Biology subjects

Campbell, H.

Publications and source records attributed to Campbell, H..

11 recordsLinked to original sources

bioRxiv2022

Epidermal threads reveal the origin of hagfish slime

Fiber-reinforced soft materials possess high flexibility with high strength but are rare in nature. Hagfishes can produce a tough, fibrous slime within a fraction of a second by ejecting two cellular products, mucus and threads, into seawater. With thousands of silk-like threads, the slime is highly effective in defending against large predators. However, the evolutionary origin of hagfish slime remains unresolved, with the presence of another, putatively homologous thread in the epidermis providing circumstantial evidence for an epidermal origin. Here, we investigated the epidermal threads produced in hagfish skin. We found that these threads average [~]2 mm in length and [~]0.5 m in diameter, or [~]80 times shorter and [~]4 times thinner than the slime threads, characterizing the second longest intracellular fiber. The entire hagfish body is covered by a dense layer of epidermal thread cells, with each square millimeter of skin storing a total of [~]96 cm threads. Experimentally induced damage to a hagfishs skin caused the release of threads, which together with mucus, formed an adhesive epidermal slime that is more fibrous and less dilute than the defensive slime. Transcriptome analyses further revealed that the epidermal threads are ancestral to the slime threads, with duplication and diversification of thread genes in parallel with the evolution of slime glands. These results support an epidermal origin of hagfish slime and slime glands, as driven by predator selection for stronger and more voluminous slime.

evolutionary biology↗

bioRxiv2021

Within-sibship GWAS improve estimates of direct genetic effects

Estimates from genome-wide association studies (GWAS) represent a combination of the effect of inherited genetic variation (direct effects), demography (population stratification, assortative mating) and genetic nurture from relatives (indirect genetic effects). GWAS using family-based designs can control for demography and indirect genetic effects, but large-scale family datasets have been lacking. We combined data on 159,701 siblings from 17 cohorts to generate population (between-family) and within-sibship (within-family) estimates of genome-wide genetic associations for 25 phenotypes. We demonstrate that existing GWAS associations for height, educational attainment, smoking, depressive symptoms, age at first birth and cognitive ability overestimate direct effects. We show that estimates of SNP-heritability, genetic correlations and Mendelian randomization involving these phenotypes substantially differ when calculated using within-sibship estimates. For example, genetic correlations between educational attainment and height largely disappear. In contrast, analyses of most clinical phenotypes (e.g. LDL-cholesterol) were generally consistent between population and within-sibship models. We also report compelling evidence of polygenic adaptation on taller human height using within-sibship data. Large-scale family datasets provide new opportunities to quantify direct effects of genetic variation on human traits and diseases.

genetics↗

bioRxiv2019

Genome-wide association study identifies 49 common genetic variants associated with handedness.

Handedness, a consistent asymmetry in skill or use of the hands, has been studied extensively because of its relationship with language and the over-representation of left-handers in some neurodevelopmental disorders. Using data from the UK Biobank, 23andMe and 32 studies from the International Handedness Consortium, we conducted the worlds largest genome-wide association study of handedness (1,534,836 right-handed, 194,198 (11.0%) left-handed and 37,637 (2.1%) ambidextrous individuals). We found 41 genetic loci associated with left-handedness and seven associated with ambidexterity at genome-wide levels of significance (P < 5x10-8). Tissue enrichment analysis implicated the central nervous system and brain tissues including the hippocampus and cerebrum in the etiology of left-handedness. Pathways including regulation of microtubules, neurogenesis, axonogenesis and hippocampus morphology were also highlighted. We found suggestive positive genetic correlations between being left-handed and some neuropsychiatric traits including schizophrenia and bipolar disorder. SNP heritability analyses indicated that additive genetic effects of genotyped variants explained 5.9% (95% CI = 5.8% - 6.0%) of the underlying liability of being left-handed, while the narrow sense heritability was estimated at 12% (95% CI = 7.2% - 17.7%). Further, we show that genetic correlation between left-handedness and ambidexterity is low (rg = 0.26; 95% CI = 0.08 - 0.43) implying that these traits are largely influenced by different genetic mechanisms. In conclusion, our findings suggest that handedness, like many other complex traits is highly polygenic, and that the genetic variants that predispose to left-handedness may underlie part of the association with some psychiatric disorders that has been observed in multiple observational studies.

genetics↗

bioRxiv2019

Physical activity reduces colorectal cancer risk independent of BMI - A two-sample Mendelian randomisation study

BackgroundEvidence from observational studies suggests a protective role for physical activity (PA) against colorectal cancer (CRC) risk. However, it has yet to be established a causal relationship. We conducted a two-sample Mendelian randomisation (MR) study to examine causality between physical activity and CRC risk.\n\nMethodsWe used common genetic variants associated with self-reported and accelerometer-based physical activity as instrumental variables (IVs) in this MR study. The IVs were derived from the largest available genome-wide association study (GWAS) of physical activity, namely UK Biobank. We analysed the effect of the IVs for physical activity in a large CRC GWAS that included 31 197 cases and 61 770 controls. We applied inverse variance weighted (IVW) method as the main analysis method.\n\nResultsOur results demonstrate a protective effect between accelerometer-based physical activity and CRC risk (the outlier-adjusted ORIVW was 0.92 per one standard deviation (SD) increase of accelerometer-base physical activity [95% CI: 0.87-0.98, P: 0.01]). The effect between self-reported physical activity and CRC risk was not statistically significant but was also supportive of an inverse association (the outlier-adjusted ORIVW was 0.61 per 1 SD increase of moderate-to-vigorous physical activity [95%CI: 0.36-1.06, P: 0.08]).\n\nConclusionsThe findings of this large MR study show for the first time that objectively measured physical activity is causally implicated in reducing CRC risk. The limitations of the study are that it is based on only two genetic instruments and that it has limited power, despite the study size. Nonetheless, at a population level, these findings provide strong reinforcing evidence to support public health policy measures that encourage exercise, even in obese individuals.

genetics↗

bioRxiv2019

A Phenome-wide Mendelian Randomisation study on genetically determined serum urate levels in UK Biobank cohort

IntroductionThe role of serum urate level has been extensively investigated in observational studies. However, the extent of any causal effect remains unclear, making it difficult to evaluate its clinical relevance.\n\nObjectivesTo explore any causal or pleiotropic association between serum urate level and a broad spectrum of disease outcomes.\n\nMethodsPhenome-wide association study (PheWAS) together with a Bayesian analysis of tree-structured phenotypic models (TreeWAS) was performed to examine disease outcomes related to genetically determined serum urate levels in 339,256 UK Biobank participants. Mendelian Randomisation (MR) analyses were performed to replicate significant findings using various GWAS consortia data. Sensitivity analyses were conducted to examine possible pleiotropic effects on metabolic traits of the genetic variants used as instruments for serum urate.\n\nResultsPheWAS analysis, examining the association with 1,431 disease outcomes, identified a multitude of disease outcomes including gout, hypertension, hypercholesterolemia, and heart diseases (e.g., coronary atherosclerosis, myocardial infarction, and ischaemic heart disease) that were associated (p<3.35e-04) with genetically determined serum urate levels. TreeWAS analysis, examining 10,750 ICD-10 diagnostic terms, identified more sub-phenotypes of cardiovascular and cerebrovascular diseases (e.g., angina pectoris, heart failure, cerebral infarction). MR analysis successfully replicated the association with gout, hypertension, heart diseases and blood lipid levels, but indicated the existence of genetic pleiotropy. Sensitivity analyses support an inference that pleiotropic effects of genetic variants on urate and metabolic traits contribute to the observational associations with cardiovascular diseases.\n\nConclusionsHigh serum urate levels are associated with different types of cardiac events. The finding of genetic pleiotropy indicates the existence of common upstream pathological elements influencing both urate and metabolic traits, and this may suggest new opportunities and challenges for developing drugs targeting a more distal mediator that would be beneficial for both the treatment of gout and the prevention of cardiovascular comorbidities.

epidemiology↗

bioRxiv2019

Proteome-by-phenome Mendelian Randomisation detects 38 proteins with causal roles in human diseases and traits

Target identification remains a crucial challenge in drug development. To enable unbiased detection of proteins and pathways that have a causal role in disease pathogenesis or progression, we propose proteome-by-phenome Mendelian Randomisation (P2MR). We first detected genetic variants associated with plasma concentration of 249 proteins. We then used 64 replicated variants in two-sample Mendelian Randomisation to quantify evidence of a causal role for each protein across 846 phenotypes: this yielded 509 robust protein-outcome links. P2MR provides substantial promise for drug target prioritisation. We provide confirmatory evidence for a causal role for the proteins encoded at multiple cardiovascular disease risk loci (FGF5, IL6R, LPL, LTA), and discovered that intestinal fatty acid binding protein (FABP2) contributes to disease pathogenesis. Additionally, we find and replicate evidence for a causal role of tyrosine-protein phosphatase non-receptor type substrate 1 (SHPS1; SIRPA) in schizophrenia. Our results provide specific prediction of the effects of changes of plasma protein concentration on complex phenotypes in humans.

genomics↗

bioRxiv2019

Global variability of the human IgG glycome

Immunoglobulin G (IgG) is the most abundant serum antibody and is a key determinant of the humoral immune response. Its structural characteristics and effector functions are modulated through the attachment of various sugar moieties called glycans. IgG N-glycome patterns change with the age of individual and in different diseases. Variability of IgG glycosylation within a population is well studied and is affected by a combination of genetic and environmental factors. However, global inter-population differences in IgG glycosylation have never been properly addressed. Here we present population-specific N-glycosylation patterns of whole IgG, analysed in 5 different populations totalling 10,482 IgG glycomes, and of IgGs fragment crystallisable region (Fc), analysed in 2,530 samples from 27 populations sampled across the world. We observed that country of residence associates with many N-glycan features and is a strong predictor of monogalactosylation variability. IgG galactosylation also strongly correlated with the development level of a country, defined by United Nations health and socioeconomic development indicators. We found that subjects from developing countries had low IgG galactosylation levels, characteristic for inflammation and ageing. Our results suggest that citizens of developing countries may be exposed to country-specific environmental factors that can cause low-grade chronic inflammation and the apparent increase in biological age.

biochemistry↗

bioRxiv2018

Developing and Evaluating Mappings of ICD-10 and ICD-10-CM codes to Phecodes

BackgroundThe PheCode system was built upon the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) for phenome-wide association studies (PheWAS) in the electronic health record (EHR).\n\nObjectiveHere, we present our work on the development and evaluation of maps from ICD-10 and ICD-10-CM codes to PheCodes.\n\nMethodsWe mapped ICD-10 and ICD-10-CM codes to PheCodes using a number of methods and resources, such as concept relationships and explicit mappings from the Unified Medical Language System (UMLS), Observational Health Data Sciences and Informatics (OHDSI), Systematized Nomenclature of Medicine - Clinical Terms (SNOMED CT), and National Library of Medicine (NLM). We assessed the coverage of the maps in two databases: Vanderbilt University Medical Center (VUMC) using ICD-10-CM and the UK Biobank (UKBB) using ICD-10. We assessed the fidelity of the ICD-10-CM map in comparison to the gold-standard ICD-9-CM[->]PheCode map by investigating phenotype reproducibility and conducting a PheWAS.\n\nResultsWe mapped >75% of ICD-10-CM and ICD-10 codes to PheCodes. Of the unique codes observed in the VUMC (ICD-10-CM) and UKBB (ICD-10) cohorts, >90% were mapped to PheCodes. We observed 70-75% reproducibility for chronic diseases and <10% for an acute disease. A PheWAS with a lipoprotein(a) (LPA) genetic variant, rs10455872, using the ICD-9-CM and ICD-10-CM maps replicated two genotype-phenotype associations with similar effect sizes: coronary atherosclerosis (ICD-9-CM: P < .001, OR = 1.60 vs. ICD-10-CM: P < .001, OR = 1.60) and with chronic ischemic heart disease (ICD-9-CM: P < .001, OR = 1.5 vs. ICD-10-CM: P < .001, OR = 1.47).\n\nConclusionsThis study introduces the initial \"beta\" versions of ICD-10 and ICD-10-CM to PheCode maps that will enable researchers to leverage accumulated ICD-10 and ICD-10-CM data for high-throughput PheWAS in the EHR.

bioinformatics↗

bioRxiv2018

Defining the genetic control of human blood plasma N-glycome using genome-wide association study

Glycosylation is a common post-translational modification of proteins. It is known, that glycans are directly involved in the pathophysiology of every major disease. Defining genetic factors altering glycosylation may provide a basis for novel approaches to diagnostic and pharmaceutical applications. Here, we report a genome-wide association study of the human blood plasma N-glycome composition in up to 3811 people. We discovered and replicated twelve loci. This allowed us to demonstrate a clear overlap in genetic control between total plasma and IgG glycosylation. Majority of loci contained genes that encode enzymes directly involved in glycosylation (FUT3/FUT6, FUT8, B3GAT1, ST6GAL1, B4GALT1, ST3GAL4, MGAT3, and MGAT5). We, however, also found loci that are likely to reflect other, more complex, aspects of plasma glycosylation process. Functional genomic annotation suggested the role of DERL3, which potentially highlights the role of glycoprotein degradation pathway, and such transcription factor as IKZF1.

genetics↗

bioRxiv2018

Genome-wide association meta-analysis of PR interval identifies 47 novel loci associated with atrial and atrioventricular electrical activity

Electrocardiographic PR interval measures atrial and atrioventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. We performed a genome-wide association study in over 92,000 individuals of European descent and identified 44 loci associated with PR interval (34 novel). Examination of the 44 loci revealed known and novel biological processes involved in cardiac atrial electrical activity, and genes in these loci were highly over-represented in several cardiac disease processes. Nearly half of the 61 independent index variants in the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with one or more missense variants. Cardiac regulatory regions of the genome as measured by cardiac DNA hypersensitivity sites were enriched for variants associated with PR interval, compared to non-cardiac regulatory regions. Joint analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation identified additional new pleiotropic loci. The majority of associations discovered in European-descent populations were also present in African-American populations. Meta-analysis examining over 105,000 individuals of African and European descent identified additional novel PR loci. These additional analyses identified another 13 novel loci. Together, these findings underscore the power of GWAS to extend knowledge of the molecular underpinnings of clinical processes.

genetics↗

bioRxiv2017

Novel Locus Influencing Retinal Venular Tortuosity Is Also Associated With Risk Of Coronary Artery Disease

Structural variation in retinal blood vessels is associated with global vascular health in humans and may provide a readily accessible indicator of several diseases of vascular origin. Increasing evidence suggests variation in retinal vasculature is highly heritable. This study aimed to identify genetic determinants of retinal vascular traits. We reported a meta-analysis of genome-wide association studies (GWAS) for quantitative retinal vascular traits derived using semi-automatic image analysis of digital retinal photographs from the Genetics of Diabetes Audit and Research in Tayside (GoDARTS) (n=1736) and the Orkney Complex Disease Study (ORCADES) (n=1358) cohorts. We identified a novel genome-wide significant locus at 19q13 (ACTN4/CAPN12) for retinal venular tortuosity (TortV), and one at 13q34 (COL4A2) for retinal arteriolar tortuosity (TortA); these two loci were subsequently confirmed in three independent cohorts (n=1413). In the combined analysis in ACTN4/CAPN12 the lead single nucleotide polymorphism (SNP) was rs1808382 (n=4507; Beta=-0.109; standard error (SE) =0.015; P=2.39x10-13) and in COL4A2 it was rs7991229 (n=4507; Beta=0.103; SE=0.015; P=4.66x10-12). Notably, the ACTN4/CAPN12 locus associated with retinal TortV is also associated with coronary artery disease and heart rate. Our findings demonstrate the contribution of genetics in retinal tortuosity traits, and provide new insights into cardiovascular diseases.\n\nAuthor SummaryRetinal vascular features are associated with wide range of diseases related to vascular health and provide an opportunity to understand early structural changes in vasculature which may help to predict disease risk. Emerging evidence indicates that retinal tortuosity traits are both associated with vascular health and highly heritable. However, the genetic architecture of retinal vascular tortuosity has not been investigated. We therefore performed a genome-wide association study on retinal arteriolar tortuosity (TortA) and retinal venular tortuosity trait (TortV) using data from two independent discovery cohorts of 3094 individuals of European-heritage. We found a novel associations at 19q13 (ACTN4/CAPN12) for TortV, and one at 13q34 (COL4A2) for TortA at discovery stage and validated in three independent cohorts. A significant association was subsequently found between lead SNPs at 19q13 and coronary artery disease, cardiovascular vascular risk factors and heart rate. We also performed genome-wide association studies for retinal vascular calibres and optic disc radius (ODradius) and replicated previously reported locus at 10q21.3 for ODradius. Our findings highlight genetic impacts on retinal venular tortuosity and it is association with cardiovascular disease. This may provide a molecular pathophysiological foundation for use of retinal vascular traits as biomarkers for cardiovascular diseases.

genomics↗