Biology subjects

Pell, J. P.

Publications and source records attributed to Pell, J. P..

7 recordsLinked to original sources

bioRxiv2019

Understanding Cognitive Impairment in Mood Disorders: Mediation Analyses in the UK Biobank Cohort

BackgroundCognitive impairment is strongly linked with persistent disability in people with mood disorders, but the factors that explain cognitive impairment in this population are unclear.\n\nAimsWe aimed to estimate the total effect of (i) bipolar disorder (BD) and (ii) major depression on cognitive function, and the magnitude of the effect that was explained by potentially modifiable intermediate factors.\n\nMethodCross-sectional study using baseline data from the UK Biobank cohort. Participants were categorised as BD (N=2,709), major depression (N=50,975), or no mood disorder (N=102,931 to 105,284). The outcomes were computerised tests of reasoning, reaction time and memory. The potential mediators were cardiometabolic disease and psychotropic medication. Analyses were informed by graphical methods, and controlled for confounding using regression, propensity score-based methods, and G-computation.\n\nResultsGroup differences of small magnitude were found on a visuospatial memory test. Z-score differences for BD were in the range -0.23 to -0.17 (95% CI range -0.39 to -0.03) across different estimation methods, and approximately -0.07 (95% CI -0.10 to -0.03) for major depression. One-quarter of the effect was mediated via psychotropic medication in the BD group (-0.05; 95% CI -0.09 to -0.01). No evidence was found for mediation via cardiometabolic disease.\n\nConclusionsIn a large community-based sample in middle to early old age, BD and depression were associated with lower visuospatial memory performance, in part potentially due to psychotropic medication use. Mood disorders and their treatments will have increasing importance for population cognitive health as the proportion of older adults continues to grow.

epidemiology↗

bioRxiv2019

The genomic basis of mood instability: identification of 46 loci in 363,705 UK Biobank participants, genetic correlation with psychiatric disorders, and association with gene expression and function.

Genome-wide association studies (GWAS) of psychiatric phenotypes have tended to focus on categorical diagnoses, but to understand the biology of mental illness it may be more useful to study traits which cut across traditional boundaries. Here we report the results of a GWAS of mood instability (MI) as a trait in a large population cohort (UK Biobank, n=363,705). We also assess the clinical and biological relevance of the findings, including whether genetic associations show enrichment for nervous system pathways. Forty six unique loci associated with MI were identified with a heritability estimate of 9%. Linkage Disequilibrium Score Regression (LDSR) analyses identified genetic correlations with Major Depressive Disorder (MDD), Bipolar Disorder (BD), Schizophrenia (SZ), anxiety and Post Traumatic Stress Disorder (PTSD). Gene-level and gene set analyses identified total 244 significant genes and 6 enriched gene sets. Tissue expression analysis from the SNP level data found enrichment in multiple brain regions, and eQTL analyses highlighted an inversion on chromosome 17 plus two brain-specific eQTLs. Additionally, we used a Phenotype Linkage Network (PLN) analysis and community analysis to assess for enrichment of nervous system gene sets using mouse orthologue databases. The PLN analysis found enrichment in nervous system PLNs for a community containing serotonin and melatonin receptors. In summary, this work has identified novel loci, tissues, and gene sets contributing to MI as a normal trait and will inform future work on the biology of mood and psychotic disorders, and to point the way towards potential for new stratified medicine approaches and the identification of novel trans-diagnostic drug targets.

genetics↗

bioRxiv2019

Associations between vascular risk factors and brain MRI indices in UK Biobank

AimsSeveral factors are known to increase risk for cerebrovascular disease and dementia, but there is limited evidence on associations between multiple vascular risk factors (VRFs) and detailed aspects of brain macro- and microstructure in large community-dwelling populations across middle- and older age.\n\nMethods and ResultsAssociations between VRFs (smoking, hypertension, pulse pressure, diabetes, hypercholersterolaemia, BMI, and waist-hip ratio) and both global and regional brain structural and diffusion MRI markers were examined in UK Biobank (N = 9722, age range 44-77 years). A larger number of VRFs was associated with greater brain atrophy, lower grey matter volume, and poorer white matter health. Effect sizes were small (brain structural R2 [≤] 1.8%). Higher aggregate vascular risk was related to multiple regional MRI hallmarks associated with dementia risk: lower frontal and temporal cortical volumes, lower subcortical volumes, higher white matter hyperintensity volumes, and poorer white matter microstructure in association and thalamic pathways. Smoking pack years, hypertension and diabetes showed the most consistent associations across all brain measures. Hypercholesterolaemia was not uniquely associated with any MRI marker.\n\nConclusionHigher levels of VRFs were associated with poorer brain health across grey and white matter macro- and microstructure. Effects are mainly additive, converging upon frontal and temporal cortex, subcortical structures, and specific classes of white matter fibres. Though effect sizes were small, these results emphasise the vulnerability of brain health to vascular factors even in relatively healthy middle and older age, and the potential to partly ameliorate cognitive decline by addressing these malleable risk factors.

neuroscience↗

bioRxiv2018

Novel genome-wide associations for suicidality in UK Biobank, genetic correlation with psychiatric disorders and polygenic association with completed suicide.

AbstractBackground: Suicide is a major issue for global public health. Suicidality describes a broad clinical spectrum of thoughts and behaviours, some of which are common in the general population.\n\nMethods: UK Biobank recruited [~]0{middle dot}5 million middle age individuals from the UK, of whom 157,000 completed an assessment of suicidality. Mutually exclusive groups were assessed in an ordinal genome-wide association study of suicidality: no suicidality controls (N=83,557); thoughts that life was not worth living (N=21,063); ever contemplated self-harm (N=13,038); an act of deliberate self-harm in the past (N=2,498); and a previous suicide attempt (N=2,666). Linkage of UK Biobank to death certification records identified a small sub-group of completed suicide (N=137).\n\nOutcomes: We identified three novel genome-wide significant loci for suicidality (on Chromosomes 9, 11 and 13) and moderate-to-strong genetic correlations between suicidality and a range of psychiatric disorders, most notably depression (rg 0{middle dot}81). Higher polygenic risk scores for suicidality were associated with increased risk of completed suicide relative to controls in an independent sub-group (N=137 vs N=5,330, OR 1{middle dot}23, 95%CI 1{middle dot}06 to 1{middle dot}41, p=0.03). Rs598046-G (chromosome 11) demonstrated a similar effect size and direction (p=0{middle dot}05) within a Danish suicidality study.\n\nInterpretation: These findings have significant implications for our understanding of genetic vulnerability to suicidal thoughts and behaviours. Future work should assess the extent to which polygenic risk scores for suicidality, in combination with non-genetic risk factors, may be useful for stratified approaches to suicide prevention at a population level.\n\nFunding: UKRI Innovation-HDR-UK Fellowship (MR/S003061/1). MRC Mental Health Data Pathfinder Award (MC_PC_17217).

genetics↗

bioRxiv2018

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

BackgroundCircadian 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.\n\nMethodsWe 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.\n\nOutcomesTwo 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{middle dot}05: OR=1{middle dot}02, 95% CI=1{middle dot}01-1{middle dot}02, p=9{middle dot}6x10-5), and with major depressive disorder (at PRS threshold 0{middle dot}1: OR=1{middle dot}03, 95% CI=1{middle dot}01-1{middle dot}05, p=0{middle dot}025) and neuroticism (at PRS threshold 0{middle dot}5: Beta=0{middle dot}02, 95% CI=0{middle dot}007-0{middle dot}04, p=0{middle dot}021).\n\nInterpretationOverall, 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.

genomics↗

bioRxiv2017

Is there association between APOE e4 genotype and structural brain ageing phenotypes, and does that association increase in older age in UK Biobank? (N = 8,395)

Apolipoprotein (APOE) e4 genotype is a purported risk factor for accelerated cognitive ageing and dementia, though its neurostructural substrates are unclear. The deleterious effects of this genotype on brain structure may increase in magnitude into older age. This study aimed to investigate in UK Biobank the association between APOE e4 allele presence vs. absence and brain imaging variables that have been associated with worse cognitive abilities; and whether this association varies by cross-sectional age. We used brain magnetic resonance imaging (MRI) and genetic data from a general-population cohort: the UK Biobank (N=8,395). We adjusted for the covariates of age in years, sex, Townsend social deprivation scores, smoking history and cardiometabolic diseases. There was a statistically significant association between APOE e4 genotype and increased (i.e. worse) white matter (WM) hyperintensity volumes (standardised beta = 0.088, 95 confidence intervals = 0.036 to 0.139, P = 0.001), a marker of poorer cerebrovascular health. There were no associations with left or right hippocampal, total grey matter (GM) or WM volumes, or WM tract integrity indexed by fractional anisotropy (FA) and mean diffusivity (MD). There were no statistically significant interactions with age. Future research in UK Biobank utilising intermediate phenotypes and longitudinal imaging hold significant promise for this area, particularly pertaining to APOE e4s potential link with cerebrovascular contributions to cognitive ageing.

genetics↗

bioRxiv2017

Genome-wide analysis of risk-taking behaviour and cross-disorder genetic correlations in 116,255 individuals from the UK Biobank cohort

Risk-taking behaviour is a key component of several psychiatric disorders and could influence lifestyle choices such as smoking, alcohol use and diet. As a phenotype, risk-taking behaviour therefore fits within a Research Domain Criteria (RDoC) approach, whereby identifying genetic determinants of this trait has the potential to improve our understanding across different psychiatric disorders. Here we report a genome wide association study in 116 255 UK Biobank participants who responded yes/no to the question \"Would you consider yourself a risk-taker?\" Risk-takers (compared to controls) were more likely to be men, smokers and have a history of psychiatric disorder. Genetic loci associated with risk-taking behaviour were identified on chromosomes 3 (rs13084531) and 6 (rs9379971). The effects of both lead SNPs were comparable between men and women. The chromosome 3 locus highlights CADM2, previously implicated in cognitive and executive functions, but the chromosome 6 locus is challenging to interpret due to the complexity of the HLA region. Risk-taking behaviour shared significant genetic risk with schizophrenia, bipolar disorder, attention deficit hyperactivity disorder and post-traumatic stress disorder, as well as with smoking and total obesity. Despite being based on only a single question, this study furthers our understanding of the biology of risk-taking behaviour, a trait which has a major impact on a range of common physical and mental health disorders.

genetics↗