title: Genome-wide time-to-event analysis on smoking progression stages in a family-based study.
abstract: Various pivotal stages in smoking behavior can be identified, including initiation, conversion from experimenting to established use, development of tolerance, and cessation. Previous studies have shown high heritability for age of smoking initiation and cessation; however, time-to-event genome-wide association studies aiming to identify underpinning genes that accelerate or delay these transitions are missing to date.
  
  
  
  We investigated which single nucleotide polymorphisms (SNPs) across the whole genome contribute to the hazard ratio of transition between different stages of smoking behavior by performing time-to-event analyses within a large Finnish twin family cohort (N = 1962), and further conducted mediation analyses of plausible intermediate traits for significant SNPs.
  
  
  
  Genome-wide significant signals were detected for three of the four transitions: (1) for smoking cessation on 10p14 (P = 4.47e-08 for rs72779075 flanked by RP11-575N15 and GATA3), (2) for tolerance on 11p13 (P = 1.29e-08 for rs11031684 in RP1-65P5.1), mediated by smoking quantity, and on 9q34.12 (P = 3.81e-08 for rs2304808 in FUBP3), independent of smoking quantity, and (3) for smoking initiation on 19q13.33 (P = 3.37e-08 for rs73050610 flanked by TRPM4 and SLC6A16) in analysis adjusted for first time sensations. Although our top SNPs did not replicate, another SNP in the TRPM4-SLC6A16 gene region showed statistically significant association after region-based multiple testing correction in an independent Australian twin family sample.
  
  
  
  Our results suggest that the functional effect of the TRPM4-SLC6A16 gene region deserves further investigation, and that complex neurotransmitter networks including dopamine and glutamate may play a critical role in smoking initiation. Moreover, comparison of these results implies that genetic contributions to the complex smoking behavioral phenotypes vary among the transitions.
authors.affiliation: Department of Public Health University of Helsinki Helsinki Finland.
authors.forename: Liang
authors.initials: L
authors.lastname: He
authors.affiliation: Department of Public Health University of Helsinki Helsinki Finland; Finnish Cancer Registry Institute for Statistical and Epidemiological Cancer Research Helsinki Finland.
authors.forename: Janne
authors.initials: J
authors.lastname: Pitkäniemi
authors.affiliation: Department of Public Health University of Helsinki Helsinki Finland; Institute for Molecular Medicine Finland (FIMM) University of Helsinki Helsinki Finland.
authors.forename: Kauko
authors.initials: K
authors.lastname: Heikkilä
authors.affiliation: Washington University School of Medicine Department of Psychiatry St. Louis Missouri.
authors.forename: Yi-Ling
authors.initials: YL
authors.lastname: Chou
authors.affiliation: Washington University School of Medicine Department of Psychiatry St. Louis Missouri.
authors.forename: Pamela A F
authors.initials: PA
authors.lastname: Madden
authors.affiliation: Department of Public Health University of Helsinki Helsinki Finland; National Institute for Health and Welfare Helsinki Finland; Institute of Public Health and Clinical Nutrition University of Eastern Finland Kuopio Finland.
authors.forename: Tellervo
authors.initials: T
authors.lastname: Korhonen
authors.affiliation: Institute for Molecular Medicine Finland (FIMM)University of Helsinki Helsinki Finland; National Institute for Health and Welfare Helsinki Finland.
authors.forename: Antti-Pekka
authors.initials: AP
authors.lastname: Sarin
authors.affiliation: Department of Public Health University of Helsinki Helsinki Finland; Institute for Molecular Medicine Finland (FIMM) University of Helsinki Helsinki Finland; Wellcome Trust Sanger Institute Hinxton Cambridge UK.
authors.forename: Samuli
authors.initials: S
authors.lastname: Ripatti
authors.affiliation: Department of Public Health University of Helsinki Helsinki Finland; Institute for Molecular Medicine Finland (FIMM) University of Helsinki Helsinki Finland; National Institute for Health and Welfare Helsinki Finland.
authors.forename: Jaakko
authors.initials: J
authors.lastname: Kaprio
authors.affiliation: Department of Public Health University of Helsinki Helsinki Finland; Institute for Molecular Medicine Finland (FIMM) University of Helsinki Helsinki Finland.
authors.forename: Anu
authors.initials: A
authors.lastname: Loukola
mesh_terms: D000368:Aged; D001315:Australia; D018450:Disease Progression; D005260:Female; D005387:Finland; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D050480:Plasma Membrane Neurotransmitter Transport Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012907:Smoking / Q000235:genetics*; D050053:TRPM Cation Channels / Q000235:genetics
chemical_list: D050480:Plasma Membrane Neurotransmitter Transport Proteins; C419411:SLC6A16 protein, human; D050053:TRPM Cation Channels; C437888:TRPM4 protein, human
keywords: Cessation; genome‐wide association study; initiation; smoking behavior; time‐to‐event analysis