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

2020 ◽  
Author(s):  
Rona J. Strawbridge ◽  
Keira J. A. Johnston ◽  
Mark E. S. Bailey ◽  
Damiano Baldasarre ◽  
Breda Cullen ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Depressive Disorders ◽  
Cardiometabolic Disease ◽  
Metabolic Profiles ◽  
Uk Biobank ◽  
Major Depressive ◽  
Increased Risk ◽  
Chi Squared

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 researcher. We explored whether genetic variation could identify individuals with different metabolic profiles. Loci previously associated with schizophrenia, bipolar disorder and major depressive disorder were identified from literature and those overlapping loci genotyped on the Illumina CardioMetabo and Immuno chips (representing cardiometabolic processes and diseases) were selected. In the IMPROVE study (high cardiovascular risk) and UK Biobank (general population) multidimensional scaling was applied to genetic variants implicated in both mental and cardiometabolic illness. Visual inspection of the resulting plots used to identify distinct clusters. Differences between clusters were assessed using chi-squared and Kruskall-Wallis tests. In IMPROVE, genetic loci associated with both cardiometabolic disease and schizophrenia (but not bipolar or major depressive disorders) identified three groups of individuals with distinct metabolic profiles. The grouping was replicated in UK Biobank, albeit with less distinction between metabolic profiles. This study provides proof of concept that common biology underlying mental and physical illness can identify subsets of individuals with different cardiometabolic profiles.

scholarly journals Multiple measures of depression to enhance validity of major depressive disorder in the UK Biobank

BJPsych Open ◽  
2021 ◽  
Vol 7 (2) ◽  
Author(s):  
Kylie P. Glanville ◽  
Jonathan R. I. Coleman ◽  
David M. Howard ◽  
Oliver Pain ◽  
Ken B. Hanscombe ◽  
...  
Keyword(s):  
Mental Health ◽  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Genetic Correlations ◽  
Genetic Contribution ◽  
Uk Biobank ◽  
Major Depressive ◽  
Multiple Measures ◽  
The Uk ◽  
Mental Health Questionnaire

Background The UK Biobank contains data with varying degrees of reliability and completeness for assessing depression. A third of participants completed a Mental Health Questionnaire (MHQ) containing the gold-standard Composite International Diagnostic Interview (CIDI) criteria for assessing mental health disorders. Aims To investigate whether multiple observations of depression from sources other than the MHQ can enhance the validity of major depressive disorder (MDD). Method In participants who did not complete the MHQ, we calculated the number of other depression measures endorsed, for example from hospital episode statistics and interview data. We compared cases defined this way with CIDI-defined cases for several estimates: the variance explained by polygenic risk scores (PRS), area under the curve attributable to PRS, single nucleotide polymorphisms (SNPs)-based heritability and genetic correlations with summary statistics from the Psychiatric Genomics Consortium MDD genome-wide association study. Results The strength of the genetic contribution increased with the number of measures endorsed. For example, SNP-based heritability increased from 7% in participants who endorsed only one measure of depression, to 21% in those who endorsed four or five measures of depression. The strength of the genetic contribution to cases defined by at least two measures approximated that for CIDI-defined cases. Most genetic correlations between UK Biobank and the Psychiatric Genomics Consortium MDD study exceeded 0.7, but there was variability between pairwise comparisons. Conclusions Multiple measures of depression can serve as a reliable approximation for case status where the CIDI measure is not available, indicating sample size can be optimised using the entire suite of UK Biobank data.

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 Genome-wide haplotype-based association analysis of major depressive disorder in Generation Scotland and UK Biobank

2016 ◽  
Author(s):  
David M. Howard ◽  
Lynsey S. Hall ◽  
Jonathan D. Hafferty ◽  
Yanni Zeng ◽  
Mark J. Adams ◽  
...  
Keyword(s):  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Replication Cohort ◽  
Discovery Cohort ◽  
Major Depressive ◽  
Genome Wide ◽  
Generation Scotland ◽  
A Genome

ABSTRACTGenome-wide association studies using genotype data have had limited success in the identification of variants associated with major depressive disorder (MDD). Haplotype data provide an alternative method for detecting associations between variants in weak linkage disequilibrium with genotyped variants and a given trait of interest. A genome-wide haplotype association study for MDD was undertaken utilising a family-based population cohort, Generation Scotland: Scottish Family Health Study (n = 18 773), as a discovery cohort with UK Biobank used as a population-based cohort replication cohort (n = 25 035). Fine mapping of haplotype boundaries was used to account for overlapping haplotypes potentially tagging the same causal variant. Within the discovery cohort, two haplotypes exceeded genome-wide significance (P < 5 × 10-8) for an association with MDD. One of these haplotypes was nominally significant in the replication cohort (P < 0.05) and was located in 6q21, a region which has been previously associated with bipolar disorder, a psychiatric disorder that is phenotypically and genetically correlated with MDD. Several haplotypes with P < 10-7 in the discovery cohort were located within gene coding regions associated with diseases that are comorbid with MDD. Using such haplotypes to highlight regions for sequencing may lead to the identification of the underlying causal variants.

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.

scholarly journals Investigating the source of increased bipolar and major depressive disorder polygenic risk in multiplex schizophrenia families

2021 ◽  
Author(s):  
Mohammad Ahangari ◽  
Robert Kirkpatrick ◽  
Tan-Hoang Nguyen ◽  
Nathan Gillespie ◽  
Irish Schizophrenia Genomics Consortium ◽  
...  
Keyword(s):  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Psychiatric Disorders ◽  
Genetic Correlation ◽  
Affective Disorders ◽  
Genetic Factors ◽  
Genetic Correlations ◽  
Polygenic Risk Score ◽  
Major Depressive ◽  
Polygenic Risk

Psychotic and affective disorders often aggregate in the relatives of probands with schizophrenia (SCZ), and genetic studies show substantial genetic correlation among SCZ, bipolar disorder (BIP) and major depressive disorder (MDD). However, the nature of this genetic overlap in polygenic risk score (PRS) analyses of multiplex families has not been fully dissected. In the current study, we investigated the polygenic risk burden of BIP and MDD in a sample of 257 multiplex SCZ families (N=1,005) and population controls (N=2,205). Furthermore, due to the strong genetic correlation among SCZ, BIP, and MDD, we examined whether increased BIP or MDD PRS in members of multiplex SCZ families can be attributed to latent genetic factors unique to BIP or MDD, or latent genetic factors that each of these two disorders share with SCZ. Our results indicate that members of multiplex SCZ families have an increased PRS for BIP and MDD, however, this observation is largely attributable to latent genetic factors that BIP or MDD share with SCZ, rather than latent genetic factors unique to them. These results provide new insight for cross-disorder PRS analyses of psychiatric disorders, by cautioning that for complete interpretation of observed cross-disorder PRS enrichment, we should account for genetic correlations across psychiatric disorders. Our findings further indicates that members of multiplex SCZ families may have an increased genetic vulnerability to both psychotic and affective disorders, and for full assessment of an individual genetic risk, familial backgrounds should be taken into consideration.

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 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.

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