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

2017 ◽  
Vol 7 (11) ◽  
Author(s):  
David M. Howard ◽  
Lynsey S. Hall ◽  
Jonathan D. Hafferty ◽  
Yanni Zeng ◽  
Mark J. Adams ◽  
...  
Keyword(s):  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Association Analysis ◽  
Uk Biobank ◽  
Major Depressive ◽  
Genome Wide ◽  
Generation Scotland

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.

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 Genetic association study of psychotic experiences in UK Biobank

2019 ◽  
Author(s):  
Sophie E. Legge ◽  
Hannah J. Jones ◽  
Kimberley M. Kendall ◽  
Antonio F. Pardiñas ◽  
Georgina Menzies ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Neurodevelopmental Disorders ◽  
Population Based ◽  
Uk Biobank ◽  
Psychotic Experiences ◽  
Psychotic Experience ◽  
Major Depressive ◽  
Genome Wide

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.

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

2017 ◽  
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.

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

2020 ◽  
Vol 25 (7) ◽  
pp. 1430-1446 ◽  
Author(s):  
Jonathan R. I. Coleman ◽  
◽  
Wouter J. Peyrot ◽  
Kirstin L. Purves ◽  
Katrina A. S. Davis ◽  
...  
Keyword(s):  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Traumatic Experiences ◽  
Uk Biobank ◽  
Major Depressive ◽  
Gene Environment ◽  
Genome Wide
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