TY - JOUR
T1 - Targeted sequencing identifies genetic polymorphisms of flavin-containing monooxygenase genes contributing to susceptibility of nicotine dependence in European American and African American
AU - Zhang, Tian Xiao
AU - Saccone, Nancy L.
AU - Bierut, Laura J.
AU - Rice, John P.
N1 - Funding Information:
We thank the participation of volunteers, patients, and their families. This work was supported by the National Institutes of Health Grant U19CA148172 to LJB and Grant R01DA026911 from the National Institute on Drug Abuse (NIDA) supported some of the principle component analysis and exome genotyping which was used to clean/confirm check the targeted sequence data. Grants and contracts from the National Institutes of Health supported the following studies and groups: COGEND (P01CA89392), AAND (R01DA025888), and CIDR (HHSN268201100011I).
Publisher Copyright:
© 2017 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.
PY - 2017/4
Y1 - 2017/4
N2 - Background: Smoking is a leading cause of preventable death. Early studies based on samples of twins have linked the lifetime smoking practices to genetic predisposition. The flavin-containing monooxygenase (FMO) protein family consists of a group of enzymes that metabolize drugs and xenobiotics. Both FMO1 and FMO3 were potentially susceptible genes for nicotine metabolism process. Methods: In this study, we investigated the potential of FMO genes to confer risk of nicotine dependence via deep targeted sequencing in 2,820 study subjects comprising 1,583 nicotine dependents and 1,237 controls from European American and African American. Specifically, we focused on the two genomic segments including FMO1, FMO3, and pseudo gene FMO6P, and aimed to investigate the potential association between FMO genes and nicotine dependence. Both common and low-frequency/rare variants were analyzed using different algorithms. The potential functional significance of SNPs with association signal was investigated with relevant bioinformatics tools. Results: We identified different clusters of significant common variants in European (with most significant SNP rs6674596, p =.0004, OR = 0.67, MAF_EA = 0.14, FMO1) and African Americans (with the most significant SNP rs6608453, p =.001, OR = 0.64, MAF_AA = 0.1, FMO6P). No significant signals were identified through haplotype-based analyses. Gene network investigation indicated that both FMO1 and FMO3 have a strong relation with a variety of genes belonging to CYP gene families (with combined score greater than 0.9). Most of the significant variants identified were SNPs located within intron regions or with unknown functional significance, indicating a need for future work to understand the underlying functional significance of these signals. Conclusions: Our findings indicated significant association between FMO genes and nicotine dependence. Replications of our findings in other ethnic groups were needed in the future. Most of the significant variants identified were SNPs located within intronic regions or with unknown functional significance, indicating a need for future work to understand the underlying functional significance of these signals.
AB - Background: Smoking is a leading cause of preventable death. Early studies based on samples of twins have linked the lifetime smoking practices to genetic predisposition. The flavin-containing monooxygenase (FMO) protein family consists of a group of enzymes that metabolize drugs and xenobiotics. Both FMO1 and FMO3 were potentially susceptible genes for nicotine metabolism process. Methods: In this study, we investigated the potential of FMO genes to confer risk of nicotine dependence via deep targeted sequencing in 2,820 study subjects comprising 1,583 nicotine dependents and 1,237 controls from European American and African American. Specifically, we focused on the two genomic segments including FMO1, FMO3, and pseudo gene FMO6P, and aimed to investigate the potential association between FMO genes and nicotine dependence. Both common and low-frequency/rare variants were analyzed using different algorithms. The potential functional significance of SNPs with association signal was investigated with relevant bioinformatics tools. Results: We identified different clusters of significant common variants in European (with most significant SNP rs6674596, p =.0004, OR = 0.67, MAF_EA = 0.14, FMO1) and African Americans (with the most significant SNP rs6608453, p =.001, OR = 0.64, MAF_AA = 0.1, FMO6P). No significant signals were identified through haplotype-based analyses. Gene network investigation indicated that both FMO1 and FMO3 have a strong relation with a variety of genes belonging to CYP gene families (with combined score greater than 0.9). Most of the significant variants identified were SNPs located within intron regions or with unknown functional significance, indicating a need for future work to understand the underlying functional significance of these signals. Conclusions: Our findings indicated significant association between FMO genes and nicotine dependence. Replications of our findings in other ethnic groups were needed in the future. Most of the significant variants identified were SNPs located within intronic regions or with unknown functional significance, indicating a need for future work to understand the underlying functional significance of these signals.
KW - flavin-containing monooxygenase
KW - genetic association
KW - rare variants
KW - targeted sequencing
UR - http://www.scopus.com/inward/record.url?scp=85015271088&partnerID=8YFLogxK
U2 - 10.1002/brb3.651
DO - 10.1002/brb3.651
M3 - Article
C2 - 28413702
AN - SCOPUS:85015271088
SN - 2162-3279
VL - 7
JO - Brain and Behavior
JF - Brain and Behavior
IS - 4
M1 - e00651
ER -