Biology subjects

Thomson, P.

Publications and source records attributed to Thomson, P..

10 recordsLinked to original sources

bioRxiv2024

A shifting role of thalamocortical connectivity in the emergence of large-scale functional brain organization across early lifespan development

While cortical patterning has been a perennial research topic in neuroscience, the mechanism for its consequence, namely functional specialization at the macro scale, remains an open question in the human brain. Here, we focused on age-dependent changes of resting-state thalamocortical connectivity to investigate its role in the emergence of large-scale functional networks across infancy, childhood and young adulthood. We found that the thalamocortical connectivity during infancy reflects an early differentiation of sensorimotor networks and genetically-influenced axonal projection. This initial role of the thalamus, however, seems to change during childhood, by establishing connectivity with the salience network and decoupling externally- and internally-oriented functional processes. Developmental simulation and perturbation analyses corroborated these findings, demonstrating the highest contribution of thalamic connectivity, especially in the later age of youth, in the formation of key characteristics of the mature brain, such as functional gradient and cortical hierarchy. Our study highlights a developmentally shifting role of the thalamus in orchestrating complex brain organization and its potential implications for developmental conditions characterized by compromised internal and external processing.

neuroscience↗

bioRxiv2022

De novo assembly and annotation of the Patagonian toothfish (Dissostichus eleginoides) genome

Patagonian toothfish (Dissostichus eleginoides) is an economically and ecologically important fish species in the family Nototheniidae, found at depths between 70 and 2,500 meters on the southern shelves and slopes around the sub-Antarctic islands of the Southern Ocean. Genomic sequence data for this species is limited. Here, we report a high-quality assembly and annotation of the D. eleginoides genome, generated using a combination of Illumina, PacBio and Omni-C sequencing technologies. To aid the genome annotation, the transcriptome derived from a variety of toothfish tissues was also generated using both short and long read sequencing methods. The final genome assembly was 797.8 Mb with a N50 scaffold length of 3.5 Mb. Approximately 31.7% of the genome consisted of repetitive elements. A total of 35,543 putative protein-coding regions were identified, of which 50% have been functionally annotated. Transcriptomics analysis showed that approximately 64% of the predicted genes (22,617 genes) were found to be expressed in the tissues sampled. Comparative genomics analysis revealed that the anti-freeze glycoprotein (AFGP) locus of D. eleginoides does not contain any AFGP proteins compared to the same locus in the Antarctic toothfish (Dissostichus mawsoni). This is in agreement with previously published results looking at hybridization signals and confirms that Patagonian toothfish do not possess AFGP coding sequences in their genome. The high-quality genome assembly of the Patagonian toothfish will provide a valuable genetic resource for ecological and evolutionary studies on this and other closely related species.

genomics↗

bioRxiv2022

Characterisation and Genetic Architecture of Major Depressive Disorder Subgroups Defined by Weight and Sleep Changes

Major depressive disorder, MDD, is highly heterogeneous and thus subgroups with different underlying aetiologies have been postulated. The aim of this work is to further characterise depression subgroups defined using sleep and weight changes. Probable lifetime MDD cases (n = 26,662) from the UK Biobank were stratified into three subgroups defined by self-reported weight and sleep changes during worst episode: (i) increased weight and sleep ({uparrow}WS), (ii) decreased weight and sleep ({downarrow}WS) and (iii) the remaining uncategorised individuals. Analyses compared the depression characteristics, mental health scores, neurological and inflammatory comorbidities and genetic architecture between subgroups and with 50,147 controls from UK Biobank. In contrast to {uparrow}WS depression, {downarrow}WS depression had a higher age of onset and lower proportion reporting countless or continuous episodes compared to uncategorised individuals. The {downarrow}WS depression also had a higher wellbeing score than the other subgroups. Analyses of subgroup comorbidities identified a novel association between {uparrow}WS depression and epilepsy. Subgroup-specific GWAS identified three genome-wide significant loci associated with {uparrow}WS in genes previously associated with immunometabolic traits and response to anticonvulsants. The effect of BMI adjustment in the genetic analyses of the subgroups and using broader weight-only definitions were also examined. The findings provide further evidence for differences in the characteristics and genetic architecture of depression subgroups defined by sleep and weight change and highlight the importance of dividing non-{uparrow}WS individuals into {downarrow}WS and uncategorised subgroups in analyses, as {downarrow}WS symptoms may identify a more acute depression subgroup.

genomics↗

bioRxiv2020

Broad and strong memory CD4+ and CD8+ T cells induced by SARS-CoV-2 in UK convalescent COVID-19 patients.

COVID-19 is an ongoing global crisis in which the development of effective vaccines and therapeutics will depend critically on understanding the natural immunity to the virus, including the role of SARS-CoV-2-specific T cells. We have conducted a study of 42 patients following recovery from COVID-19, including 28 mild and 14 severe cases, comparing their T cell responses to those of 16 control donors. We assessed the immune memory of T cell responses using IFN{gamma} based assays with overlapping peptides spanning SARS-CoV-2 apart from ORF1. We found the breadth, magnitude and frequency of memory T cell responses from COVID-19 were significantly higher in severe compared to mild COVID-19 cases, and this effect was most marked in response to spike, membrane, and ORF3a proteins. Total and spike-specific T cell responses correlated with the anti-Spike, anti-Receptor Binding Domain (RBD) as well as anti-Nucleoprotein (NP) endpoint antibody titre (p<0.001, <0.001 and =0.002). We identified 39 separate peptides containing CD4+ and/or CD8+ epitopes, which strikingly included six immunodominant epitope clusters targeted by T cells in many donors, including 3 clusters in spike (recognised by 29%, 24%, 18% donors), two in the membrane protein (M, 32%, 47%) and one in the nucleoprotein (Np, 35%). CD8+ responses were further defined for their HLA restriction, including B*4001-restricted T cells showing central memory and effector memory phenotype. In mild cases, higher frequencies of multi-cytokine producing M- and NP-specific CD8+ T cells than spike-specific CD8+ T cells were observed. They furthermore showed a higher ratio of SARS-CoV-2-specific CD8+ to CD4+ T cell responses. Immunodominant epitope clusters and peptides containing T cell epitopes identified in this study will provide critical tools to study the role of virus-specific T cells in control and resolution of SARS-CoV-2 infections. The identification of T cell specificity and functionality associated with milder disease, highlights the potential importance of including non-spike proteins within future COVID-19 vaccine design.

immunology↗

bioRxiv2019

Healthcare related activity following kidney transplantation: an observational cohort study.

BACKGROUND BACKGROUND METHODS RESULTS DISCUSSION Post-Transplant Activity Applicability Summary Competing interests Patient consent for publication Funding REFERENCES Renal transplantation is regarded as the gold standard of renal replacement therapy (RRT) with evidence of improved life expectancy, quality of life and superior cost-effectiveness when compared to dialysis (1-6). In recent years there has been a steady rise in the incidence of renal transplantation within most developed healthcare economies (7). Such has been the observed benefit that transplantation is now being considered across an increasingly wide range of patient age, BMI and comor ...

epidemiology↗

bioRxiv2018

Genome-wide by environment interaction studies (GWEIS) of depressive symptoms and psychosocial stress in UK Biobank and Generation Scotland.

Stress is associated with poorer physical and mental health. To improve our understanding of this link, we performed genome-wide association studies (GWAS) of depressive symptoms and genome-wide by environment interaction studies (GWEIS) of depressive symptoms and stressful life events (SLE) in two UK population cohorts (Generation Scotland and UK Biobank). No SNP was individually significant in either GWAS, but gene-based tests identified six genes associated with depressive symptoms in UK Biobank (DCC, ACSS3, DRD2, STAG1, FOXP2 and KYNU; p < 2.77x10-6). Two SNPs with genome-wide significant GxE effects were identified by GWEIS in Generation Scotland: rs12789145 (53kb downstream PIWIL4; p = 4.95x10-9; total SLE) and rs17070072 (intronic to ZCCHC2; p = 1.46x10-8; dependent SLE). A third locus upstream CYLC2 (rs12000047 and rs12005200, p < 2.00x10-8; dependent SLE) when the joint effect of the SNP main and GxE effects was considered. GWEIS gene-based tests identified: MTNR1B with GxE effect with dependent SLE in Generation Scotland; and PHF2 with the joint effect in UK Biobank (p < 2.77x10-6). Polygenic risk scores (PRS) analyses incorporating GxE effects improved the prediction of depressive symptom scores, when using weights derived from either the UK Biobank GWAS of depressive symptoms (p = 0.01) or the PGC GWAS of major depressive disorder (p = 5.91x10-3). Using an independent sample, PRS derived using GWEIS GxE effects provided evidence of shared aetiologies between depressive symptoms and schizotypal personality, heart disease and COPD. Further such studies are required and may result in improved treatments for depression and other stress-related conditions.

genetics↗

bioRxiv2018

Replication of the diathesis-stress model for depression in Generation Scotland.

Depression has well-established influences from genetic and environmental risk factors. This has led to the diathesis-stress theory, which assumes a multiplicative gene-by-environment interaction (GxE) effect on risk. Recently, Colodro-Conde et al. empirically tested this theory, using the polygenic risk score for major depressive disorder (PRS, genes) and stressful life events (SLE, environment) effects on depressive symptoms, identifying significant GxE effects with an additive contribution to liability. We have tested the diathesis-stress theory on an independent sample of 4 919 individuals.\n\nWe identified nominally significant positive GxE effects in the full cohort (R2 = 0.08%, p = 0.049) and in women (R2 = 0.19%, p = 0.017), but not in men (R2 = 0.15%, p = 0.07). GxE effects were nominally significant, but only in women, when SLE were split into those in which the respondent plays an active or passive role (R2 = 0.15%, p = 0.038; R2 = 0.16%, p = 0.033, respectively). High PRS increased the risk of depression in participants reporting high numbers of SLE (p = 2.86 x 10-4). However, in those participants who reported no recent SLE, a higher PRS appeared to increase the risk of depressive symptoms in men ({beta} = 0.082, p = 0.016) but had a protective effect in women ({beta} = -0.061, p = 0.037). This difference was nominally significant (p = 0.017). Our study reinforces the evidence of additional risk in the aetiology of depression due to GxE effects. However, larger sample sizes are required to robustly validate these findings.

genomics↗

bioRxiv2017

Genetic and environmental determinants of stressful life events and their overlap with depression and neuroticism

BackgroundStressful life events (SLEs) and neuroticism are risk factors for major depressive disorder (MDD). However, SLEs and neuroticism are heritable traits that are correlated with genetic risk for MDD. In the current study, we sought to investigate the genetic and environmental contributions to SLEs in a large family-based sample, and quantify any genetic overlap with MDD and neuroticism.\n\nMethodsA subset of Generation Scotland: the Scottish Family Health Study, consisting of 9618 individuals comprise the present study. We estimated the heritability of SLEs using pedigree-based and molecular genetic data. The environment was assessed by modelling familial, couple and sibling components. Using polygenic risk scores (PRS) and LD score regression we analysed the genetic overlap between MDD, neuroticism and SLEs.\n\nResultsPast 6-month life events were positively correlated with lifetime MDD status ({beta}=0.21, r2=1.1%, p=2.5 x 10-25) and neuroticism ({beta} =0.13, r2=1.9%, p=1.04 x 10-37). Common SNPs explained 8% of the variance in personal life events (those directly affecting the individual) (S.E.=0.03, p=9 x 10-4). A significant effect of couple environment accounted for 13% (S.E.=0.03, p=0.016) of variation in SLEs. PRS analyses found that individuals with higher PRS for MDD reported more SLEs ({beta} =0.05, r2=0.3%, p=3 x 10-5). LD score regression demonstrated genetic correlations between MDD and both SLEs (rG=0.33, S.E.=0.08) and neuroticism (rG=0.15, S.E.=0.07).\n\nConclusionsThese findings suggest that SLEs are partially heritable and this heritability is shared with risk for MDD and neuroticism. Further work should determine the causal direction and source of these associations.

genetics↗

bioRxiv2017

Genome-wide interaction study of stress-sensitivity and its prediction of major depressive disorder in UK Biobank and Generation Scotland

Individual 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 = 1.48x10-7; Bonferroni-corrected significance threshold p < 2.79x10-6). 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.

genetics↗

bioRxiv2016

Rare disruptive variants in the DISC1 Interactome and Regulome: association with cognitive ability and schizophrenia

Schizophrenia (SCZ), bipolar disorder (BD) and recurrent major depressive disorder (rMDD) are common psychiatric illnesses. All have been associated with lower cognitive ability, and show evidence of genetic overlap and substantial evidence of pleiotropy with cognitive function and neuroticism. Disrupted in schizophrenia 1 (DISC1) protein directly interacts with a large set of proteins (DISC1 Interactome) that are involved in brain development and signaling. Modulation of DISC1 expression alters the expression of a circumscribed set of genes (DISC1 Regulome) that are also implicated in brain biology and disorder. Here, we report targeted sequencing of 59 DISC1 Interactome genes and 154 Regulome genes in 654 psychiatric patients and 889 cognitively-phenotyped control subjects, on whom we previously reported evidence for trait association from complete sequencing of the DISC1 locus. Burden analyses of rare and singleton variants predicted to be damaging were performed for psychiatric disorders, cognitive variables and personality traits. The DISC1 Interactome and Regulome showed differential association across the phenotypes tested. After family-wise error correction across all traits (FWERacross), an increased burden of singleton disruptive variants in the Regulome was associated with SCZ (FWERacross P=0.0339). The burden of singleton disruptive variants in the DISC1 Interactome was associated with low cognitive ability at age 11 (FWERacross P=0.0043). These results suggest that variants in the DISC1 Interactome effect the risk of psychiatric illness through altered expression of schizophrenia-associated genes. The biological impact of rare variants highlighted here merit further study.

genetics↗