Embracing multi-ethnicity in studying the genetics of smoking behaviour

拥抱多种族研究吸烟行为的遗传学

• 批准号: MR/S003762/1
• 负责人: Chiara Batini
• 金额: $ 37.33万
• 依托单位: University of Leicester
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS003762%2F1
• 关键词: Embracing; multi; ethnicity; studying; genetics

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.

生物医学研究对欧洲血统个体的偏见是公认的，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、欧洲和中低收入国家（LMICs）的不同种族人口的更公平的医疗保健至关重要。精确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，祖先起着重要作用。吸烟是全球五大死因（包括心脏和呼吸系统疾病）中的主要风险因素之一，每年导致约600万人死亡。世界各区域的吸烟者人数各不相同，在全世界10亿吸烟者中，80%生活在中低收入国家。令人欣慰的是，世卫组织模拟的预测显示，未来十年大多数地区的吸烟率将有所下降；然而，非洲和东地中海则呈现相反的趋势。在英国，约17%的成年人经常吸烟；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发病率上升。遗传变异与吸烟行为之间的最强关联一直显示在15q25.1位点，包含编码烟碱乙酰胆碱受体亚基的CHRNA5-A3-B4基因簇。在大脑中，尼古丁与nachr结合，刺激几种神经递质的释放，包括多巴胺、血清素和谷氨酸，影响奖励途径、学习和记忆。到目前为止，已经确定了14个遗传位点，包括nachr基因（8p11和15q25），尼古丁代谢酶和参与神经传递的蛋白质（DBH， BDNF）。值得注意的是，5/14个位点是在英国生物银行（UKBB）的第一次遗传研究中发现的，该研究由将主办拟议奖学金的团队领导。然而，与大多数全基因组关联研究（GWASs）一样，研究的重点主要集中在欧洲血统的个体上。为了克服这一限制，我将解开欧洲、亚洲和非洲个体吸烟行为的基因，并将调查混合个体，以促进基因发现。为此，我将对特定祖先群体进行发现和复制GWAS，并对所有祖先进行跨种族荟萃分析。然后，我将结合群体遗传学和遗传流行病学的方法，制定一种策略，将混合个体纳入关联测试，并提高关联研究的能力。由于英国的多样性，所有的祖先都代表在英国生物银行的50万个人中，这将用于发现分析；将进行复制分析，包括通过合作提供的特定谱系队列。该项目的结果将突出吸烟依赖的生物学背景，并有助于根据尼古丁依赖和血统更好地识别治疗和分层患者。该项目的更广泛影响将包括开发用于分析大型健康和基因组数据的管道，这些数据将转移到其他性状；它将有助于形成关于民族健康的知识体系，这将有助于形成未来的研究；它将为我提供完美的工具来完成我在健康数据科学方面的培训。

项目成果

Genome-wide association study of ACE inhibitor-induced cough implicates neuropeptides and shows genetic overlap with chronic dry cough

• DOI: 10.1101/2022.06.30.22277097
• 发表时间: 2022-06
• 作者: Kayesha Coley;David J. Shepherd;R. Packer;C. John;R. Free;J. Edward;Hollox;L. Wain;M. Tobin;C. Batini

Smoking cessation on the African continent: Challenges and opportunities

非洲大陆的戒烟：挑战与机遇

• DOI: 10.7196/sarj.2019.v25i2.015
• 发表时间: 2019
• 期刊: African Journal of Thoracic and Critical Care Medicine
• 作者: Batini C

Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci.

• DOI: 10.1038/s41380-018-0313-0
• 发表时间: 2020-10
• 期刊: Molecular psychiatry
• 影响因子: 11
• 作者: Erzurumluoglu AM;Liu M;Jackson VE;Barnes DR;Datta G;Melbourne CA;Young R;Batini C;Surendran P;Jiang T;Adnan SD;Afaq S;Agrawal A;Altmaier E;Antoniou AC;Asselbergs FW;Baumbach C;Bierut L;Bertelsen S;Boehnke M;Bots ML;Brazel DM;Chambers JC;Chang-Claude J;Chen C;Corley J;Chou YL;David SP;de Boer RA;de Leeuw CA;Dennis JG;Dominiczak AF;Dunning AM;Easton DF;Eaton C;Elliott P;Evangelou E;Faul JD;Foroud T;Goate A;Gong J;Grabe HJ;Haessler J;Haiman C;Hallmans G;Hammerschlag AR;Harris SE;Hattersley A;Heath A;Hsu C;Iacono WG;Kanoni S;Kapoor M;Kaprio J;Kardia SL;Karpe F;Kontto J;Kooner JS;Kooperberg C;Kuulasmaa K;Laakso M;Lai D;Langenberg C;Le N;Lettre G;Loukola A;Luan J;Madden PAF;Mangino M;Marioni RE;Marouli E;Marten J;Martin NG;McGue M;Michailidou K;Mihailov E;Moayyeri A;Moitry M;Müller-Nurasyid M;Naheed A;Nauck M;Neville MJ;Nielsen SF;North K;Perola M;Pharoah PDP;Pistis G;Polderman TJ;Posthuma D;Poulter N;Qaiser B;Rasheed A;Reiner A;Renström F;Rice J;Rohde R;Rolandsson O;Samani NJ;Samuel M;Schlessinger D;Scholte SH;Scott RA;Sever P;Shao Y;Shrine N;Smith JA;Starr JM;Stirrups K;Stram D;Stringham HM;Tachmazidou I;Tardif JC;Thompson DJ;Tindle HA;Tragante V;Trompet S;Turcot V;Tyrrell J;Vaartjes I;van der Leij AR;van der Meer P;Varga TV;Verweij N;Völzke H;Wareham NJ;Warren HR;Weir DR;Weiss S;Wetherill L;Yaghootkar H;Yavas E;Jiang Y;Chen F;Zhan X;Zhang W;Zhao W;Zhao W;Zhou K;Amouyel P;Blankenberg S;Caulfield MJ;Chowdhury R;Cucca F;Deary IJ;Deloukas P;Di Angelantonio E;Ferrario M;Ferrières J;Franks PW;Frayling TM;Frossard P;Hall IP;Hayward C;Jansson JH;Jukema JW;Kee F;Männistö S;Metspalu A;Munroe PB;Nordestgaard BG;Palmer CNA;Salomaa V;Sattar N;Spector T;Strachan DP;Understanding Society Scientific Group, EPIC-CVD, GSCAN, Consortium for Genetics of Smoking Behaviour, CHD Exome+ consortium;van der Harst P;Zeggini E;Saleheen D;Butterworth AS;Wain LV;Abecasis GR;Danesh J;Tobin MD;Vrieze S;Liu DJ;Howson JMM
• 通讯作者: Howson JMM

Respiratory health among adolescents living in the Highveld Air Pollution Priority Area in South Africa.

• DOI: 10.1186/s12889-022-14497-8
• 发表时间: 2022-11-21
• 期刊: BMC public health
• 影响因子: 4.5

Genetic insights into smoking behaviours in 10,558 men of African ancestry from continental Africa and the UK.

• DOI: 10.1038/s41598-022-22218-9
• 发表时间: 2022-11-05
• 期刊: Scientific reports
• 影响因子: 4.6