High Throughput Science - Genomic and metabolmic analysis of haemorrhagic in the China Kadoorie Biobank
Lead Research Organisation:
University of Oxford
Abstract
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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.
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.
Organisations
- University of Oxford, United Kingdom (Collaboration, Lead Research Organisation)
- Global Lipids Genetic Consortium (GLGC) (Collaboration)
- ReproGen Consortium (Collaboration)
- UK Biobank, United Kingdom (Collaboration)
- Beijing Genomics Institute (BGI) (Collaboration)
- University of Bristol, United Kingdom (Collaboration)
- Imperial College London, United Kingdom (Collaboration)
- Peking University, China (Collaboration)
- Nightingale Health Ltd. (Collaboration)
- University of Cambridge, United Kingdom (Collaboration)
- Social Science Genetics Association Consortium (Collaboration)
- Broad Institute (Collaboration)
- McGill University, Canada (Collaboration)
- University of Oulu, Finland (Collaboration)
- University of North Carolina at Chapel Hill (Collaboration)
- Massachusetts General Hospital (Collaboration)
- Nanjing Medical University (Collaboration)
- University of Leicester, United Kingdom (Collaboration)
People |
ORCID iD |
Zhengming Chen (Principal Investigator) |
Publications

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

Millwood IY
(2019)
Alcohol consumption and vascular disease: other points to consider - Authors' reply.
in Lancet (London, England)

Millwood IY
(2018)
Association of CETP Gene Variants With Risk for Vascular and Nonvascular Diseases Among Chinese Adults.
in JAMA cardiology

Yu C
(2018)
Association of low-activity ALDH2 and alcohol consumption with risk of esophageal cancer in Chinese adults: A population-based cohort study
in International Journal of Cancer



Clark DW
(2019)
Associations of autozygosity with a broad range of human phenotypes.
in Nature communications


Gan W
(2017)
Bone mineral density and risk of type 2 diabetes and coronary heart disease: A Mendelian randomization study.
in Wellcome open research

Sun L
(2019)
Causal associations of blood lipids with risk of ischemic stroke and intracerebral hemorrhage in Chinese adults.
in Nature medicine
Title | China Kadoorie Biobank - research Database |
Description | China Kadoorie Biobank (CKB) is a blood-based prospective cohort study of 512,000 adults, recruited from 10 diverse areas across China (during 2004-08), with extensive data collection at baseline and subsequent resurveys and long-term storage of biological samples. These exposure and outcome data are complemented by separately funded genotyping (currently for 102,000 participants), whole genome sequencing, and conventional and multi-omics assays for nested case-control studies of specific diseases. |
Type Of Material | Database/Collection of data |
Year Produced | 2015 |
Provided To Others? | Yes |
Impact | Group staff and collaborating institution have published over 250 papersusing the CKB database. Since opening CKB data up for open access in September 2015, 574 researchers have registered on the CKB Data Access System. By 12 February 2020, 262 new applications for datasets have been registered including 113 from open access users. |
URL | https://www.ckbiobank.org/site/Data+Access |
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 | Hospitals |
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 | Charity/Non Profit |
PI Contribution | Access to data resulting from genotyping. |
Collaborator Contribution | Collaborated in the design of a customised genotyping array for genome-wide 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 | Alcohol and CVD paper engangement activities |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Media coverage of publication of alcohol and CVD, including BBC TV and radio interviews, and a press conference for national newspapers, April 2019. |
Year(s) Of Engagement Activity | 2019 |
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 |