High Throughput Science - Genomic and metabolmic analysis of haemorrhagic in the China Kadoorie Biobank

Lead Research Organisation: University of Oxford

Abstract

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

Technical Summary

Stroke is the second leading cause of death globally, with much less known about its genetic and non-genetic determinants than for other major diseases such as ischaemic heart disease (IHD). In the UK, although intracerebral haemorrhage (ICH) accounts for only 10-15% of stroke cases, it causes more than half of all stroke deaths, and much severe disability. In China, about 30% of incident cases of stroke are due to ICH and almost all suspected cases of stroke will have CT/MRI after admission to hospital, allowing reliable determination of stroke subtypes. Better understanding of genetic and non-genetic risk factors for stroke subtypes is essential for improved prediction and prevention, and the development of new therapies.
Twin studies and other family studies indicate a substantial genetic component to stroke risk, but there are to date no reports of well-powered GWAS studies of ICH. We will investigate the genetic contribution to ICH in a case-control study nested within the prospective China Kadoorie Biobank (CKB) study of 0.5 million people, which included extensive data by questionnaires and physical measurements and long-term storage of blood samples. In the CKB follow-up through linkage to death and disease registries and to the nationwide health insurance system on all hospitalised events has accumulated >20,000 first strokes. The GWAS will include 5,000 scan-confirmed incident cases of ICH and 10,000 controls, frequency-matched by area, age, sex, time of enrollment, etc. We will use a 800,000 SNP Affymetrix Axiom® myDesign® array, custom-designed to maximise whole-genome coverage in the Chinese population, enabling imputation of 6-10M SNPs and indels using relevant publically available reference panels. The 10,000 control subjects will also form a set of “common controls” for genotyping studies of other diseases (e.g. ischaemic stroke, IHD).
Genome-wide significant associations will be validated by direct genotyping, and up to 100 variants identified as putatively associated with stroke risk (e.g. P<10 6) will be prioritised for replication in additional incident cases from CKB and other cohorts from China and East Asia, together with in silico replication in imputed GWAS data from available ethnically diverse cohorts.
In future, we plan to supplement the genetic analysis of these 15,000 subjects with metabolomic measurements on blood plasma based on mass spectrometry and proton nuclear magnetic resonance spectroscopy, and standard blood biomarker assays. Using system biology approaches to combine these ‘-omics’ data with detailed environmental and lifestyle information, we aim ultimately to understand the molecular basis of haemorrhagic stroke.

Publications

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Bennett DA (2018) Advances in Stroke: Population Studies in Stroke

 
Description BDI 
Organisation University of Oxford
Department Big Data Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution Analyses of CKB data conducted according to group protocols and summary results supplied.
Collaborator Contribution Development of Anlaysis protocol for GWAS for miscarriage.
Impact Paper in preparation
Start Year 2017
 
Description Beijing Genomics Institute 
Organisation Beijing Genomics Institute
Country China 
Sector Academic/University 
PI Contribution In kind contributions to assay costs for various DNA projects. CKB are working with BGI on various research projects including DNA extraction and large-scale GWAS of 100,000 CKB samples. We are also collaborating with BGI's Research organisation on a Mitochondrial DNA Project. This Project involves a pilot project of high-coverage sequencing of the mitochondrial genomes of up to 100 parent-offspring trios (300 samples) from the China Kadoorie Biobank, followed by the main project of sequencing of 15,000 additional samples. These results can be used to assess the inheritance patterns of mitochondrial genomes, including the extent of heteroplasmy and paternal inheritance. Also conducting whole-genome sequencing of 10,000 samples from the China Kadoorie Biobank. The results of this project can be used to construct sequencing reference panels for imputation of genetic variants in individuals of Chinese ancestry, to assess the quality of genome-wide genotyping data, to investigate human population diversity, both within China and globally, and to identify novel genetic variants of potential relevance to human disease. Assisting with a Replication of BMI and height associations from low-coverage NGS association analyses. Framework agreements for the above projects and future research collaborations ( eg on methylation, microbiome DNA) have been agreed and are awaiting signature. Also conducting whole-genome sequencing of 10,000 samples from the China Kadoorie Biobank. The results of this project can be used to construct sequencing reference panels for imputation of genetic variants in individuals of Chinese ancestry, to assess the quality of genome-wide genotyping data, to investigate human population diversity, both within China and globally, and to identify novel genetic variants of potential relevance to human disease. Assisting with a Replication of BMI and height associations from low-coverage NGS association analyses. Framework agreements for the above projects and future research collaborations ( eg on methylation, microbiome DNA) have been agreed and being finalised
Collaborator Contribution BGI are providing the facilities and technical infrastructure for the conduct of genomic assays including data handling and shared analysis
Impact Large scale GWAS of 100,000 CKB samples complete data available for analysis. Lookup of GWAS association for ~1900 SNPs provided. Manuscript published in Cell for BMI and height GWAS
Start Year 2015
 
Description Broad Institute 
Organisation Broad Institute
Country United States 
Sector Charity/Non Profit 
PI Contribution Sitting/standing height ratio GWAS
Collaborator Contribution Sitting/standing height ratio GWAS
Impact Analysis plan complete. Initial analyses ongoing
Start Year 2018
 
Description Cambridge Cardiology 
Organisation University of Cambridge
Country United Kingdom 
Sector Academic/University 
PI Contribution Metaanalysis of NMR metabolomics GWAS
Collaborator Contribution Metaanalysis of NMR metabolomics GWAS
Impact Analysis complete, data supplied
Start Year 2019
 
Description GIANT: Genetic Investigation of ANthropometric Traits 
Organisation Broad Institute
Department The Genetic Investigation of ANthropometric Traits (GIANT)
Country United States 
Sector Academic/University 
PI Contribution GWAS Data for ~28k subjects supplied to assist various meta analyses being conducted by this group. CKB involved in convening the trans-ethnic analysis sub-group.
Collaborator Contribution Large meta-analysis of Height, BMI, WHR, WHRadjBMI; Joint / consortium publications
Impact papers under preparation
Start Year 2017
 
Description GLGC 
Organisation Global Lipids Genetic Consortium (GLGC)
Country United States 
Sector Charity/Non Profit 
PI Contribution GWAS Data for ~18k subjects supplied to assist various meta analyses being conducted by this group.
Collaborator Contribution Large meta-analysis of TC, LDL-c, HDL-c, TG
Impact Papers under preparation
Start Year 2017
 
Description Global Lipids Genetics Consortium 
Organisation Global Lipids Genetic Consortium (GLGC)
Country United States 
Sector Charity/Non Profit 
PI Contribution CKB plans to share genomics data or contribute to GWAS meta analyses being conducted by this group.
Collaborator Contribution Access to additional GWAS data to increase the likelihood of novel significant findings.
Impact In progress
Start Year 2017
 
Description Imperial College London 
Organisation Imperial College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Signals of natural selection for lipid traits
Collaborator Contribution Signals of natural selection for lipid traits
Impact Draft analysis plan received. KK visitor within CKB, conducting analyses. Manuscript submitted.
Start Year 2019
 
Description International Stroke Genetics Consortium 
Organisation Massachusetts General Hospital
Department International Stroke Genetics Consortium
Country United States 
Sector Charity/Non Profit 
PI Contribution CKB plans to share genomics data or contribute to GWAS meta-analyses being conducted by this group. Summary statistics have been shared for GWAS of: (i) sub-arachnoid haemorrhage/ unruptured intracranial aneurysm; (ii) incident all stroke; (iii) fatal stroke, and mortality of incident stroke. Results of other analyses will only be shared after publication of CKB specific stroke genetics paper.
Collaborator Contribution Long-term collaboration. Access to additional GWAS data to increase the likelihood of novel significant findings.
Impact In Progress
Start Year 2016
 
Description McGill University 
Organisation McGill University
Country Canada 
Sector Academic/University 
PI Contribution Validation of genetic risk score for bone mineral density
Collaborator Contribution List of variants and weights supplied.
Impact Analysis ongoing
Start Year 2018
 
Description Nanjing Medical University 
Organisation Nanjing Medical University
Country China 
Sector Academic/University 
PI Contribution Access to data resulting from genotyping.
Collaborator Contribution Contributing research and analystical expertise. CKB/ Oxford hosted a post-doctoral researcher from Nanjing who is continuing to work on this project since his return.
Impact Papers currently being drafted.
Start Year 2015
 
Description Nightingale Health, Finland 
Organisation Nightingale Health Ltd.
Country Finland 
Sector Private 
PI Contribution Metaanalysis of SNPs and gene-specific GRSs with lipid/NMR data. Results sent for 13 SNPs, 3 GRSs, 228 traits, up to 17k samples.
Collaborator Contribution academic partnership
Impact Paper published in Circulation
Start Year 2018
 
Description Peking University PKU 
Organisation Peking University
Country China 
Sector Academic/University 
PI Contribution Replication of fingerprint GWAS. Lookup of GWAS association for 118 SNPs with 20 fingerprint features provided. Results of GWAS provided for metaanalysis.
Collaborator Contribution academic partnership
Impact Paper published in Circulation
Start Year 2018
 
Description ROHgen - (Runs of Homozygosity) 
Organisation ReproGen Consortium
Country Global 
Sector Academic/University 
PI Contribution CKB plans to share genomics data or contribute to GWAS meta analyses being conducted by this group.
Collaborator Contribution Access to additional GWAS data to increase the likelihood of novel significant findings.
Impact In progress
Start Year 2016
 
Description Reprogen 
Organisation ReproGen Consortium
Country Global 
Sector Academic/University 
PI Contribution Conducting GWAS of reproductive traits.
Collaborator Contribution GWAS analyses complete. Currently doing lookup of existing (known) hits, and various heritability analyses. In discussion about future joint analyses/papers
Impact Joint papers
Start Year 2017
 
Description Social Science Genetics Association Consortium 
Organisation Social Science Genetics Association Consortium
Country Global 
Sector Charity/Non Profit 
PI Contribution GWAS of socioeconomic traits
Collaborator Contribution GWAS results supplied for ~10 different traits.
Impact Discussions continuing
Start Year 2018
 
Description Spirometer/BiLEVE 
Organisation University of Leicester
Department Department of Health Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Analysis in CKB of associations between spirometry measures/COPD and genetic loci identified by the Leicester group.
Collaborator Contribution Ongoing long-term collaboration.
Impact Two papers published in Nature Genetics "Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets", "New genetic signals for lung function highlight pathways and pleiotropy, and chronic obstructive pulmonary disease associations across multiple ancestries"
Start Year 2015
 
Description UK BiLEVE 
Organisation UK Biobank
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution GWAS Data for ~33k subjects supplied to assist various meta analyses being conducted by this group.
Collaborator Contribution Consortium is investigating SNP and GRS associations with COPD and COPD exacerbations.
Impact One peer-reviewed paper published, others under preparation
Start Year 2017
 
Description UNC School of Medicine 
Organisation University of North Carolina at Chapel Hill
Country United States 
Sector Academic/University 
PI Contribution GWAS of various psychiatric and related traits
Collaborator Contribution Analysis plan received for GWAS of Major Depression and for Depressive Symptoms. GWAS completed, summary statistics supplied.
Impact Central analysis ongoing
Start Year 2018
 
Description University of Bristol 
Organisation University of Bristol
Department MRC Integrative Epidemiology Unit
Country United Kingdom 
Sector Academic/University 
PI Contribution GWAS of flushing
Collaborator Contribution Visiting researcher from Bristol working within CKB.
Impact Analyses ongoing
Start Year 2018
 
Description University of Cambridge - Dept of Medicine 
Organisation University of Cambridge
Country United Kingdom 
Sector Academic/University 
PI Contribution Provision of controls data (300 CKB samples) for GWAS of ANCA vasculitis being conducted by Cambridge.
Collaborator Contribution The genotype data suppliedto Oxford is being used to compare the performance of the China Kadoorie Biobank and UK BioBank arrays in ethnically distinct cohorts.
Impact Joint research papers.
Start Year 2016
 
Description University of Leicester 
Organisation University of Leicester
Department Department of Health Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Access to data resulting from genotyping, joint analyses
Collaborator Contribution CKB has included additional custom respiratory content into its array design and Prof Tobin will assist in examining this GWAs data alongside baseline and prospective datasets
Impact Nature genetics paper. Nat Genet 2017; 49(3):416-425. More under preparation
Start Year 2015
 
Description University of Oulu 
Organisation University of Oulu
Country Finland 
Sector Academic/University 
PI Contribution Results sent for 13 SNPs, 3 GRSs, 228 traits, up to 17k samples
Collaborator Contribution Meta-analysis of SNPs and gene-specific GRSs with lipid/NMR data. Also providing expertise on MNR metabolomics platform and analysis of CKB samples (stroke case-control study and Pancreatic cancer case-control study).
Impact paper published in Circulation: Metabolomic consequences of genetic inhibition of PCSK9 compared with statin treatment
Start Year 2017
 
Description University of Oxford - OCDEM 
Organisation University of Oxford
Department Oxford Centre for Diabetes Endocrinology and Metabolism (OCDEM)
Country United Kingdom 
Sector Academic/University 
PI Contribution Access to relevant CKB data including genomics data and diabetes outcome data. Paper drafting and internal genomics expertise and supervision.
Collaborator Contribution Provision of a post graduate research assistant working on the the identification and characterization of genetic variants that influence predisposition to type 2 diabetes and related traits.
Impact Contributed several novel and interesting findings including published research papers
Start Year 2014
 
Description Wellcome Trust Centre for Human Genetics 
Organisation University of Oxford
Department Wellcome Trust Centre for Human Genetics
Country United Kingdom 
Sector Academic/University 
PI Contribution Access to data resulting from genotyping.
Collaborator Contribution Collaborated in the design of a customised genotyping array for genomewide analysis, which is complementary to the UK Biobank array, and will facilitate future joint projects in the genomics of common diseases.
Impact Groups at the WTCHG work closely with the CKB team in genome wide data imputation and analysis, for work on stroke, as well as the partial cohort-wide genotyping funded by the MRC-Newton fund.
Start Year 2015
 
Description Coverage on study in Pharmaceutical industry trade journal 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Some coverage of paper on LPa2 emphasising the implications for drug target discovery and pharmaceutical inductrial practice.

https://www.drugtargetreview.com/news/12376/prospective-biobank-studies/
Year(s) Of Engagement Activity 2016
URL http://www.drugtargetreview.com/news/12376/prospective-biobank-studies/
 
Description WuxiApp Tec, Shanghai, China 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact WuxiApp Tec, Shanghai, China
Year(s) Of Engagement Activity 2015,2016