The goal is to lay foundations for new preventive efforts by identifying and evaluating causal risk factors for selected major diseases, including vascular diseases, cancers, neurodegenerative diseases, diabetes, and other age-related conditions.
We have led the discovery of over 350 genetic loci in a range of common diseases (eg, breast, prostate, and ovarian cancers; coronary disease; type 2 diabetes) and risk factors (eg, lipids; insulin resistance) reported in Nature and Nature Genetics since 2008. These findings have opened new avenues of biology and mechanistic understanding and helped develop new risk prediction tools in widespread use.
Using the principle of “Mendelian randomisation”, we have identified risk factors likely to have causal roles (eg, triglyceride pathways and IL-6 signalling in coronary disease [Lancet 2011; Lancet 2012]; natriuretic peptides in type 2 diabetes [PLoS Medicine 2011]), and others that appear non-causal (eg, C-reactive protein [BMJ 2012, Lancet 2011]). These studies have yielded implications for industry, eg: Novartis (triglycerides results), Roche (IL-6 results), and ISIS pharmaceuticals (C-reactive protein results).
We have quantified the impact of risk factors amenable to therapeutic modification, such as subclinical hypothyroidism in coronary disease (JAMA 2010) and dysglycaemia in relation to vascular and non-vascular conditions (NEJM 2011). We are testing the latter hypothesis in an HTA-funded trial of metformin.
We have shown that different subtypes of breast cancer defined by biological markers show important differences in prognosis (PLoS Medicine 2010), suggesting implications for targeting adjuvant chemotherapy.
We are integrating “multi-omics” (eg, genomics, epigenomics, metabolomics) in participants linked to multiple NHS e-health records in 100,000 well-phenotyped individuals.
We are establishing an e-health study involving 2 million blood donors in England; and we are extending studies of 90,000 participants in non-European populations in which certain risk factor levels are unusually high (eg, toxic metals in Bangladesh; consanguinity in Pakistan; hepatitis C infection in Africa) and in which cardiometabolic risk is also high. We are extending major genetic sequencing efforts in Africans (eg, the African Genome Variation Project) to over 20,000 South Asians.