in UK Biobank (n=33,525). In both GS:SFHS and UK Biobank we found significant interactions between SCZ-PGRS and MDD status for measures of psychological distress and neuroticism. In both cohorts there was a reduction of case-control differences on a background of higher genetic risk of SCZ. These findings suggest that depression on a background of high genetic risk for SCZ may show attenuated associations with distress and neuroticism. This may represent a causally distinct form of MDD more closely related to SCZ.

scholarly journals Association of whole-genome and NETRIN1 signaling pathway-derived polygenic risk scores for Major Depressive Disorder and thalamic radiation white matter microstructure in UK Biobank

2018 ◽  
Author(s):  
Miruna C. Barbu ◽  
Yanni Zeng ◽  
Xueyi Shen ◽  
Simon R. Cox ◽  
Toni-Kim Clarke ◽  
...  
Keyword(s):  
Major Depressive Disorder ◽  
White Matter ◽  
Depressive Disorder ◽  
Signaling Pathway ◽  
Risk Scores ◽  
Whole Genome ◽  
Uk Biobank ◽  
Major Depressive ◽  
Polygenic Risk ◽  
White Matter Microstructure

AbstractBackgroundMajor Depressive Disorder (MDD) is a clinically heterogeneous psychiatric disorder with a polygenic architecture. Genome-wide association studies have identified a number of risk-associated variants across the genome, and growing evidence of NETRIN1 pathway involvement. Stratifying disease risk by genetic variation within the NETRIN1 pathway may provide an important route for identification of disease mechanisms by focusing on a specific process excluding heterogeneous risk-associated variation in other pathways. Here, we sought to investigate whether MDD polygenic risk scores derived from the NETRIN1 signaling pathway (NETRIN1-PRS) and the whole genome excluding NETRIN1 pathway genes (genomic-PRS) were associated with white matter integrity.MethodsWe used two diffusion tensor imaging measures, fractional anisotropy (FA) and mean diffusivity (MD), in the most up-to-date UK Biobank neuroimaging data release (FA: N = 6,401; MD: N = 6,390).ResultsWe found significantly lower FA in the superior longitudinal fasciculus (β = -0.035, pcorrected = 0.029) and significantly higher MD in a global measure of thalamic radiations (β = 0.029, pcorrected = 0.021), as well as higher MD in the superior (β = 0.034, pcorrected = 0.039) and inferior (β = 0.029, pcorrected = 0.043) longitudinal fasciculus and in the anterior (β = 0.025, pcorrected = 0.046) and superior (β = 0.027, pcorrected = 0.043) thalamic radiation associated with NETRIN1-PRS. Genomic-PRS was also associated with lower FA and higher MD in several tracts.ConclusionsOur findings indicate that variation in the NETRIN1 signaling pathway may confer risk for MDD through effects on thalamic radiation white matter microstructure.

scholarly journals Genome-wide interaction study of a proxy for stress-sensitivity and its prediction of major depressive disorder

2017 ◽  
Author(s):  
Aleix Arnau-Soler ◽  
Mark J. Adams ◽  
Caroline Hayward ◽  
Pippa A. Thomson ◽  
◽  
...  
Keyword(s):  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Stress Sensitivity ◽  
Negative Regulator ◽  
Risk Scores ◽  
Uk Biobank ◽  
Major Depressive ◽  
Polygenic Risk ◽  
Genome Wide ◽  
Generation Scotland

AbstractIndividual response to stress is correlated with neuroticism and is an important predictor of both neuroticism and the onset of major depressive disorder (MDD). Identification of the genetics underpinning individual differences in response to negative events (stress-sensitivity) may improve our understanding of the molecular pathways involved, and its association with stress-related illnesses. We sought to generate a proxy for stress-sensitivity through modelling the interaction between SNP allele and MDD status on neuroticism score in order to identify genetic variants that contribute to the higher neuroticism seen in individuals with a lifetime diagnosis of depression compared to unaffected individuals. Meta-analysis of genome-wide interaction studies (GWIS) in UK Biobank (N = 23,092) and Generation Scotland: Scottish Family Health Study (N = 7,155) identified no genome-wide significance SNP interactions. However, gene-based tests identified a genome-wide significant gene, ZNF366, a negative regulator of glucocorticoid receptor function implicated in alcohol dependence (p = 1.48×10-7; Bonferroni-corrected significance threshold p < 2.79×10-6). Using summary statistics from the stress-sensitivity term of the GWIS, SNP heritability for stress-sensitivity was estimated at 5.0%. In models fitting polygenic risk scores of both MDD and neuroticism derived from independent GWAS, we show that polygenic risk scores derived from the UK Biobank stress-sensitivity GWIS significantly improved the prediction of MDD in Generation Scotland. This study may improve interpretation of larger genome-wide association studies of MDD and other stress-related illnesses, and the understanding of the etiological mechanisms underpinning stress-sensitivity.

scholarly journals Pleiotropy between neuroticism and physical and mental health: findings from 108 038 men and women in UK Biobank

2015 ◽  
Author(s):  
Catharine Gale ◽  
Saskia P Hagenaars ◽  
Gail Davies ◽  
W David Hill ◽  
David CM Liewald ◽  
...  
Keyword(s):  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Physical Health ◽  
Genetic Correlations ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Major Depressive ◽  
Polygenic Risk ◽  
Increased Risk ◽  
Health Related

There is considerable evidence that people with higher levels of the personality trait neuroticism have an increased risk of several types of mental disorder. Higher neuroticism has also been associated, less consistently, with increased risk of various physical health outcomes. We hypothesised that these associations may, in part, be due to shared genetic influences. We tested for pleiotropy between neuroticism and 12 mental and physical diseases or health traits using linkage disequilibrium regression and polygenic profile scoring. Genetic correlations were derived between neuroticism scores in 108 038 people in UK Biobank and health-related measures from 12 large genome-wide association studies(GWAS). Summary information for the 12 GWAS was used to create polygenic risk scores for the health-related measures in the UK Biobank participants. Associations between the health-related polygenic scores and neuroticism were examined using regression, adjusting for age, sex, genotyping batch, genotyping array, assessment centre, and population stratification. Genetic correlations were identified between neuroticism and anorexia nervosa(rg = 0.17), major depressive disorder (rg = 0.66) and schizophrenia (rg = 0.21). Polygenic risk for several health-related measures were associated with neuroticism, in a positive direction in the case of bipolar disorder (β = 0.017), major depressive disorder (β = 0.036), schizophrenia (β = 0.036), and coronary artery disease (β = 0.011), and in a negative direction in the case of BMI (β = -0.0095). These findings indicate that a high level of pleiotropy exists between neuroticism and some measures of mental and physical health, particularly major depressive disorder and schizophrenia.

scholarly journals The overlap of genetic susceptibility to schizophrenia and cardiometabolic disease can be used to identify metabolically different groups of individuals

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rona J. Strawbridge ◽  
Keira J. A. Johnston ◽  
Mark E. S. Bailey ◽  
Damiano Baldassarre ◽  
Breda Cullen ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
European Ancestry ◽  
Cardiometabolic Disease ◽  
Metabolic Profiles ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Major Depressive ◽  
Increased Risk

AbstractUnderstanding why individuals with severe mental illness (Schizophrenia, Bipolar Disorder and Major Depressive Disorder) have increased risk of cardiometabolic disease (including obesity, type 2 diabetes and cardiovascular disease), and identifying those at highest risk of cardiometabolic disease are important priority areas for researchers. For individuals with European ancestry we explored whether genetic variation could identify sub-groups with different metabolic profiles. Loci associated with schizophrenia, bipolar disorder and major depressive disorder from previous genome-wide association studies and loci that were also implicated in cardiometabolic processes and diseases were selected. In the IMPROVE study (a high cardiovascular risk sample) and UK Biobank (general population sample) multidimensional scaling was applied to genetic variants implicated in both psychiatric and cardiometabolic disorders. Visual inspection of the resulting plots used to identify distinct clusters. Differences between these clusters were assessed using chi-squared and Kruskall-Wallis tests. In IMPROVE, genetic loci associated with both schizophrenia and cardiometabolic disease (but not bipolar disorder or major depressive disorder) identified three groups of individuals with distinct metabolic profiles. This grouping was replicated within UK Biobank, with somewhat less distinction between metabolic profiles. This work focused on individuals of European ancestry and is unlikely to apply to more genetically diverse populations. Overall, this study provides proof of concept that common biology underlying mental and physical illness may help to stratify subsets of individuals with different cardiometabolic profiles.

scholarly journals Clinical laboratory tests and five-year incidence of major depressive disorder: a prospective cohort study of 433,890 participants from the UK Biobank

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Michael Wainberg ◽  
Stefan Kloiber ◽  
Breno Diniz ◽  
Roger S. McIntyre ◽  
Daniel Felsky ◽  
...  
Keyword(s):  
Public Health ◽  
Major Depressive Disorder ◽  
Cohort Study ◽  
Confidence Interval ◽  
Depressive Disorder ◽  
Blood Cell ◽  
Biological Processes ◽  
Uk Biobank ◽  
Major Depressive ◽  
The Uk

AbstractPrevention of major depressive disorder (MDD) is a public health priority. Identifying biomarkers of underlying biological processes that contribute to MDD onset may help address this public health need. This prospective cohort study encompassed 383,131 white British participants from the UK Biobank with no prior history of MDD, with replication in 50,759 participants of other ancestries. Leveraging linked inpatient and primary care records, we computed adjusted odds ratios for 5-year MDD incidence among individuals with values below or above the 95% confidence interval (<2.5th or >97.5th percentile) on each of 57 laboratory measures. Sensitivity analyses were performed across multiple percentile thresholds and in comparison to established reference ranges. We found that indicators of liver dysfunction were associated with increased 5-year MDD incidence (even after correction for alcohol use and body mass index): elevated alanine aminotransferase (AOR = 1.35, 95% confidence interval [1.16, 1.58]), aspartate aminotransferase (AOR = 1.39 [1.19, 1.62]), and gamma glutamyltransferase (AOR = 1.52 [1.31, 1.76]) as well as low albumin (AOR = 1.28 [1.09, 1.50]). Similar observations were made with respect to endocrine dysregulation, specifically low insulin-like growth factor 1 (AOR = 1.34 [1.16, 1.55]), low testosterone among males (AOR = 1.60 [1.27, 2.00]), and elevated glycated hemoglobin (HbA1C; AOR = 1.23 [1.05, 1.43]). Markers of renal impairment (i.e. elevated cystatin C, phosphate, and urea) and indicators of anemia and macrocytosis (i.e. red blood cell enlargement) were also associated with MDD incidence. While some immune markers, like elevated white blood cell and neutrophil count, were associated with MDD (AOR = 1.23 [1.07, 1.42]), others, like elevated C-reactive protein, were not (AOR = 1.04 [0.89, 1.22]). The 30 significant associations validated as a group in the multi-ancestry replication cohort (Wilcoxon p = 0.0005), with a median AOR of 1.235. Importantly, all 30 significant associations with extreme laboratory test results were directionally consistent with an increased MDD risk. In sum, markers of liver and kidney dysfunction, growth hormone and testosterone deficiency, innate immunity, anemia, macrocytosis, and insulin resistance were associated with MDD incidence in a large community-based cohort. Our results support a contributory role of diverse biological processes to MDD onset.

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.

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