Analysis of MRI-derived spleen iron in the UK Biobank identifies genetic variation linked to iron recycling and erythrocyte morphology

AbstractAging, and the pathogenesis of many common diseases, involves iron homeostasis. A key role in iron homeostasis is played by the spleen, which is the largest filter of the blood and performs iron reuptake from old or damaged erythrocytes. Despite this important role, spleen iron content has not been measured previously in a large, population-based cohort. In this study, we quantify spleen iron in 41,764 participants of the UK Biobank using magnetic resonance imaging (MRI). We find that epidemiologic and environmental factors such as increased age, higher red meat consumption and lower alcohol intake correlate with higher spleen iron. Through genome-wide association study, we identify genetic associations between spleen iron and common variation at seven loci, including in two hereditary spherocytosis (HS) genes, ANK1 and SPTA1. HS-causing mutations in these genes are associated with lower reticulocyte volume and increased reticulocyte percentage, while our common alleles are associated with increased expression of ANK1 and SPTA1 in blood and with larger reticulocyte volume and reduced reticulocyte percentage. As genetic modifiers, these common alleles may explain mild spherocytosis phenotypes observed in some HS allele carriers. Further, we identify an association between spleen iron and MS4A7, which colocalizes with a quantitative trait locus for MS4A7 alternative splicing in whole blood, and with monocyte count and fraction. Through quantification of spleen iron in a large human cohort, we extend our understanding of epidemiological and genetic factors associated with iron recycling and erythrocyte morphology.

Download Full-text

Comparison of prognostic models to predict the occurrence of colorectal cancer in asymptomatic individuals: a systematic literature review and external validation in the EPIC and UK Biobank prospective cohort studies

Gut ◽

10.1136/gutjnl-2017-315730 ◽

2018 ◽

Vol 68 (4) ◽

pp. 672-683 ◽

Cited By ~ 6

Author(s):

Todd Smith ◽

David C Muller ◽

Karel G M Moons ◽

Amanda J Cross ◽

Mattias Johansson ◽

...

Keyword(s):

Colorectal Cancer ◽

Systematic Review ◽

Prediction Models ◽

Large Population ◽

External Validation ◽

Population Based ◽

Prognostic Models ◽

Uk Biobank ◽

Asymptomatic Individuals ◽

The Uk

ObjectiveTo systematically identify and validate published colorectal cancer risk prediction models that do not require invasive testing in two large population-based prospective cohorts.DesignModels were identified through an update of a published systematic review and validated in the European Prospective Investigation into Cancer and Nutrition (EPIC) and the UK Biobank. The performance of the models to predict the occurrence of colorectal cancer within 5 or 10 years after study enrolment was assessed by discrimination (C-statistic) and calibration (plots of observed vs predicted probability).ResultsThe systematic review and its update identified 16 models from 8 publications (8 colorectal, 5 colon and 3 rectal). The number of participants included in each model validation ranged from 41 587 to 396 515, and the number of cases ranged from 115 to 1781. Eligible and ineligible participants across the models were largely comparable. Calibration of the models, where assessable, was very good and further improved by recalibration. The C-statistics of the models were largely similar between validation cohorts with the highest values achieved being 0.70 (95% CI 0.68 to 0.72) in the UK Biobank and 0.71 (95% CI 0.67 to 0.74) in EPIC.ConclusionSeveral of these non-invasive models exhibited good calibration and discrimination within both external validation populations and are therefore potentially suitable candidates for the facilitation of risk stratification in population-based colorectal screening programmes. Future work should both evaluate this potential, through modelling and impact studies, and ascertain if further enhancement in their performance can be obtained.

Download Full-text

0154 A new, efficient web-based tool to collect and code lifetime job histories in large population-based studies: the COPD project in the UK Biobank cohort

Occupational and Environmental Medicine ◽

10.1136/oemed-2014-102362.59 ◽

2014 ◽

Vol 71 (Suppl 1) ◽

pp. A19.1-A19

Author(s):

Sara De Matteis ◽

Lesley Rushton ◽

Debbie Jarvis ◽

Magda Wheatley ◽

Hadia Azhar ◽

...

Keyword(s):

Large Population ◽

Population Based ◽

Uk Biobank ◽

Web Based ◽

The Uk

Download Full-text

Optical Coherence Tomography in the UK Biobank Study – Rapid Automated Analysis of Retinal Thickness for Large Population-Based Studies

PLoS ONE ◽

10.1371/journal.pone.0164095 ◽

2016 ◽

Vol 11 (10) ◽

pp. e0164095 ◽

Cited By ~ 12

Author(s):

Pearse A. Keane ◽

Carlota M. Grossi ◽

Paul J. Foster ◽

Qi Yang ◽

Charles A. Reisman ◽

...

Keyword(s):

Optical Coherence Tomography ◽

Retinal Thickness ◽

Large Population ◽

Automated Analysis ◽

Population Based ◽

Optical Coherence ◽

Uk Biobank ◽

The Uk

Download Full-text

A novel variant in GLIS3 is associated with osteoarthritis

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2017-211848 ◽

2018 ◽

Vol 77 (4) ◽

pp. 620-623 ◽

Cited By ~ 13

Author(s):

Elisabetta Casalone ◽

Ioanna Tachmazidou ◽

Eleni Zengini ◽

Konstantinos Hatzikotoulas ◽

Sophie Hackinger ◽

...

Keyword(s):

Complex Disease ◽

Genome Wide Association Study ◽

Total Joint Replacement ◽

Population Based ◽

Uk Biobank ◽

Proteomics Data ◽

Glucose Levels ◽

Genome Wide ◽

A Genome ◽

The Uk

ObjectivesOsteoarthritis (OA) is a complex disease, but its genetic aetiology remains poorly characterised. To identify novel susceptibility loci for OA, we carried out a genome-wide association study (GWAS) in individuals from the largest UK-based OA collections to date.MethodsWe carried out a discovery GWAS in 5414 OA individuals with knee and/or hip total joint replacement (TJR) and 9939 population-based controls. We followed-up prioritised variants in OA subjects from the interim release of the UK Biobank resource (up to 12 658 cases and 50 898 controls) and our lead finding in operated OA subjects from the full release of UK Biobank (17 894 cases and 89 470 controls). We investigated its functional implications in methylation, gene expression and proteomics data in primary chondrocytes from 12 pairs of intact and degraded cartilage samples from patients undergoing TJR.ResultsWe detect a genome-wide significant association at rs10116772 with TJR (P=3.7×10−8; for allele A: OR (95% CI) 0.97 (0.96 to 0.98)), an intronic variant in GLIS3, which is expressed in cartilage. Variants in strong correlation with rs10116772 have been associated with elevated plasma glucose levels and diabetes.ConclusionsWe identify a novel susceptibility locus for OA that has been previously implicated in diabetes and glycaemic traits.

Download Full-text

The molecular genetics of hand preference revisited

10.1101/447177 ◽

2018 ◽

Cited By ~ 1

Author(s):

Carolien G.F. de Kovel ◽

Clyde Francks

Keyword(s):

Complex Traits ◽

Large Population ◽

Enrichment Analysis ◽

Hand Preference ◽

Population Based ◽

Gene Set Enrichment Analysis ◽

Uk Biobank ◽

Genome Wide ◽

A Genome ◽

The Uk

AbstractHand preference is a prominent behavioural trait linked to human brain asymmetry. A handful of genetic variants have been reported to associate with hand preference or quantitative measures related to it. Most of these reports were on the basis of limited sample sizes, by current standards for genetic analysis of complex traits. Here we performed a genome-wide association analysis of hand preference in the large, population-based UK Biobank cohort (N=331,037). We used gene-set enrichment analysis to investigate whether genes involved in visceral asymmetry are particularly relevant to hand preference, following one previous report. We found no evidence implicating any specific candidate variants previously reported. We also found no evidence that genes involved in visceral laterality play a role in hand preference. It remains possible that some of the previously reported genes or pathways are relevant to hand preference as assessed in other ways, or else are relevant within specific disorder populations. However, some or all of the earlier findings are likely to be false positives, and none of them appear relevant to hand preference as defined categorically in the general population. Within the UK Biobank itself, a significant association implicates the gene MAP2 in handedness.

Download Full-text

A genome-wide association study finds novel genetic associations with broadly-defined headache in UK Biobank (N = 223,773)

10.1101/217786 ◽

2017 ◽

Author(s):

Weihua Meng ◽

Mark J Adams ◽

Harry L Hebert ◽

Ian J Deary ◽

Andrew M McIntosh ◽

...

Keyword(s):

Association Study ◽

Genome Wide Association Study ◽

Genetic Correlations ◽

Genome Wide Association ◽

Uk Biobank ◽

Genetic Associations ◽

Psychological Traits ◽

Genome Wide ◽

A Genome ◽

The Uk

AbstractHeadache is the most common neurological symptom and a leading cause of years lived with disability. We sought to identify the genetic variants associated with a broadly-defined headache phenotype in 223,773 subjects from the UK Biobank cohort. We defined headache based on a specific question answered by the UK Biobank participants. We performed a genome-wide association study of headache as a single entity, using 74,461 cases and 149,312 controls. We identified 3,343 SNPs which reached the genome-wide significance level of P < 5 × 10−8. The SNPs were located in 28 loci, with the top SNP of rs11172113 in the LRP1 gene having a P value of 4.92 × 10−47. Of the 28 loci, 14 have previously been associated with migraine. Among 14 new loci, rs77804065 with a P value of 5.87 × 10−15 in the LINC02210-CRHR1 gene was the top SNP.Positive relationships (P < 0.001) between multiple brain tissues and genetic associations were identified through tissue expression analysis, whereas no vascular related tissues showed significant relationships. We identified several significant positive genetic correlations between headache and other psychological traits including neuroticism, depressive symptoms, insomnia, and major depressive disorder.Our results suggest that brain function is closely related to broadly-defined headache. In addition, we also found that many psychological traits have genetic correlations with headache.

Download Full-text

A population scale analysis of rare SNCA variation in the UK Biobank

10.1101/2020.08.11.20172866 ◽

2020 ◽

Author(s):

Cornelis Blauwendraat ◽

Mary B. Makarious ◽

Hampton L. Leonard ◽

Sara Bandres-Ciga ◽

Hirotaka Iwaki ◽

...

Keyword(s):

Copy Number ◽

Human Genetics ◽

Large Population ◽

Point Mutations ◽

Population Based ◽

Alpha Synuclein ◽

Uk Biobank ◽

Snca Gene ◽

Large Complex ◽

The Uk

Parkinson disease (PD) is a complex neurodegenerative disease with a variety of genetic and environmental factors contributing to disease. The SNCA gene encodes for the alpha-synuclein protein which plays a central role in PD, where aggregates of this protein are one of pathological hallmarks of disease. Rare point mutations and copy number gains of the SNCA gene have been shown to cause autosomal dominant PD and common DNA variants identified using GWAS are a moderate risk factor for PD. The UK Biobank is a large prospective study including 500,000 individuals and has revolutionized human genetics. Here we assessed the frequency of SNCA variation in this cohort and identified 26 subjects carrying variants of interest including duplications (n=6), deletions (n=6) and large complex likely mosaic events (n=14). No known pathogenic missense variants were identified. None of these subjects were reported to be a PD case, although it is possible that these individuals may develop PD at a later age, and whilst three had known prodromal features, these did not meet defined thresholds for being considered prodromal cases. Four of the 14 large complex carriers showed a history of blood based cancer. Overall, we identified copy number variants in the SNCA region in a large population based cohort without reported PD phenotype and symptoms. Putative mosaicism of the SNCA gene was identified, however it is unclear whether it is associated with Parkinson's disease. These individuals are potential candidates for further investigation by performing SNCA RNA and protein expression studies, as well as promising clinical trial candidates to understand how duplication carriers potentially escape PD.

Download Full-text

GWAS of allometric body-shape indices in UK Biobank identifies loci suggesting associations with morphogenesis, organogenesis, adrenal cell renewal and cancer

Scientific Reports ◽

10.1038/s41598-021-89176-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Sofia Christakoudi ◽

Evangelos Evangelou ◽

Elio Riboli ◽

Konstantinos K. Tsilidis

Keyword(s):

Body Shape ◽

Genome Wide Association Study ◽

Shape Index ◽

Cell Renewal ◽

Uk Biobank ◽

Genetic Associations ◽

Adrenal Cell ◽

Shape Indices ◽

Using Data ◽

The Uk

AbstractGenetic studies have examined body-shape measures adjusted for body mass index (BMI), while allometric indices are additionally adjusted for height. We performed the first genome-wide association study of A Body Shape Index (ABSI), Hip Index (HI) and the new Waist-to-Hip Index and compared these with traditional indices, using data from the UK Biobank Resource for 219,872 women and 186,825 men with white British ancestry and Bayesian linear mixed-models (BOLT-LMM). One to two thirds of the loci identified for allometric body-shape indices were novel. Most prominent was rs72959041 variant in RSPO3 gene, expressed in visceral adipose tissue and regulating adrenal cell renewal. Highly ranked were genes related to morphogenesis and organogenesis, previously additionally linked to cancer development and progression. Genetic associations were fewer in men compared to women. Prominent region-specific associations showed variants in loci VEGFA and HMGA1 for ABSI and KLF14 for HI in women, and C5orf67 and HOXC4/5 for ABSI and RSPO3, VEGFA and SLC30A10 for HI in men. Although more variants were associated with waist and hip circumference adjusted for BMI compared to ABSI and HI, associations with height had previously been reported for many of the additional variants, illustrating the importance of adjusting correctly for height.

Download Full-text

Components of genetic associations across 2,138 phenotypes in the UK Biobank highlight novel adipocyte biology

10.1101/442715 ◽

2018 ◽

Cited By ~ 3

Author(s):

Yosuke Tanigawa ◽

Jiehan Li ◽

Johanne Marie Justesen ◽

Heiko Horn ◽

Matthew Aguirre ◽

...

Keyword(s):

Population Based ◽

Uk Biobank ◽

Genetic Associations ◽

Loss Of Function ◽

Association Analyses ◽

Genome Wide ◽

Disease Predisposition ◽

Latent Structures ◽

The Uk ◽

Value Decomposition

AbstractPopulation-based biobanks with genomic and dense phenotype data provide opportunities for generating effective therapeutic hypotheses and understanding the genomic role in disease predisposition. To characterize latent components of genetic associations, we applied truncated singular value decomposition (DeGAs) to matrices of summary statistics derived from genome-wide association analyses across 2,138 phenotypes measured in 337,199 White British individuals in the UK Biobank study. We systematically identified key components of genetic associations and the contributions of variants, genes, and phenotypes to each component. As an illustration of the utility of the approach to inform downstream experiments, we report putative loss of function variants, rs114285050 (GPR151) and rs150090666 (PDE3B), that substantially contribute to obesity-related traits, and experimentally demonstrate the role of these genes in adipocyte biology. Our approach to dissect components of genetic associations across the human phenome will accelerate biomedical hypothesis generation by providing insights on previously unexplored latent structures.

Download Full-text

Large-scale neuroimaging and genetic study reveals genetic architecture of brain white matter microstructure

10.1101/288555 ◽

2018 ◽

Cited By ~ 2

Author(s):

Bingxin Zhao ◽

Jingwen Zhang ◽

Joseph G. Ibrahim ◽

Rebecca C. Santelli ◽

Yun Li ◽

...

Keyword(s):

White Matter ◽

Genetic Architecture ◽

Large Population ◽

Genetic Correlations ◽

Population Based ◽

Imaging Genetics ◽

Large Sample Size ◽

Uk Biobank ◽

Brain White Matter ◽

The Uk

AbstractMicrostructural changes of white matter (WM) tracts are known to be associated with various neuropsychiatric disorders/diseases. Heritability of structural changes of WM tracts has been examined using diffusion tensor imaging (DTI) in family-based studies for different age groups. The availability of genetic and DTI data from recent large population-based studies offers opportunity to further improve our understanding of genetic contributions. Here, we analyzed the genetic architecture of WM tracts using DTI and single-nucleotide polymorphism (SNP) data of unrelated individuals in the UK Biobank (n ∼ 8000). The DTI parameters were generated using the ENIGMA-DTI pipeline. We found that DTI parameters are substantially heritable on most WM tracts. We observed a highly polygenic or omnigenic architecture of genetic influence across the genome as well as the enrichment of SNPs in active chromatin regions. Our bivariate analyses showed strong genetic correlations for several pairs of WM tracts as well as pairs of DTI parameters. We performed voxel-based analysis to illustrate the pattern of genetic effects on selected parts of the tract-based spatial statistics skeleton. Comparing the estimates from the UK Biobank to those from small population-based studies, we illustrated that sufficiently large sample size is essential for genetic architecture discovery in imaging genetics. We confirmed this finding with a simulation study.

Download Full-text