ORCID Profile
0000-0003-0821-1112
Current Organisation
University of Oxford
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Springer Science and Business Media LLC
Date: 21-11-2016
DOI: 10.1038/NG.3725
Publisher: Springer Science and Business Media LLC
Date: 22-01-2018
DOI: 10.1038/S41398-017-0052-Z
Abstract: Brain white matter abnormalities are evident in in iduals with schizophrenia, and also their first-degree relatives, suggesting that some alterations may relate to underlying genetic risk. The ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 2 ( ST8SIA2) gene, which encodes the alpha-2,8-sialyltransferase 8B enzyme that aids neuronal migration and synaptic plasticity, was previously implicated as a schizophrenia susceptibility gene. This study examined the extent to which specific haplotypes in ST8SIA2 influence white matter microstructure using diffusion-weighted imaging of in iduals with schizophrenia ( n = 281) and healthy controls ( n = 172), recruited across five Australian sites. Interactions between diagnostic status and the number of haplotype copies (0 or ≥1) were tested across all white matter voxels with cluster-based statistics. Fractional anisotropy (FA) in the right parietal lobe was found to show a significant interaction between diagnosis and ST8SIA2 protective haplotype ( p 0.05, family-wise error rate (FWER) cluster-corrected). The protective haplotype was associated with increased FA in controls, but this effect was reversed in people with schizophrenia. White matter fiber tracking revealed that the region-of-interest was traversed by portions of the superior longitudinal fasciculus, corona radiata, and posterior limb of internal capsule. Post hoc analysis revealed that reduced FA in this regional juncture correlated with reduced IQ in people with schizophrenia. The ST8SIA2 risk haplotype copy number did not show any differential effects on white matter. This study provides a link between a common disease-associated haplotype and specific changes in white matter microstructure, which may relate to resilience or risk for mental illness, providing further compelling evidence for involvement of ST8SIA2 in the pathophysiology of schizophrenia.
Publisher: Cold Spring Harbor Laboratory
Date: 22-09-2023
Publisher: American Association for the Advancement of Science (AAAS)
Date: 20-03-2020
Abstract: The cerebral cortex underlies our complex cognitive capabilities. Variations in human cortical surface area and thickness are associated with neurological, psychological, and behavioral traits and can be measured in vivo by magnetic resonance imaging (MRI). Studies in model organisms have identified genes that influence cortical structure, but little is known about common genetic variants that affect human cortical structure. To identify genetic variants associated with human cortical structure at both global and regional levels, we conducted a genome-wide association meta-analysis of brain MRI data from 51,665 in iduals across 60 cohorts. We analyzed the surface area and average thickness of the whole cortex and 34 cortical regions with known functional specializations. We identified 369 nominally genome-wide significant loci ( P 5 × 10 −8 ) associated with cortical structure in a discovery s le of 33,992 participants of European ancestry. Of the 360 loci for which replication data were available, 241 loci influencing surface area and 66 influencing thickness remained significant after replication, with 237 loci passing multiple testing correction ( P 8.3 × 10 −10 187 influencing surface area and 50 influencing thickness). Common genetic variants explained 34% (SE = 3%) of the variation in total surface area and 26% (SE = 2%) in average thickness surface area and thickness showed a negative genetic correlation ( r G = −0.32, SE = 0.05, P = 6.5 × 10 −12 ), which suggests that genetic influences have opposing effects on surface area and thickness. Bioinformatic analyses showed that total surface area is influenced by genetic variants that alter gene regulatory activity in neural progenitor cells during fetal development. By contrast, average thickness is influenced by active regulatory elements in adult brain s les, which may reflect processes that occur after mid-fetal development, such as myelination, branching, or pruning. When considered together, these results support the radial unit hypothesis that different developmental mechanisms promote surface area expansion and increases in thickness. To identify specific genetic influences on in idual cortical regions, we controlled for global measures (total surface area or average thickness) in the regional analyses. After multiple testing correction, we identified 175 loci that influence regional surface area and 46 that influence regional thickness. Loci that affect regional surface area cluster near genes involved in the Wnt signaling pathway, which is known to influence areal identity. We observed significant positive genetic correlations and evidence of bidirectional causation of total surface area with both general cognitive functioning and educational attainment. We found additional positive genetic correlations between total surface area and Parkinson’s disease but did not find evidence of causation. Negative genetic correlations were evident between total surface area and insomnia, attention deficit hyperactivity disorder, depressive symptoms, major depressive disorder, and neuroticism. This large-scale collaborative work enhances our understanding of the genetic architecture of the human cerebral cortex and its regional patterning. The highly polygenic architecture of the cortex suggests that distinct genes are involved in the development of specific cortical areas. Moreover, we find evidence that brain structure is a key phenotype along the causal pathway that leads from genetic variation to differences in general cognitive function. ( A ) Measurement of cortical surface area and thickness from MRI. ( B ) Genomic locations of common genetic variants that influence global and regional cortical structure. ( C ) Our results support the radial unit hypothesis that the expansion of cortical surface area is driven by proliferating neural progenitor cells. ( D ) Cortical surface area shows genetic correlation with psychiatric and cognitive traits. Error bars indicate SE. IMAGE CREDITS: (A) K. COURTNEY (C) M. R. GLASS
Publisher: Cold Spring Harbor Laboratory
Date: 16-08-2023
DOI: 10.1101/2023.08.14.23294084
Abstract: Circulating proteins are integral to many biological processes. We aimed to assess differences in the plasma proteome between people of different dietary groups defined by degree of animal food consumption. The UK Biobank recruited middle-aged adults (mostly 40 to 69 years) throughout the UK between 2006-2010. Relative concentrations of 1463 plasma proteins were quantified using the Olink Proximity Extension Assay on blood s les from 49,326 participants, who were also asked to report their ethnicity and consumption of red and processed meat, poultry, fish, dairy and eggs. We defined six diet groups among the white British participants (23,116 regular meat eaters, 23,323 low meat eaters, 484 poultry eaters, 1074 fish eaters, 722 vegetarians, and 54 vegans), and two diet groups among the British Indians (390 meat eaters and 163 vegetarians). We used multivariable-adjusted linear regressions to assess differences in protein concentrations between diet groups, with correction for multiple testing. We observed significant differences in many plasma proteins by diet group (683 proteins in white British participants, 1 in British Indians), in particular many proteins that are majority expressed in the digestive system. Of the biggest differences, compared with regular meat eaters, the non-meat eaters had significantly higher FGF21 (e.g. +0.40 SD in vegetarians), GUCA2A (+0.33), FOLR1 (+0.32), IGFBP2 (+0.31) and DSG2 (+0.30) all groups except the vegans had lower HAVCR1 (-0.38 in vegetarians). The observed differences were generally similar in direction in both ethnicities. In this first comprehensive assessment of plasma proteins by diet group, we identified many differences in proteins between groups defined by animal food consumption this variation in protein levels suggests differences in various biological activities, including gastrointestinal tract and kidney function, which may relate to differences in future disease risk.
Publisher: Cold Spring Harbor Laboratory
Date: 29-06-2023
DOI: 10.1101/2023.06.20.23291538
Abstract: International differences in the incidence of many cancer types indicate the existence of carcinogen exposures which make a substantial contribution to cancer burden, vary geographically, and have underlying agents thus far unidentified by conventional epidemiology 1 . This pertains to clear cell renal cell carcinomas (ccRCC), for which obesity, hypertension, and tobacco smoking are risk factors but do not explain its geographical variation in incidence 2 . Some carcinogens generate somatic mutations and past exposures can be inferred from the patterns of mutations found in cancer genomes. Therefore, we sequenced the whole genomes of 962 ccRCC from 11 countries of varying incidence. Somatic mutation profiles differed between countries. In Romania, Serbia and Thailand, mutational signatures likely caused by extracts of Aristolochia plants were present in most cases and rare elsewhere. In Japan, a mutational signature of unknown cause was found in % cases and % elsewhere. Another mutational signature of unknown cause was ubiquitous and associated with kidney cancer incidence rates (p-value × 10 −18 ), with higher numbers of mutations in countries with higher risk. Known signatures of tobacco smoking correlated with tobacco consumption, but no signature was associated with obesity or hypertension suggesting non-mutagenic mechanisms of action underlying these risk factors. The results indicate the existence of multiple, widespread, geographically variable mutagenic exposures to known and unknown agents, which may contribute to the incidence of kidney cancer.
Publisher: Cold Spring Harbor Laboratory
Date: 14-05-2021
DOI: 10.1101/2021.05.11.21257061
Abstract: There is a long-standing interest in exploring the relationship between blood-based biomarkers of biological exposures and psychiatric disorders, despite their causal role being difficult to resolve in observational studies. In this study, we leverage genome-wide association study data for a large panel of heritable biochemical traits measured from serum to refine our understanding of causal effect in biochemical-psychiatric trait parings. In accordance with expectation we observed widespread evidence of positive and negative genetic correlation between psychiatric disorders and biochemical traits. We then implemented causal inference to distinguish causation from correlation and found strong evidence that C-reactive protein (CRP) exerts a causal effect on psychiatric disorders, along with other putatively causal relationships involving urate and glucose. Strikingly, these analyses suggested CRP has a protective effect on three disorders including anorexia nervosa, obsessive-compulsive disorder, and schizophrenia, whilst being a risk factor for major depressive disorder. Multivariable models that conditioned CRP effects on interleukin-6 signalling and body mass index suggested that CRP-schizophrenia relationship was not likely mediated by those factors. Collectively, these data suggest that there are shared pathways that influence both biochemical traits and psychiatric illness, including factors such as CRP that are likely to constitute a causal effect and could be targets for therapeutic intervention and precision medicine.
Publisher: Springer Science and Business Media LLC
Date: 18-10-2021
DOI: 10.1038/S41588-021-00928-6
Abstract: Esophageal squamous cell carcinoma (ESCC) shows remarkable variation in incidence that is not fully explained by known lifestyle and environmental risk factors. It has been speculated that an unknown exogenous exposure(s) could be responsible. Here we combine the fields of mutational signature analysis with cancer epidemiology to study 552 ESCC genomes from eight countries with varying incidence rates. Mutational profiles were similar across all countries studied. Associations between specific mutational signatures and ESCC risk factors were identified for tobacco, alcohol, opium and germline variants, with modest impacts on mutation burden. We find no evidence of a mutational signature indicative of an exogenous exposure capable of explaining differences in ESCC incidence. Apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like (APOBEC)-associated mutational signatures single-base substitution (SBS)2 and SBS13 were present in 88% and 91% of cases, respectively, and accounted for 25% of the mutation burden on average, indicating that APOBEC activation is a crucial step in ESCC tumor development.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 08-04-2022
Abstract: There is a long-standing interest in exploring the relationship between blood-based biomarkers and psychiatric disorders, despite their causal role being difficult to resolve in observational studies. In this study, we leverage genome-wide association study data for a large panel of heritable serum biochemical traits to refine our understanding of causal effect in biochemical-psychiatric trait pairings. We observed widespread positive and negative genetic correlation between psychiatric disorders and biochemical traits. Causal inference was then implemented to distinguish causation from correlation, with strong evidence that C-reactive protein (CRP) exerts a causal effect on psychiatric disorders. Notably, CRP demonstrated both protective and risk-increasing effects on different disorders. Multivariable models that conditioned CRP effects on interleukin-6 signaling and body mass index supported that the CRP-schizophrenia relationship was not driven by these factors. Collectively, these data suggest that there are shared pathways that influence both biochemical traits and psychiatric illness.
Publisher: Springer Science and Business Media LLC
Date: 20-02-2019
Publisher: Cold Spring Harbor Laboratory
Date: 03-06-2019
DOI: 10.1101/655001
Abstract: In iduals with complex disorders typically have a heritable burden of common variation that can be expressed as a polygenic risk score (PRS). While PRS has some predictive utility, it lacks the molecular specificity to be directly informative for clinical interventions. We therefore sought to develop a framework to quantify an in idual’s common variant enrichment in clinically actionable systems responsive to existing drugs. This was achieved with a metric designated the pharmagenic enrichment score (PES), which we demonstrate for in idual SNP profiles in a cohort of cases with schizophrenia. A large proportion of these had elevated PES in one or more of eight clinically actionable gene-sets enriched with schizophrenia associated common variation. Notable candidates targeting these pathways included vitamins, insulin modulating agents, and protein kinase inhibitors with putative neuroprotective properties. Interestingly, elevated PES was also observed in in iduals with otherwise low common variant burden. The biological saliency of PES profiles were observed directly through their impact on gene expression in a subset of the cohort with matched transcriptomic data, supporting our assertion that this framework can integrate an in idual’s common variant risk to inform personalised interventions, including drug repositioning, for complex disorders such as schizophrenia.
Publisher: Cold Spring Harbor Laboratory
Date: 30-04-2021
DOI: 10.1101/2021.04.26.21254132
Abstract: Germline genetic variants are involved in lung cancer (LC) susceptibility. Previous genome-wide association studies (GWAS) have implicated genes involved in smoking propensity and DNA repair but further work is required to identify additional LC susceptibility variants and to investigate LC disease development dynamics. We have undertaken a family history-based genome-wide association (GWAx) study of LC, analysing 48,843 European cases with a parent/sibling with LC compared to 195,387 controls from the UK Biobank. This was meta-analysed with previously described LC GWAS results. We performed Polygenic Risk Scores (PRS) analyses and further evaluated the PRS influence on the somatic environment in exome (N=736) and genome sequencing (N=61) profiled cohorts. Eight novel loci were identified including DNA repair genes ( CHEK1, MDM4 ), metabolic genes ( CYP1A1 ) and variants that were also associated with smoking propensity, such as both subunits of the neuronal α4β2 nicotinic acetylcholine receptor ( CHRNA4 and CHRNB2) . PRS analysis demonstrated that variants related to eQTLs and/or smoking propensity are enriched for susceptibility variants, including variants below genome-wide significant threshold. PRS of LC variants related to smoking propensity were associated with somatic mutation burden in two case cohorts, with in iduals with higher polygenic genetic risk having increased numbers of somatic mutations in their lung tumours. This study has expanded the number of susceptibility loci linked with LC and provided insights into the molecular mechanisms by which these susceptibility variants contribute to the development of lung cancer.
Publisher: Springer Science and Business Media LLC
Date: 23-01-2020
DOI: 10.1038/S41467-019-14079-0
Abstract: Population health research is increasingly focused on the genetic determinants of healthy ageing, but there is no public resource of whole genome sequences and phenotype data from healthy elderly in iduals. Here we describe the first release of the Medical Genome Reference Bank (MGRB), comprising whole genome sequence and phenotype of 2570 elderly Australians depleted for cancer, cardiovascular disease, and dementia. We analyse the MGRB for single-nucleotide, indel and structural variation in the nuclear and mitochondrial genomes. MGRB in iduals have fewer disease-associated common and rare germline variants, relative to both cancer cases and the gnomAD and UK Biobank cohorts, consistent with risk depletion. Age-related somatic changes are correlated with grip strength in men, suggesting blood-derived whole genomes may also provide a biologic measure of age-related functional deterioration. The MGRB provides a broadly applicable reference cohort for clinical genetics and genomic association studies, and for understanding the genetics of healthy ageing.
Publisher: Wiley
Date: 09-07-2022
DOI: 10.1002/IJC.34180
Abstract: Deucravacitinib, a novel, selective inhibitor of TYK2 is currently under review at the FDA and EMA for treatment of moderate‐to‐severe plaque psoriasis. It is unclear whether recent safety concerns (ie, elevated rates of lung cancer and lymphoma) related to similar medications (ie, other JAK inhibitors) are shared with this novel TYK2 inhibitor. We used a partial loss‐of‐function variant in TYK2 (rs34536443), previously shown to protect against psoriasis and other autoimmune diseases, to evaluate the potential effect of therapeutic TYK2 inhibition on risk of lung cancer and non‐Hodgkin lymphoma. Summary genetic association data on lung cancer risk were obtained from a GWAS meta‐analysis of 29 266 cases and 56 450 controls in the Integrative Analysis of Lung Cancer Risk and Aetiology (INTEGRAL) consortium. Summary genetic association data on non‐Hodgkin lymphoma risk were obtained from a GWAS meta‐analysis of 8489 cases and 374 506 controls in the UK Biobank and InterLymph consortium. In the primary analysis, each copy of the minor allele of rs34536443, representing partial TYK2 inhibition, was associated with an increased risk of lung cancer (OR 1.15, 95% CI 1.09‐1.23, P = 2.29 × 10 −6 ) and non‐Hodgkin lymphoma (OR 1.18, 95% CI 1.05‐1.33, P = 5.25 × 10 −3 ). Our analyses using an established partial loss‐of‐function mutation to mimic TYK2 inhibition provide genetic evidence that therapeutic TYK2 inhibition may increase risk of lung cancer and non‐Hodgkin lymphoma. These findings, consistent with recent reports from postmarketing trials of similar JAK inhibitors, could have important implications for future safety assessment of deucravacitinib and other TYK2 inhibitors in development.
Publisher: Cold Spring Harbor Laboratory
Date: 05-08-2023
DOI: 10.1101/2023.07.28.23293330
Abstract: Proteins are essential for the development and progression of cancer and for the human body’s defense against tumor onset. The availability of a large panel of protein measurements and whole exome sequence data in the UK Biobank has enabled the simultaneous examination of plasma protein associations with risk across multiple cancer sites and their potential role in cancer etiology. We investigated the associations of plasma proteins with incidence of 19 cancers and 9 cancer subsites in up to 44,645 middle-aged adults in the UK Biobank, who had measurements of 1,463 plasma proteins generated using Olink Explore Proximity Extension Assay in baseline blood s les (2006-2010). Using multivariable-adjusted Cox regression, we estimated the risk of each protein with each cancer overall and by time-to-diagnosis after correction for multiple-testing. Identified protein-cancer associations were further assessed in an analysis of cancer risk using cis -pQTL and exome-wide protein genetic scores (exGS) in all UK Biobank participants (n=337,543). We identified 371 proteins associated with the risk of at least one incident cancer, represented by a total of 621 protein-cancer associations. These proteins were associated with cancers of the blood (201 proteins), liver (131), kidney (51), lung (28), esophagus (22), colorectum (15), stomach (8), breast (5), prostate (3), endometrium (3), ovary (2), bladder (1), head and neck (1), and brain (1). 100 of these 621 protein-cancer associations persisted for cases diagnosed more than seven years after blood draw. Of these 621 associations, there was further support from cis -pQTL analyses for the etiological role of TNFRSF14 in risk of non-Hodgkin lymphoma (NHL), and from whole exome protein score (exGS) analyses for 28 other protein-cancer associations, including SRP14 and risk of leukemia. Proteins with directionally concordant evidence from long time-to-diagnosis analyses and from both cis -pQTL and exGS analyses were SFTPA2 for lung cancer, TNFRSF1B and CD74 for NHL, and ADAM8 for leukemia. For the first time using an integrated multi-omics and cross-cancer approach, we have comprehensively assessed the plasma proteome in relation to cancer risk and identified multiple novel etiological candidates. Differences in the levels of many circulating proteins were detectable more than seven years before cancer diagnosis while some of these are likely to be markers of early cancer processes that may inform risk stratification, and/or risk factors, concordant evidence from genetic analyses suggests that some may have a role in cancer development.
Publisher: Oxford University Press (OUP)
Date: 02-05-2022
DOI: 10.1093/JNCI/DJAC087
Abstract: Germline genetic variation contributes to lung cancer (LC) susceptibility. Previous genome-wide association studies (GWAS) have implicated susceptibility loci involved in smoking behaviors and DNA repair genes, but further work is required to identify susceptibility variants. To identify LC susceptibility loci, a family history-based genome-wide association by proxy (GWAx) of LC (48 843 European proxy LC patients, 195 387 controls) was combined with a previous LC GWAS (29 266 patients, 56 450 controls) by meta-analysis. Colocalization was used to explore candidate genes and overlap with existing traits at discovered susceptibility loci. Polygenic risk scores (PRS) were tested within an independent validation cohort (1 666 LC patients vs 6 664 controls) using variants selected from the LC susceptibility loci and a novel selection approach using published GWAS summary statistics. Finally, the effects of the LC PRS on somatic mutational burden were explored in patients whose tumor resections have been profiled by exome (n = 685) and genome sequencing (n = 61). Statistical tests were 2-sided. The GWAx–GWAS meta-analysis identified 8 novel LC loci. Colocalization implicated DNA repair genes (CHEK1), metabolic genes (CYP1A1), and smoking propensity genes (CHRNA4 and CHRNB2). PRS analysis demonstrated that these variants, as well as subgenome-wide significant variants related to expression quantitative trait loci and/or smoking propensity, assisted in LC genetic risk prediction (odds ratio = 1.37, 95% confidence interval = 1.29 to 1.45 P & .001). Patients with higher genetic PRS loads of smoking-related variants tended to have higher mutation burdens in their lung tumors. This study has expanded the number of LC susceptibility loci and provided insights into the molecular mechanisms by which these susceptibility variants contribute to LC development.
Publisher: Cold Spring Harbor Laboratory
Date: 22-03-2022
DOI: 10.1101/2022.03.20.22272666
Abstract: Genetically informed drug development and repurposing is an attractive prospect for improving outcomes in patients with psychiatric illness however, the effectiveness of these endeavours can be confounded by heterogeneity. In this study, we propose a novel approach that links interventions implicated by disorder-associated genetic risk, at the population level, to a framework that can target these compounds to in iduals. Specifically, results from genome-wide association studies are integrated with expression data to prioritise in idual 'directional anchor' genes for which the predicted risk-increasing direction of expression could be counteracted by an existing drug. While these compounds represent plausible therapeutic candidates, they are not likely to be equally efficacious for all in iduals. To account for this heterogeneity, we constructed polygenic scores restricted to variants annotated to the network of genes that interact with each directional anchor gene. These metrics, we call pharmagenic enrichment scores (PES), identify in iduals with a higher burden of genetic risk, localised in biological processes related to the candidate drug target, to inform precision drug repurposing. We used this approach to investigate schizophrenia and bipolar disorder and reveal several compounds targeting specific directional anchor genes that could be plausibly repurposed, including antioxidants, vitamins, antiarrhythmics, and lipid modifying agents. These genetic risk scores, mapped to the networks associated with target genes, revealed biological insights that cannot be observed in undifferentiated genome-wide polygenic risk score (PRS). For ex le, an enrichment of these partitioned scores in schizophrenia cases with otherwise low PRS and distinct correlations with measured biochemical traits. In summary, genetic risk could be used more specifically to direct drug repurposing candidates that target particular genes implicated in psychiatric and other complex disorders.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Joshua Atkins.