Embracing multi-ethnicity in studying the genetics of smoking behaviour

点击翻译按钮获取中文摘要

The bias of biomedical studies towards individuals of European origin is widely recognised and, in a world where migration is becoming ever more common, overcoming this limitation is essential for a fairer healthcare of the diverse ethnic population in the UK, and Europe, and in low and middle income countries (LMICs). Precision medicine is underpinned by understanding the diverse response of human beings to diseases and treatments, and there is no doubt that ancestry plays a major role. Smoking is one of the leading risk factors of the top five causes of death world-wide, including heart and respiratory diseases, killing around 6 million people a year. The number of smokers varies among world regions, and of the 1 billion smokers worldwide, 80% live in LMICs. Reassuringly predictions modelled by WHO show a reduction in smoking prevalence in most areas over the next ten years; however, Africa and the Eastern Mediterranean show an opposite trend. In the UK, ~17% of the adult population smokes regularly; in England, this figure varies considerably between ethnicities, with Black Caribbean and Asian groups showing a rising prevalence. The strongest associations between genetic variation and smoking behaviour have been consistently shown at locus 15q25.1, containing the cluster of CHRNA5-A3-B4 genes which encode subunits of the nicotinic acetylcholine receptors (nAChRs). In the brain, nicotine binds to nAChRs stimulating the release of several neurotransmitters, including dopamine, serotonin and glutamate, impacting the reward pathway, learning and memory. To date, 14 genetic loci have been identified, including genes for nAChRs (on 8p11 as well as 15q25), nicotine-metabolizing enzymes and proteins involved in neurotransmission (DBH, BDNF). Notably, 5/14 loci were discovered in the first genetic study in UK Biobank (UKBB), led by the team that will host the proposed Fellowship. However, as in most genome-wide association studies (GWASs), the focus has been mostly on individuals of European origin. To overcome this limitation I will disentangle the genetics of smoking behaviour in European, Asian and African individuals and will investigate admixed individuals to boost genetic discovery. To this end, I will undertake a discovery and a replication GWAS on ancestry-specific groups as well as performing a trans-ethnic meta-analysis across all ancestries. I will then combine methods from population genetics and genetic epidemiology to develop a strategy for including admixed individuals in association testing and boost power for association studies.Thanks to the diversity in the UK all the ancestries are represented in the half million individuals included in UK Biobank which will be used for discovery analyses; replication analyses will be carried out including ancestry-specific cohorts made available through collaborations. The outcomes of this project will highlight the biological background of smoking dependence and help towards a better identification of treatment and stratification of patients by nicotine-dependence and ancestry. The wider impact of this project will include developing pipelines for the analysis of big health and genomics data which will be transferable to other traits; it will contribute to the body of knowledge on ethnic health, which will help shaping future studies; and it will provide me with the perfect vehicle to complete my training in health data science.