Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci.
paper
Primary
Public
- Authors
- Erzurumluoglu, A Mesut; Liu, Mengzhen; Jackson, Victoria E; Barnes, Daniel R; Datta, Gargi; Melbourne, Carl A; Young, Robin; Batini, Chiara; Surendran, Praveen; Jiang, Tao; Adnan, Sheikh Daud; Afaq, Saima; Agrawal, Arpana; Altmaier, Elisabeth; Antoniou, Antonis C; Asselbergs, Folkert W; Baumbach, Clemens; Bierut, Laura; Bertelsen, Sarah; Boehnke, Michael; Bots, Michiel L; Brazel, David M; Chambers, John C; Chang-Claude, Jenny; Chen, Chu; Corley, Janie; Chou, Yi-Ling; David, Sean P; de Boer, Rudolf A; de Leeuw, Christiaan A; Dennis, Joe G; Dominiczak, Anna F; Dunning, Alison M; Easton, Douglas F; Eaton, Charles; Elliott, Paul; Evangelou, Evangelos; Faul, Jessica D; Foroud, Tatiana; Goate, Alison; Gong, Jian; Grabe, Hans J; Haessler, Jeff; Haiman, Christopher; Hallmans, Göran; Hammerschlag, Anke R; Harris, Sarah E; Hattersley, Andrew; Heath, Andrew; Hsu, Chris; Iacono, William G; Kanoni, Stavroula; Kapoor, Manav; Kaprio, Jaakko; Kardia, Sharon L; Karpe, Fredrik; Kontto, Jukka; Kooner, Jaspal S; Kooperberg, Charles; Kuulasmaa, Kari; Laakso, Markku; Lai, Dongbing; Langenberg, Claudia; Le, Nhung; Lettre, Guillaume; Loukola, Anu; Luan, Jian'an; Madden, Pamela A F; Mangino, Massimo; Marioni, Riccardo E; Marouli, Eirini; Marten, Jonathan; Martin, Nicholas G; McGue, Matt; Michailidou, Kyriaki; Mihailov, Evelin; Moayyeri, Alireza; Moitry, Marie; Müller-Nurasyid, Martina; Naheed, Aliya; Nauck, Matthias; Neville, Matthew J; Nielsen, Sune Fallgaard; North, Kari; Perola, Markus; Pharoah, Paul D P; Pistis, Giorgio; Polderman, Tinca J; Posthuma, Danielle; Poulter, Neil; Qaiser, Beenish; Rasheed, Asif; Reiner, Alex; Renström, Frida; Rice, John; Rohde, Rebecca; Rolandsson, Olov; Samani, Nilesh J; Samuel, Maria; Schlessinger, David; Scholte, Steven H; Scott, Robert A; Sever, Peter; Shao, Yaming; Shrine, Nick; Smith, Jennifer A; Starr, John M; Stirrups, Kathleen; Stram, Danielle; Stringham, Heather M; Tachmazidou, Ioanna; Tardif, Jean-Claude; Thompson, Deborah J; Tindle, Hilary A; Tragante, Vinicius; Trompet, Stella; Turcot, Valerie; Tyrrell, Jessica; Vaartjes, Ilonca; van der Leij, Andries R; van der Meer, Peter; Varga, Tibor V; Verweij, Niek; Völzke, Henry; Wareham, Nicholas J; Warren, Helen R; Weir, David R; Weiss, Stefan; Wetherill, Leah; Yaghootkar, Hanieh; Yavas, Ersin; Jiang, Yu; Chen, Fang; Zhan, Xiaowei; Zhang, Weihua; Zhao, Wei; Zhao, Wei; Zhou, Kaixin; Amouyel, Philippe; Blankenberg, Stefan; Caulfield, Mark J; Chowdhury, Rajiv; Cucca, Francesco; Deary, Ian J; Deloukas, Panos; Di Angelantonio, Emanuele; Ferrario, Marco; Ferrières, Jean; Franks, Paul W; Frayling, Tim M; Frossard, Philippe; Hall, Ian P; Hayward, Caroline; Jansson, Jan-Håkan; Jukema, J Wouter; Kee, Frank; Männistö, Satu; Metspalu, Andres; Munroe, Patricia B; Nordestgaard, Børge Grønne; Palmer, Colin N A; Salomaa, Veikko; Sattar, Naveed; Spector, Timothy; Strachan, David Peter; Understanding Society Scientific Group, EPIC-CVD, GSCAN, Consortium for Genetics of Smoking Behaviour, CHD Exome+ consortium; van der Harst, Pim; Zeggini, Eleftheria; Saleheen, Danish; Butterworth, Adam S; Wain, Louise V; Abecasis, Goncalo R; Danesh, John; Tobin, Martin D; Vrieze, Scott; Liu, Dajiang J; Howson, Joanna M M
- Year
- 2020
- Journal
- Molecular psychiatry
- PMID
- 30617275
- DOI
- 10.1038/s41380-018-0313-0
- PMCID
- PMC7515840
Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.
Study design including the discovery and replication stages. NB: Gene-based studies, conditional analyses, and replication in African American ancestry samples not shown here for clarity. *GFG and NAGOZALC studies contributed additional custom content
A concentric Circos plot of the association results for smoking initiation (SI; outer ring), cigarettes per day (CPD) and smoking cessation (SC; inner ring) for chromosomes 1–22 (Pack-years results, which can be found in Supp. Figure 1, are omitted for clarity). Each dot represents a SNV, with the X and Y axes corresponding to genomic location in Mb and -log10P-values, respectively. Labels show the nearest gene to the novel sentinel variants identified in the discovery stage and taken forward to replication. The top signals were truncated at 10−10 for clarity. Novel and previously reported signals are highlighted in red and dark blue, respectively. Grey rings on the y-axis increase by increments of 2 (initial ring corresponding to P = 0.001, then 0.00001 etc.); and the outer and inner red rings correspond to the genome-wide significance level (P = 5 × 10−8) and P = 5 × 10−7, respectively. Image was created using Circos (v0.65)
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| Title | Authors | Journal | Year | Link |
|---|---|---|---|---|
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| Identification of rs2036527 as a cis-regulatory variant for CHRNA3 and CHRNA5 by allele-specific expression and implications for nicotine dependence and lung cancer. | Peng T et al. | — | 2026 | → |
| Large-scale behavioral characterization of oxycodone self-administration in heterogeneous stock rats reveals initial analgesic effects are associated with addiction-like behaviors. | Kallupi M et al. | — | 2026 | → |
| A blood- and brain-based EWAS of smoking. | Chybowska AD et al. | — | 2025 | → |
| A Comprehensive Study Employing Computational Analysis and Mendelian Randomization Has Revealed the Impact of Key Genes on Liver Cancer. | Li S et al. | — | 2025 | → |
| Exposure to Higher Cigarette Taxes during Adolescence Reduces Lifetime Smoking in Individuals with Elevated Genetic Risk | Alemu R et al. | — | 2025 | — |
| Externalizing as a common genetic influence for a broad spectrum of substance use and behavioral conditions: A developmental perspective from the Avon Longitudinal Study of Parents and Children. | Deng WQ et al. | — | 2025 | → |
| Multivariate Bayesian variable selection for multi-trait genetic fine mapping. | Canida T et al. | — | 2025 | → |
| A multi-ancestry cerebral cortex transcriptome-wide association study identifies genes associated with smoking behaviors. | Tan Q et al. | — | 2024 | → |
| Association between tobacco exposure and bladder cancer recurrence: A systematic review and meta-analysis. | Xiang L et al. | — | 2024 | → |
| Association of cigarette smoking, smoking cessation with the risk of cardiometabolic multimorbidity in the UK Biobank. | Zhang S et al. | — | 2024 | → |
| Cross-ancestry genetic investigation of schizophrenia, cannabis use disorder, and tobacco smoking. | Johnson EC et al. | — | 2024 | → |
| Deep sequencing of candidate genes identified 14 variants associated with smoking abstinence in an ethnically diverse sample. | Cinciripini PM et al. | — | 2024 | → |
| Estimation of genetic variation in vitiligo associated genes: Population genomics perspective. | Bharti N et al. | — | 2024 | → |
| Examining the Effect of Genes on Depression as Mediated by Smoking and Modified by Sex. | Voorhies K et al. | — | 2024 | → |
| Genetic control of DNA methylation is largely shared across European and East Asian populations. | Hatton AA et al. | — | 2024 | → |
| Multi-ancestry meta-analysis of tobacco use disorder identifies 461 potential risk genes and reveals associations with multiple health outcomes. | Toikumo S et al. | — | 2024 | → |
| Polygenic profiles define aspects of clinical heterogeneity in attention deficit hyperactivity disorder. | LaBianca S et al. | — | 2024 | → |
| Shared genetic basis connects smoking behaviors and bone health: insights from a genome-wide cross-trait analysis. | Qin C et al. | — | 2024 | → |
| The association of genetic polymorphisms within the dopaminergic system with nicotine dependence: A narrative review. | Yang J et al. | — | 2024 | → |
| [The association of single-nucleotide polymorphism rs6265 of the brain-derived neurotrophic factor gene with clinical features in Parkinson's disease]. | Nikitina MA et al. | — | 2024 | → |
| Unravelling the complex causal effects of substance use behaviours on common diseases. | Xue A et al. | — | 2024 | → |
| Analysis of the brain transcriptome for substance-associated genes: An update on large-scale genome-wide association studies. | Zhao Y et al. | — | 2023 | → |
| An in-depth association analysis of genetic variants within nicotine-related loci: Meeting in middle of GWAS and genetic fine-mapping. | Mo C et al. | — | 2023 | → |
| A scoping review of smoking cessation pharmacogenetic studies to advance future research across racial, ethnic, and ancestral populations. | Prom-Wormley EC et al. | — | 2023 | → |
| Association between smoking and incident back pain: A prospective cohort study with 438 510 participants. | Xu HR et al. | — | 2023 | → |
| Evaluating the causal effect of tobacco smoking on white matter brain aging: a two-sample Mendelian randomization analysis in UK Biobank. | Mo C et al. | — | 2023 | → |
| Evaluating the interaction between 3'aQTL and alcohol consumption/smoking on anxiety and depression: 3'aQTL-by-environment interaction study in UK Biobank cohort. | Yang X et al. | — | 2023 | → |
| Genome-wide by environment interaction studies of maternal smoking and educational score in UK biobank. | Huang H et al. | — | 2023 | → |
| GWAS meta-analysis of 16 790 patients with Barrett's oesophagus and oesophageal adenocarcinoma identifies 16 novel genetic risk loci and provides insights into disease aetiology beyond the single marker level. | Schröder J et al. | — | 2023 | → |
| Heritable Risk and Protective Genetic Components of Glaucoma Medication Non-Adherence. | Barr JL et al. | — | 2023 | → |
| Molecular insights into GPCR mechanisms for drugs of abuse. | Sanchez-Reyes OB et al. | — | 2023 | → |
| Rare coding variants in CHRNB2 reduce the likelihood of smoking. | Rajagopal VM et al. | — | 2023 | → |
| Testing Association of Previously Implicated Gene Sets and Gene-Networks in Nicotine Exposed Mouse Models with Human Smoking Phenotypes. | Mize TJ et al. | — | 2023 | → |
| The Joint Link of the rs1051730 and rs1902341 Polymorphisms and Cigarette Smoking to Peripheral Artery Disease and Atherosclerotic Lesions of Different Arterial Beds. | Zhabin S et al. | — | 2023 | → |
| Univariable and multivariable mendelian randomization study revealed the modifiable risk factors of urolithiasis. | Fang H et al. | — | 2023 | → |
| Capturing additional genetic risk from family history for improved polygenic risk prediction. | Lu T et al. | — | 2022 | → |
| Genetic basis of job attainment characteristics and the genetic sharing with other SES indices and well-being. | Song Z et al. | — | 2022 | → |
| Genetic insights into smoking behaviours in 10,558 men of African ancestry from continental Africa and the UK. | Piga NN et al. | — | 2022 | → |
| Genetics, leadership position, and well-being: An investigation with a large-scale GWAS. | Song Z et al. | — | 2022 | → |
| Heart Disease and Stroke Statistics-2022 Update: A Report From the American Heart Association. | Tsao CW et al. | — | 2022 | → |
| Large-scale genome-wide association study of coronary artery disease in genetically diverse populations. | Tcheandjieu C et al. | — | 2022 | → |
| Prediction of Coronary Artery Disease and Major Adverse Cardiovascular Events Using Clinical and Genetic Risk Scores for Cardiovascular Risk Factors. | Ramírez J et al. | — | 2022 | → |
| Rare genetic variants explain missing heritability in smoking. | Jang SK et al. | — | 2022 | → |
| Smoking quantitatively increases risk for COVID-19. | Zhang F et al. | — | 2022 | → |
| Smoking remains associated with education after controlling for social background and genetic factors in a study of 18 twin cohorts. | Silventoinen K et al. | — | 2022 | → |
| The potential of DNA methylation as a biomarker for obesity and smoking. | Heikkinen A et al. | — | 2022 | → |
| A 5-Factor Framework for Assessing Tobacco Use Disorder. | Bucklin M | — | 2021 | → |
| Addiction-Associated Genetic Variants Implicate Brain Cell Type- and Region-Specific Cis-Regulatory Elements in Addiction Neurobiology. | Srinivasan C et al. | — | 2021 | → |
| A Likelihood Ratio Test for Gene-Environment Interaction Based on the Trend Effect of Genotype Under an Additive Risk Model Using the Gene-Environment Independence Assumption. | de Rochemonteix M et al. | — | 2021 | → |
| A Robust Test for Additive Gene-Environment Interaction Under the Trend Effect of Genotype Using an Empirical Bayes-Type Shrinkage Estimator. | Sanyal N et al. | — | 2021 | → |
| Cigarette smoking-associated isoform switching and 3' UTR lengthening via alternative polyadenylation. | Xu Z et al. | — | 2021 | → |
| Drinking and smoking polygenic risk is associated with childhood and early-adulthood psychiatric and behavioral traits independently of substance use and psychiatric genetic risk. | De Angelis F et al. | — | 2021 | → |
| Dynamic change in the association of a cigarettes-per-day polygenic risk score across the numeric range of its corresponding phenotype over adolescence and young adulthood. | Deutsch AR et al. | — | 2021 | → |
| Etiologies of Melanoma Development and Prevention Measures: A Review of the Current Evidence. | Djavid AR et al. | — | 2021 | → |
| Gene-based association analysis reveals involvement of LAMA5 and cell adhesion pathways in nicotine dependence in African- and European-American samples. | Fan R et al. | — | 2021 | → |
| Genetic architecture of four smoking behaviors using partitioned SNP heritability. | Evans LM et al. | — | 2021 | → |
| Genetic impacts on DNA methylation: research findings and future perspectives. | Villicaña S et al. | — | 2021 | → |
| Genetic mechanisms of COVID-19 and its association with smoking and alcohol consumption. | Rao S et al. | — | 2021 | → |
| Genetic overlap and causal associations between smoking behaviours and mental health. | Barkhuizen W et al. | — | 2021 | → |
| Genetic predispositions moderate the effectiveness of tobacco excise taxes. | Slob EAW et al. | — | 2021 | → |
| Heart Disease and Stroke Statistics-2021 Update: A Report From the American Heart Association. | Virani SS et al. | — | 2021 | → |
| Integration of evidence across human and model organism studies: A meeting report. | Palmer RHC et al. | — | 2021 | → |
| Meta-Analysis of Transcriptome-Wide Association Studies across 13 Brain Tissues Identified Novel Clusters of Genes Associated with Nicotine Addiction. | Ye Z et al. | — | 2021 | → |
| Perinatal exposure to maternal smoking and adulthood smoking behaviors in predicting cardiovascular diseases: A prospective cohort study. | Song Q et al. | — | 2021 | → |
| Sex-specific nicotine sensitization and imprinting of self-administration in rats inform GWAS findings on human addiction phenotypes. | Kozlova A et al. | — | 2021 | → |
| The Cocaine and Oxycodone Biobanks, Two Repositories from Genetically Diverse and Behaviorally Characterized Rats for the Study of Addiction. | Carrette LLG et al. | — | 2021 | → |
| The Effect of Model Directionality on Cell-Type-Specific Differential DNA Methylation Analysis. | Rahmani E et al. | — | 2021 | → |
| The phenomics and genetics of addictive and affective comorbidity in opioid use disorder. | Freda PJ et al. | — | 2021 | → |
| The Role of Pharmacogenetics in Smoking. | El-Boraie A et al. | — | 2021 | → |
| White Matter Integrity and Nicotine Dependence: Evaluating Vertical and Horizontal Pleiotropy. | Ye Z et al. | — | 2021 | → |
| Differential effects of nicotine delivery rate on subjective drug effects, urges to smoke, heart rate and blood pressure in tobacco smokers. | Jensen KP et al. | — | 2020 | → |
| Expanding the genetic architecture of nicotine dependence and its shared genetics with multiple traits. | Quach BC et al. | — | 2020 | → |
| Genome-wide association study of smoking trajectory and meta-analysis of smoking status in 842,000 individuals. | Xu K et al. | — | 2020 | → |
| Heterogeneity and Polygenicity in Psychiatric Disorders: A Genome-Wide Perspective. | Wendt FR et al. | — | 2020 | → |
| Identification of <i>slit3</i> as a locus affecting nicotine preference in zebrafish and human smoking behaviour. | García-González J et al. | — | 2020 | → |
| Smoking-by-genotype interaction in type 2 diabetes risk and fasting glucose. | Wu P et al. | — | 2020 | → |
| Stability in effects of different smoking-related polygenic risk scores over age and smoking phenotypes. | Deutsch AR et al. | — | 2020 | → |
| Variants in the CHRNA5-CHRNA3-CHRNB4 Region of Chromosome 15 Predict Gastrointestinal Adverse Events in the Transdisciplinary Tobacco Use Research Center Smoking Cessation Trial. | Culverhouse RC et al. | — | 2020 | → |
| The Older Finnish Twin Cohort - 45 Years of Follow-up. | Kaprio J et al. | — | 2019 | → |
| Tobacco Genomics: Complexity and Translational Challenges. | Bergen AW et al. | — | 2019 | → |
| Using genomic profiling for understanding and improving response to smoking cessation treatment. | Bierut LJ | — | 2019 | → |