Correction: Genome-wide gene-environment analyses of major depressive disorder and reported lifetime traumatic experiences in UK Biobank

AbstractPsychotic experiences, such as hallucinations and delusions, are reported by approximately 5%-10% of the general population, though only a small proportion of individuals develop psychotic disorders such as schizophrenia or bipolar disorder. Studying the genetic aetiology of psychotic experiences in the general population, and its relationship with the genetic aetiology of other disorders, may increase our understanding of their pathological significance. Using the population-based UK Biobank sample, we performed the largest genetic association study of psychotic experiences in individuals without a psychotic disorder. We conducted three genome-wide association studies (GWAS) for (i) any psychotic experience (6123 cases vs. 121,843 controls), (ii) distressing psychotic experiences (2143 cases vs. 121,843 controls), and (iii) multiple occurrence psychotic experiences (3337 cases vs. 121,843 controls). Analyses of polygenic risk scores (PRS), genetic correlation, and copy number variation (CNV) were conducted to assess whether genetic liability to psychotic experiences is shared with schizophrenia and/or other neuropsychiatric disorders and traits. GWAS analyses identified four loci associated with psychotic experiences including a locus in Ankyrin-3 (ANK3, OR=1.16,p=3.06 × 10−8) with any psychotic experience and a locus in cannabinoid receptor 2 gene (CNR2,OR=0.66,p=3.78×10−8) with distressing psychotic experiences. PRS analyses identified associations between psychotic experiences and genetic liability for schizophrenia, major depressive disorder, and bipolar disorder, and these associations were stronger for distressing psychotic experiences. Genetic correlation analysis identified significant genetic correlations between psychotic experiences and major depressive disorder, schizophrenia, autism spectrum disorder and a cross-disorder GWAS. Individuals reporting psychotic experiences had an increased burden of CNVs previously associated with schizophrenia (OR=2.04,p=2.49×10−4) and of those associated with neurodevelopmental disorders more widely (OR=1.75,p=1.41×10−3). In conclusion, we identified four genome-wide significant loci in the largest GWAS of psychotic experiences from the population-based UK Biobank sample and found support for a shared genetic aetiology between psychotic experiences and schizophrenia, but also major depressive disorder, bipolar disorder and neurodevelopmental disorders.

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

10.1101/068643 ◽

2016 ◽

Cited By ~ 1

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.

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116 independent genetic variants influence the neuroticism personality trait in over 329,000 UK Biobank individuals

10.1101/168906 ◽

2017 ◽

Cited By ~ 4

Author(s):

Michelle Luciano ◽

Saskia P Hagenaars ◽

Gail Davies ◽

W David Hill ◽

Toni-Kim Clarke ◽

...

Keyword(s):

Major Depressive Disorder ◽

Depressive Disorder ◽

Personality Trait ◽

Meta Analysis ◽

Genetic Correlations ◽

Twin Studies ◽

Uk Biobank ◽

Genetic Loci ◽

Major Depressive ◽

Genome Wide

Neuroticism is a stable personality trait 1; twin studies report heritability between 30% and 50% 2, and SNP-based heritability is about 15% 3. Higher levels of neuroticism are associated with poorer mental and physical health 4,5, and the economic burden of neuroticism for societies is high 6. To date, genome-wide association (GWA) studies of neuroticism have identified up to 11 genetic loci 3,7. Here we report 116 significant independent genetic loci from a GWA of neuroticism in 329,821 UK Biobank participants, with replication available in a GWA meta-analysis of neuroticism in 122,867 individuals. Genetic signals for neuroticism were enriched in neuronal genesis and differentiation pathways, and substantial genetic correlations were found between neuroticism and depressive symptoms (rg = .82, SE=.03), major depressive disorder (rg = .69, SE=.07) and subjective wellbeing (rg = -.68, SE=.03) alongside other mental health traits. These discoveries significantly advance our understanding of neuroticism and its association with major depressive disorder.

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

10.1101/194290 ◽

2017 ◽

Cited By ~ 1

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.

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Genome-wide analysis in UK Biobank identifies four loci associated with mood instability and genetic correlation with major depressive disorder, anxiety disorder and schizophrenia

10.1101/117796 ◽

2017 ◽

Cited By ~ 1

Author(s):

Joey Ward ◽

Rona J. Strawbridge ◽

Mark E. S. Bailey ◽

Nicholas Graham ◽

Ferguson Amy ◽

...

Keyword(s):

Major Depressive Disorder ◽

Anxiety Disorder ◽

Depressive Disorder ◽

Genetic Correlation ◽

Translation Initiation Factor ◽

Uk Biobank ◽

Major Depressive ◽

Mood Instability ◽

Simple Measure ◽

Genome Wide

AbstractMood instability is a core clinical feature of affective and psychotic disorders. In keeping with the Research Domain Criteria (RDoC) approach, it may be a useful construct for identifying biology that cuts across psychiatric categories. We aimed to investigate the biological validity of a simple measure of mood instability and evaluate its genetic relationship with several psychiatric disorders, including major depressive disorder (MDD), bipolar disorder (BD), schizophrenia, attention deficit hyperactivity disorder (ADHD), anxiety disorder and post-traumatic stress disorder (PTSD). We conducted a genome-wide association study (GWAS) of mood instability in 53,525 cases and 60,443 controls from UK Biobank, identifying four independently-associated loci (on chromosomes eight, nine, 14 and 18), and a common single nucleotide polymorphism (SNP)-based heritability estimate of approximately 8%. We found a strong genetic correlation between mood instability and MDD (rg=0.60, SE=0.07, p=8.95 × 10−17) and a small but significant genetic correlation with both schizophrenia (rg=0.11, SE=0.04, p=0.01) and anxiety disorders (rg=0.28, SE=0.14, p=0.04), although no genetic correlation with BD, ADHD or PTSD. Several genes at the associated loci may have a role in mood instability, including the DCC netrin 1 receptor (DCC) gene, eukaryotic translation initiation factor 2B subunit beta (eIF2B2), placental growth factor (PGF), and protein tyrosine phosphatase, receptor type D (PTPRD). Strengths of this study include the very large sample size, but our measure of mood instability may be limited by the use of a single question. Overall, this work suggests a polygenic basis for mood instability. This simple measure can be obtained in very large samples; our findings suggest that doing so may offer the opportunity to illuminate the fundamental biology of mood regulation.

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Genome-wide association study of circadian rhythmicity in 71 500 UK Biobank participants and polygenic association with mood instability

10.1101/350983 ◽

2018 ◽

Author(s):

Amy Ferguson ◽

Laura M. Lyall ◽

Joey Ward ◽

Rona J. Strawbridge ◽

Breda Cullen ◽

...

Keyword(s):

Major Depressive Disorder ◽

Depressive Disorder ◽

Association Study ◽

Genome Wide Association Study ◽

Circadian Rhythmicity ◽

Genome Wide Association ◽

Uk Biobank ◽

Major Depressive ◽

Mood Instability ◽

Genome Wide

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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