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

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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.