Nicotine dependence risk and lung cancer risk are associated with variants in a region of chromosome 15 encompassing genes encoding the nicotinic receptor subunits CHRNA5, CHRNA3 and CHRNB4. To identify potential biological mechanisms that underlie this risk, we tested for cis -acting eQTLs for CHRNA5, CHRNA3 and CHRNB4 in human brain. Using gene expression and disease association studies, we provide evidence that both nicotine-dependence risk and lung cancer risk are influenced by functional variation in CHRNA5. We demonstrated that the risk allele of rs16969968 primarily occurs on the low mRNA expression allele of CHRNA5. The non-risk allele at rs16969968 occurs on both high and low expression alleles tagged by rs588765 within CHRNA5. When the non-risk allele occurs on the background of low mRNA expression of CHRNA5, the risk for nicotine dependence and lung cancer is significantly lower compared to those with the higher mRNA expression. Together, these variants identify three levels of risk associated with CHRNA5. We conclude that there are at least two distinct mechanisms conferring risk for nicotine dependence and lung cancer: altered receptor function caused by a D398N amino acid variant in CHRNA5 (rs16969968) and variability in CHRNA5 mRNA expression.
Bibliographical noteFunding Information:
In memory of Theodore Reich, founding Principal Investigator of Collaborative Genetic Study of Nicotine Dependence (COGEND), we are indebted to his leadership in the establishment and nurturing of COGEND and acknowledge with great admiration his seminal scientific contributions to the field. The COGEND project is a collaborative research group and part of the NIDA Genetics Consortium. Subject collection was supported by NIH grant CA89392 (PI-L Bierut) from the National Cancer Institute. Lead investigators directing data collection are Laura Bierut, Naomi Breslau, Dorothy Hatsukami and Eric Johnson. The authors thank Heidi Kromrei and Tracey Richmond for their assistance in data collection. Genotyping work at Perlegen Sciences was performed under NIDA Contract HHSN271200477471C. Phenotypic and genotypic data are stored in the NIDA Center for Genetic Studies (NCGS) at http://zork.wustl.edu/ under NIDA Contract HHSN271200477451C (PIs J Tischfield and J Rice). Genotyp-ing services were also provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096.
We are grateful to the families for their participation in the studies at the Washington University Alzheimer’s Disease Research Center (ADRC) and at the Australian Brain Donor Program (ABDP), Sydney, Australia. Funding for the research at the ADRC was provided by grants from the National Institute on Aging: P50 AG05681 and P01 AG03991 to J.C.M. We thank Dr Henry Lester for helpful discussions.
Edenberg, L. Bierut, includes nine different centers where data collection, analysis and storage take place. The nine sites and Principal Investigators and Co-investigators are: University of Connecticut (V. Hesselbrock); Indiana University (H.J. Edenberg, J. Nurnberger Jr, T. Foroud); University of Iowa (S. Kuperman); SUNY Downstate (B. Porjesz); Washington University in St Louis (L. Bierut, A. Goate, J. Rice); University of California at San Diego (M. Schuckit); Howard University (R. Taylor); Rutgers University (J. Tisch-field); Southwest Foundation (L. Almasy). Q. Max Guo is the NIAAA Staff Collaborator. This national collaborative study is supported by the NIH Grant U10AA008401 from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the National Institute on Drug Abuse (NIDA). In memory of Henri Begleiter and Theodore Reich, Principal and Co-Principal investigators of COGA since its inception; we are indebted to their leadership in the establishment and nurturing of COGA, and acknowledge with great admiration their seminal scientific contributions to the field.
This study is partially supported by the COGA project. The Collaborative Study on the Genetics of Alcoholism (COGA), Co-Principal Investigators B. Porjesz, V. Hesselbrock, H.
The Genetic Epidemiology of Lung Cancer Consortium (GELCC) was formed by scientists from several US universities, plus the National Cancer Institute and the Human Genome Research Institute to identify lung cancer susceptibility genes in familial lung cancer populations. The Principal Investigator is Dr Marshall Anderson, and the members of GELCC are: University of Cincinnati (M Anderson, SM Pinney, J Lee, E Kupert), Washington University (M You, Y Wang, P Liu, H Vikis, Y Lu), Mayo Foundation & Clinic (M de Andrade, P Yang, GM Petersen), Karmanos Cancer Center (AG Schwartz), University of Colorado Health Science (PR Fain), University of Toledo College of Medicine (C Gaba), University of Texas Southwestern Medical Center (J Minna, A Gazdar), Louisiana State University (Diptasri Mandal), National Cancer Institute (D Seminara), National Human Genome Research Institute (JE Bailey-Wilson), MD Anderson Cancer Center (CI Amos). This work was supported by the NIH grant U01CA076293 from the National Cancer Institute. The following authors are included under the GELCC collaborators: Haris Vikis1, Yan Lu1, Yian Wang1, Ping Yang2, Susan M. Pinney3, Gloria M. Petersen2, Mariza de Andrade2, Ann G. Schwartz4, Adi Gazdar5, Colette Gaba6, Diptasri Mandal7, Elena Kupert3, Juwon Lee3, Daniela Seminara8, Pamela R. Fain9, John Minna5, Joan E. Bailey-Wilson10, Yafang Li11, Christopher I. Amos11 1Department of Surgery, Washington University, St Louis, MO, USA. 2Mayo Clinic, Rochester, MN, USA. 3University of Cincinnati, Cincinnati, OH, USA. 4Karmanos Cancer Institute, Detroit, MI, USA. 5University of Texas Southwestern Medical Center, Dallas, TX, USA. 6University of Toledo College of Medicine, Toledo, OH, USA. 7Louisiana State University Health Science Center from Louisiana State University, New Orleans, LA, USA. 8National Cancer Institute, Bethesda, MD, USA. 9University of Colorado, Denver, CO, USA.