Addiction is a common and costly public health problem, and tobacco use is the leading cause of preventable deaths in the US, leading to an estimated 438,000 premature deaths per year. Nicotine is the substance in tobacco which is responsible for its addictive properties. The goal of our project is to identify gene variants that contribute to nicotine dependence, using both linkage and association studies of subjects from the Icelandic population. To study the genetics of nicotine dependence we have recruited over 5,000 smokers and re-phenotyped them using questionnaires and by interviews. To isolate susceptibility variants we have fine mapped regions linked to nicotine dependence through fully multipoint allele sharing linkage analysis that does not assume a particular inheritance model. Significant linkage peaks with high information content are ultrafine-mapped with hundreds of markers to define the underlying LD structure. The regions have been assessed in a case-control analysis to look for significant haplotype association to nicotine dependence. Genes found in Iceland using this approach are tested for their impact in outside populations already collected by scientific collaborators. The extensive phenotype data on the nicotine dependent patients and relatives will be used in more careful genotype-phenotype correlations as a way to understand their role in nicotine dependence and its co-morbidities.and treatment for this common and intractable problem, in humans representing most important risk factors for numerous diseases. The project is also conducting genome-wide association studies of smoking behavior in a large sample of smokers. The studies have already lead to the identification of three sequence variants correlating with ND. All variants also confer risk of lung cancer, underscoring the public health importance of understanding the genetics of nicotine dependence. In the continuation we plan to increase sample size for GWA studies in Iceland using long-range phasing approaches and joint analyses of large datasets. We will conduct pool sequencing for the discovery of less frequent variants that will subsequently be typed on a set of 2,500 samples that have been chosen to optimize their usefulness for propagating human sequence information into the rest of the Icelandic population using long-range-phasing approaches. The pools will be enriched in samples from carriers of variants detected in GWA studies, and high-risk haplotypes detected by long-range phasing analysis with a focus on linkage regions. In addition we will pay special attention to copy number variants in our approaches. To validate variants in identified in this manner in other populations we will rely on large sets of foreign ND and smoking behavior case-control samples, and a larger set of samples rich in information on both smoking-related diseases and psychiatric disorders. .

Public Health Relevance

Addiction is a common and costly public health problem, and tobacco use is the leading cause of preventable deaths in the US. Understanding the genetic basis of nicotine dependence has enormous public health relevance, as the project has already demonstrated by identifying several genetic variants conferring risk of both nicotine dependence and lung cancer.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Pollock, Jonathan D
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Decode Genetics, Ehf
Zip Code
Pan, Yongchu; Liu, Hongliang; Wang, Yanru et al. (2017) Associations between genetic variants in mRNA splicing-related genes and risk of lung cancer: a pathway-based analysis from published GWASs. Sci Rep 7:44634
Sigurdsson, Snaevar; Alexandersson, Kristjan F; Sulem, Patrick et al. (2017) Sequence variants in ARHGAP15, COLQ and FAM155A associate with diverticular disease and diverticulitis. Nat Commun 8:15789
Steinberg, Stacy; Gudmundsdottir, Steinunn; Sveinbjornsson, Gardar et al. (2017) Truncating mutations in RBM12 are associated with psychosis. Nat Genet 49:1251-1254
Feng, Yun; Wang, Yanru; Liu, Hongliang et al. (2017) Genetic variants of PTPN2 are associated with lung cancer risk: a re-analysis of eight GWASs in the TRICL-ILCCO consortium. Sci Rep 7:825
Lo, Min-Tzu; Hinds, David A; Tung, Joyce Y et al. (2017) Genome-wide analyses for personality traits identify six genomic loci and show correlations with psychiatric disorders. Nat Genet 49:152-156
Hancock, D B; Guo, Y; Reginsson, G W et al. (2017) Genome-wide association study across European and African American ancestries identifies a SNP in DNMT3B contributing to nicotine dependence. Mol Psychiatry :
Zhou, Fei; Wang, Yanru; Liu, Hongliang et al. (2017) Susceptibility loci of CNOT6 in the general mRNA degradation pathway and lung cancer risk-A re-analysis of eight GWASs. Mol Carcinog 56:1227-1238
Zink, Florian; Stacey, Simon N; Norddahl, Gudmundur L et al. (2017) Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly. Blood 130:742-752
Kang, Xiaozheng; Liu, Hongliang; Onaitis, Mark W et al. (2016) Polymorphisms of the centrosomal gene (FGFR1OP) and lung cancer risk: a meta-analysis of 14,463 cases and 44,188 controls. Carcinogenesis 37:280-289
Yuan, Hua; Liu, Hongliang; Liu, Zhensheng et al. (2016) A Novel Genetic Variant in Long Non-coding RNA Gene NEXN-AS1 is Associated with Risk of Lung Cancer. Sci Rep 6:34234

Showing the most recent 10 out of 22 publications