Biology subjects

Ward, J.

Publications and source records attributed to Ward, J..

14 recordsLinked to original sources

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

How non-veridical perception drives actions in healthy humans - Evidence from Synaesthesia

We continually perform actions driven by our perception and it is commonly held that only objectively perceived changes within the real world affect behaviour. Exceptions are usually only made for clinical conditions associated with hallucinations, where objectively non-existent percepts can influence behavior. Using synaesthesia as a model condition, we show that even in healthy populations irrelevant non-veridical precepts exert an effect on action. By non-veridical we refer to stimulus dimensions that are only subjectively perceived to be there. Applying electrophysiological (EEG) methods, we show that although these examined peculiarities are perceptual in nature, not primarily perceptual processes underlie the effects of irrelevant non-veridical perceptions on actions. Rather, high-order processes linking perceptions and motor control in medial frontal cortices reflect the underlying mechanism how irrelevant non-veridical perceptions modulate behaviour. Our results challenge assumptions about the determinants of healthy human behaviour but can be embedded within existing frameworks detailing perception action interactions.

neuroscience↗

bioRxiv2018

Reduced visual and frontal cortex activation during visual working memory in grapheme-colour synaesthetes relative to young and older adults.

The sensory recruitment model envisages visual working memory (VWM) as an emergent property that is encoded and maintained in sensory (visual) regions. The model implies that enhanced sensory-perceptual functions, as in synaesthesia, entail a dedicated VWM-system, showing reduced visual cortex activity as a result of neural specificity. By contrast, sensory-perceptual decline, as in old age, is expected to show enhanced visual cortex activity as a result of neural broadening. To test this model, young grapheme-colour synaesthetes, older adults and young controls engaged in a delayed pair-associative retrieval and a delayed matching-to-sample task, consisting of achromatic fractal stimuli that do not induce synaesthesia. While a previous analysis of this dataset (Pfeifer et al., 2016) has focused on cued retrieval and recognition of pair-associates (i.e. long-term memory), the current study focuses on visual working memory and considers, for the first time, the crucial delay period in which no visual stimuli are present, but working memory processes are engaged. Participants were trained to criterion and demonstrated comparable behavioural performance on VWM tasks. Whole-brain and region-of-interest-analyses revealed significantly lower activity in the synaesthetes middle frontal gyrus and visual regions (cuneus, inferior temporal cortex) respectively, suggesting greater neural efficiency relative to young and older adults in both tasks. The results support the sensory recruitment model and can explain age and individual WM-differences based on neural specificity in visual cortex.

neuroscience↗

bioRxiv2018

Genome-wide meta-analysis of depression in 807,553 individuals identifies 102 independent variants with replication in a further 1,507,153 individuals

Major depression is a debilitating psychiatric illness that is typically associated with low mood, anhedonia and a range of comorbidities. Depression has a heritable component that has remained difficult to elucidate with current sample sizes due to the polygenic nature of the disorder. To maximise sample size, we meta-analysed data on 807,553 individuals (246,363 cases and 561,190 controls) from the three largest genome-wide association studies of depression. We identified 102 independent variants, 269 genes, and 15 gene-sets associated with depression, including both genes and gene-pathways associated with synaptic structure and neurotransmission. Further evidence of the importance of prefrontal brain regions in depression was provided by an enrichment analysis. In an independent replication sample of 1,306,354 individuals (414,055 cases and 892,299 controls), 87 of the 102 associated variants were significant following multiple testing correction. Based on the putative genes associated with depression this work also highlights several potential drug repositioning opportunities. These findings advance our understanding of the complex genetic architecture of depression and provide several future avenues for understanding aetiology and developing new treatment approaches.

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↗

bioRxiv2018

PCSK9 genetic variants, life-long lowering of LDL-cholesterol and cognition: a large-scale Mendelian randomization study

AimsPCSK9 inhibitors lower LDL cholesterol and are efficacious at reducing risk of vascular disease, however questions remain about potential adverse effects on cognitive function. We examined the association of LDL cholesterol-lowering genetic variants in PCSK9 with continuous measures of cognitive ability\n\nMethods and ResultsSix independent SNPs in PCSK9 were used in up to 337,348 individuals from the UK Biobank who underwent measures of cognitive ability (fluid reasoning, reaction time, trial making test and digit symbol coding. Scaled to a 50mg/dL lower LDL cholesterol, the PCSK9 allele score was associated with a lower risk of CHD (odds ratio 0.73; 95% CI: 0.60 to 0.90, P = 0.003). The scaled PCSK9 allele score nominally associated with worse log reaction time (0.04 standard deviations; 95%CI: 0.00, 0.08; P=0.038). Although no strong associations of the PCSK9 allele score were identified with any cognitive trait, the imprecision around the estimates meant that we could not exclude a similar magnitude of effect of genetic inhibition of PCSK9 to that seen with established risk factors, including APOEe4 or smoking status for any of the individual cognition traits. Point estimates for the PCSK9 allele score and cognition traits were all on the harmful side of unity.\n\nConclusionsUsing currently available data in UK Biobank, we are not able to rule out meaningful associations of PCSK9 genetic variants with cognition traits. These data highlight the need for further large-scale genetic analyses and, in parallel, continued pharmacovigilance for patients currently treated with PCSK9 inhibitors.

epidemiology↗

bioRxiv2018

Polygenic risk scores for major depressive disorder and neuroticism as predictors of antidepressant response: meta-analysis of three treatment cohorts.

There are currently no reliable approaches for correctly identifying which patients with major depressive disorder (MDD) will respond well to antidepressant therapy. However, recent genetic advances suggest that Polygenic Risk Scores (PRS) could allow MDD patients to be stratified for antidepressant response. We used PRS for MDD and PRS for neuroticism as putative predictors of antidepressant response within three treatment cohorts: The Genome-based Therapeutic Drugs for Depression (GENDEP) cohort, and 2 sub-cohorts from the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomics Study PRGN-AMPS (total patient number = 783). Results across cohorts were combined via meta-analysis within a random effects model. Overall, PRS for MDD and neuroticism did not significantly predict antidepressant response but there was a consistent direction of effect, whereby greater genetic loading for both MDD (best MDD result, p < 5*10-5 MDD-PRS at 4 weeks, {beta} = -0.019, S.E = 0.008, p = 0.01) and neuroticism (best neuroticism result, p < 0.1 neuroticism-PRS at 8 weeks, {beta} = -0.017, S.E = 0.008, p = 0.03) were associated with less favourable response. We conclude that the PRS approach may offer some promise for treatment stratification in MDD and should now be assessed within larger clinical cohorts.

genetics↗

bioRxiv2018

Early lethality of embryos derived from transgenic Xenopus females is associated with reduced ovarian grem1 expression

The grem1 gene codes a protein that inhibits the action of multiple members of a growth factor family known as bone morphogenetic proteins (BMPs). Certain members of this BMP family can regulate both fecundity and fertility in mammals via their action on oocyte (egg) development, and grem1 has been identified as a marker of oocyte quality in humans. The model amphibian Xenopus laevis is far more fecund than mammals, producing thousands of eggs in a clutch. However, female transgenic frogs carrying grem1 under the control of a stress inducible hsp70 promoter (\"G\" frogs) produce very few viable offspring. Here, we show that this is not due to reduced fecundity or fertilization rate, but results from a significant reduction in subsequent survival over the first day of development. Embryos that successfully survive for the first day were found to go on to develop normally when compared to their peers. Both the morphology and stage distribution of oocytes from G females appears normal, and oocytes develop at expected rates, although stage VI oocytes were found to have a lower response to in vitro progesterone treatment. Unexpectedly, levels of grem1 mRNA were found to be consistently lower in the female ovaries from four independent G transgenic lines than in wild type ovaries. Both transgenic and wild type offspring were equally affected, confirming a maternal effect. Our study shows that transgenic females with the lowest levels of grem1 transcripts in the ovary have the lowest rates of survival past the first day of amphibian embryogenesis, equivalent to pre-implantation staged mammalian embryos. The reduced expression of grem1 in the oocytes of transgenic females suggests transgene supression of an endogenous locus may occur in the Xenopus female germline, an unexpected finding.

developmental biology↗

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

Quantitative Imaging of Receptor-Ligand Engagement in Intact Live Animals

Maintaining an intact tumor environment is critical for quantitation of receptor-ligand engagement in a targeted drug development pipeline. However, measuring receptor-ligand engagement in vivo and non-invasively in preclinical settings is extremely challenging. We found that quantitation of intracellular receptor-ligand binding can be achieved using whole-body macroscopic lifetime-based Forster Resonance Energy Transfer (FRET) imaging in intact, live animals bearing tumor xenografts. We determined that FRET levels report on ligand binding to transferrin receptors conversely to raw fluorescence intensity. We then established that FRET levels in heterogeneous tumors correlate with intracellular ligand binding but strikingly, not with ubiquitously used ex vivo receptor expression assessment. Hence, MFLI-FRET provides a direct measurement of systemic delivery, target availability and intracellular drug delivery in intact animals. Here, we have used MFLI to measure FRET longitudinally in intact animals for the first time. MFLI-FRET is well-suited for guiding the development of targeted drug therapy in heterogeneous intact, live small animals.

cancer biology↗

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↗

bioRxiv2017

Genome-Wide Analysis Of 113,968 Individuals In UK Biobank Identifies Four Loci Associated With Mood Instability.

Mood 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 x 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.

neuroscience↗

bioRxiv2017

Improper Localization of the OmcS Cytochrome May Explain the Inability of the xapD-Deficient Mutant of Geobacter sulfurreducens to Reduce Fe(III) Oxide

Extracellular electron transfer through a redox-active exopolysaccharide matrix has been proposed as a strategy for extracellular electron transfer to Fe(III) oxide by Geobacter sulfurreducens, based on the phenotype of a xapD-deficient strain. Central to this model was the assertion that the xapD-deficient strain produced pili decorated with the multi-heme c-type cytochrome OmcS in manner similar to the wild-type strain. Further examination of the xapD-deficient strain with immunogold labeling of OmcS and transmission electron microscopy revealed that OmcS was associated with the outer cell surface rather than pili. PilA, the pilus monomer, could not be detected in the xapD-deficient strain under conditions in which it was readily detected in the wild-type strain. Multiple lines of evidence in previous studies have suggested that long-range electron transport to Fe(III) oxides proceeds through electrically conductive pili and that OmcS associated with the pili is necessary for electron transfer from the pili to Fe(III) oxides. Therefore, an alternative explanation for the Fe(III) oxide reduction phenotype of the xapD-deficient strain is that the pili-OmcS route for extracellular electron transport to Fe(III) oxide has been disrupted in the xapD-deficient strain.

microbiology↗

bioRxiv2016

Cannabis use and risk of schizophrenia:a Mendelian randomization study

Cannabis use is observationally associated with an increased risk of schizophrenia, however whether the relationship is causal is not known. To determine the nature of the association between cannabis use on risk of schizophrenia using Mendelian randomization (MR) analysis, we used ten genetic variants previously identified to associate with cannabis use in 32,330 individuals. Genetic variants were used in a MR analyses of the association of genetically determined cannabis on risk of schizophrenia in 34,241 cases and 45,604 controls from predominantly European descent. Estimates from MR were compared to a metaanalysis of observational studies reporting effect estimates for ever use of cannabis and risk of schizophrenia or related disorders. Genetically determined use of cannabis was associated with increased risk of schizophrenia (OR of schizophrenia for users vs. non-users of cannabis: 1.37; 95%CI, 1.09 to 1.67; P-value=0.007). The corresponding estimate from observational analysis was 1.50 (95% CI, 1.10 to 2.00; P-value for heterogeneity = 0.88). The genetic instrument did not show evidence of pleiotropy on MR-Egger (Egger test, P-value=0.292) nor on multivariable MR accounting for tobacco exposure (OR of schizophrenia for users vs. nonusers of cannabis, adjusted for ever vs. never smoker: 1.41; 95% CI, 1.09-1.83). Furthermore, the causal estimate remained robust to sensitivity analyses. These findings strongly support a causal association between genetically determined use of cannabis and risk of schizophrenia. Such robust evidence may inform public health message about the risks of cannabis use, especially regarding its potential mental health consequences.

epidemiology↗