Incorporating age at onset of smoking into genetic models for nicotine dependence: evidence for interaction with multiple genes.
- Authors
- Grucza, Richard A; Johnson, Eric O; Krueger, Robert F; Breslau, Naomi; Saccone, Nancy L; Chen, Li-Shiun; Derringer, Jaime; Agrawal, Arpana; Lynskey, Michael; Bierut, Laura J
- Year
- 2010
- Journal
- Addiction biology
- PMID
- 20624154
- DOI
- 10.1111/j.1369-1600.2010.00220.x
- PMCID
- PMC3085318
Nicotine dependence is moderately heritable, but identified genetic associations explain only modest portions of this heritability. We analyzed 3369 SNPs from 349 candidate genes and investigated whether incorporation of SNP-by-environment interaction into association analyses might bolster gene discovery efforts and prediction of nicotine dependence. Specifically, we incorporated the interaction between allele count and age at onset of regular smoking (AOS) into association analyses of nicotine dependence. Subjects were from the Collaborative Genetic Study of Nicotine Dependence and included 797 cases ascertained for Fagerström nicotine dependence and 811 non-nicotine-dependent smokers as controls, all of European descent. Compared with main effect models, SNP x AOS interaction models resulted in higher numbers of nominally significant tests, increased predictive utility at individual SNPs and higher predictive utility in a multi-locus model. Some SNPs previously documented in main effect analyses exhibited improved fits in the joint analysis, including rs16969968 from CHRNA5 and rs2314379 from MAP3K4. CHRNA5 exhibited larger effects in later-onset smokers, in contrast with a previous report that suggested the opposite interaction (Weiss et al. 2008). However, a number of SNPs that did not emerge in main effect analyses were among the strongest findings in the interaction analyses. These include SNPs located in GRIN2B (P = 1.5 x 10(-5)), which encodes a subunit of the N-methyl-D-aspartate receptor channel, a key molecule in mediating age-dependent synaptic plasticity. Incorporation of logically chosen interaction parameters, such as AOS, into genetic models of substance use disorders may increase the degree of explained phenotypic variation and constitutes a promising avenue for gene discovery.
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| Name | Type |
|---|---|
| ADCY8 | gene |
| ADHD | phenotype |
| adolescents | cohort |
| age | phenotype |
| age at first full cigarette local | phenotype |
| age at first full drink local | phenotype |
| age at first use | phenotype |
| age at onset of regular drinking local | phenotype |
| age at onset of regular smoking local | phenotype |
| age-at-onset of regular smoking local | phenotype |
| Age-at-onset of regular smoking (AOS) local | phenotype |
| age at onset of regular use local | phenotype |
| age-at-onset of smoking local | phenotype |
| age at smoking initiation | phenotype |
| age of onset | phenotype |
| Age of onset (AOS) local | phenotype |
| AGPAT4 local | gene |
| alcohol | phenotype |
| alcohol-related phenotypes | phenotype |
| Alcohol Use | phenotype |
| candidate gene study | cohort |
| case-control pairs local | cohort |
| case/control status | phenotype |
| cases | cohort |
| CHRN local | gene |
| Chrna3 | gene |
| CHRNA5 | gene |
| Chrnb4 | gene |
| cigarettes | phenotype |
| COGEND | cohort |
| Collaborative Study for the Genetics of Nicotine Dependence (COGEND) local | cohort |
| common polymorphism local | variant |
| controls | cohort |
| DBH | gene |
| DBI | gene |
| drug dependence | phenotype |
| DSM-IV | phenotype |
| Earlier onset smokers local | phenotype |
| earlier onset smoking local | phenotype |
| early onset smokers local | phenotype |
| early substance use | phenotype |
| European population | cohort |
| Fagerström Test for Nicotine Dependence | phenotype |
| FTND | phenotype |
| GABRR1 | gene |
| gene | gene |
| GRIN2B | gene |
| GRIN2B SNPs local | variant |
| IREB2 | gene |
| Kcnb1 | gene |
| Kcnj6 | gene |
| later onset smokers local | phenotype |
| Later onset smokers local | phenotype |
| later onset smoking local | phenotype |
| MAP3K4 local | gene |
| nicotine | drug |
| nicotine dependence | phenotype |
| pAOS local | phenotype |
| psychiatric disorders | phenotype |
| rAFC local | phenotype |
| rAFD local | phenotype |
| rAOD local | phenotype |
| rAOS local | phenotype |
| Recoded Age of Onset local | phenotype |
| regular alcohol use | phenotype |
| regular smoking | phenotype |
| rs16969968 | variant |
| rs17760877 local | variant |
| rs890 local | variant |
| sex | phenotype |
| single nucleotide polymorphism | variant |
| smoking | phenotype |
| smoking initiation | phenotype |
| SNP | cohort |
| SNP x rAOS interaction local | variant |
| substance use | phenotype |
| tobacco use | phenotype |
| top 30 SNPs local | variant |
| top SNP findings local | variant |
| VAPA local | gene |
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