Embracing multi-ethnicity in studying the genetics of smoking behaviour

生物医学研究对欧洲血统个人的偏见被广泛认识到，在一个移民变得越来越普遍的世界里，克服这一限制对于英国、欧洲以及低收入和中等收入国家(LMIC)不同种族人口的更公平的医疗保健至关重要。精准医学的基础是了解人类对疾病和治疗的不同反应，毫无疑问，祖先扮演着重要角色。吸烟是全球五大死因的主要风险因素之一，包括心脏病和呼吸系统疾病，每年导致约600万人死亡。世界不同地区的吸烟者人数各不相同，在全球10亿吸烟者中，80%生活在低收入国家。世卫组织模拟的令人放心的预测显示，未来十年大多数地区的吸烟率将下降；然而，非洲和东地中海地区显示出相反的趋势。在英国，约17%的成年人口经常吸烟；在英格兰，这一数字在不同种族之间差异很大，加勒比黑人和亚洲群体的吸烟率呈上升趋势。遗传变异与吸烟行为之间的关联一直以来都显示在15q25.1，包含编码烟碱型乙酰胆碱受体(NAChRs)亚单位的CHRNA5-A3-B4基因簇。在大脑中，尼古丁与nAChRs结合，刺激包括多巴胺、5-羟色胺和谷氨酸在内的几种神经递质的释放，影响奖励途径、学习和记忆。到目前为止，已确定了14个遗传位点，包括nAChRs基因(位于8p11和15q25上)、尼古丁代谢酶基因和参与神经传递的蛋白质(DBH、BDNF)。值得注意的是，在英国生物库(UKBB)的第一项遗传研究中发现了5/14个基因座，该研究由将主办拟议联谊会的团队领导。然而，与大多数全基因组关联研究(GWAS)一样，重点主要放在欧洲血统的个体上。为了克服这一限制，我将梳理欧洲、亚洲和非洲人吸烟行为的遗传学，并将研究混杂的个人，以促进基因发现。为此，我将对特定于祖先的群体进行发现和复制，并对所有祖先进行跨种族的荟萃分析。然后，我将结合群体遗传学和遗传流行病学的方法，制定一种将混合个体纳入关联测试的策略，并提高关联研究的能力。由于英国的多样性，所有祖先都代表在英国生物库中包括的50万个个体中，这将用于发现分析；复制分析将进行，包括通过合作获得的特定祖先队列。该项目的成果将突出吸烟依赖的生物学背景，并有助于更好地确定尼古丁依赖和祖先对患者的治疗和分层。该项目的更广泛影响将包括开发用于分析健康和基因组学大数据的管道，这些数据将可转移到其他特征；它将有助于形成关于民族健康的知识体系，这将有助于塑造未来的研究；它将为我提供完成健康数据科学培训的完美工具。

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.