Genome-wide time-to-event analysis on smoking progression stages in a family-based study

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He , L , Pitkäniemi , J , Heikkila , K , Chou , Y-L , Madden , P A F , Korhonen , T , Sarin , A-P , Ripatti , S , Kaprio , J & Loukola , A 2016 , ' Genome-wide time-to-event analysis on smoking progression stages in a family-based study ' , Brain and Behavior , vol. 6 , no. 5 , 00462 .

Title: Genome-wide time-to-event analysis on smoking progression stages in a family-based study
Author: He, Liang; Pitkäniemi, Janne; Heikkila, Kauko; Chou, Yi-Ling; Madden, Pamela A. F.; Korhonen, Tellervo; Sarin, Antti-Pekka; Ripatti, Samuli; Kaprio, Jaakko; Loukola, Anu
Contributor organization: Clinicum
Department of Public Health
Institute for Molecular Medicine Finland
Samuli Olli Ripatti / Principal Investigator
Jaakko Kaprio / Principal Investigator
Biostatistics Helsinki
Complex Disease Genetics
Genetic Epidemiology
Date: 2016-05
Language: eng
Number of pages: 14
Belongs to series: Brain and Behavior
ISSN: 2162-3279
Abstract: Background: 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. Methods: 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. Results: 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. Conclusion: 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.
Subject: Cessation
genome-wide association study
smoking behavior
time-to-event analysis
3142 Public health care science, environmental and occupational health
Peer reviewed: Yes
Usage restriction: openAccess
Self-archived version: publishedVersion

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