Genome-wide single nucleotide polymorphism heritability of nicotine dependence as a multidimensional phenotype

Abstract

Background: Heritability estimates from twin studies of the multi-faceted phenotype of nicotine dependence (ND) range from moderate to high (31-60%), but vary substantially based on the specific ND-related construct examined. The current study estimated the aggregate role of common genetic variants on key ND constructs.

Method: Genomic-relationship-matrix restricted maximum likelihood (GREML) was used to decompose phenotypic variance across multiple ND indices using 796 125 polymorphisms from 2346 unrelated 'lifetime ever smokers' of European ancestry. Measures included DSM-IV ND and Fagerström Test for Nicotine Dependence (FTND) summary measures and constituent constructs (e.g. withdrawal severity, tolerance, heaviness of smoking and time spent smoking). Exploratory and confirmatory factor models were used to describe the covariance structure across ND measures; resulting factor(s) were the subject(s) of GREML analyses.

Results: Factor models indicated highly correlated DSM-IV and FTND factors for ND (0.545, 95% confidence interval 0.50-0.60) that could be represented as a higher-order factor (NIC DEP). Additive genetic influence on NIC DEP was 33% (s.e. = 0.14, p = 0.009). Post-hoc analyses indicated moderate genetic effects on the DSM-IV (34%, s.e. = 0.14, p = 0.008) and FTND (26%, s.e. = 0.14, p = 0.032) factors, both of which were influenced by the same genetic effects (r G-SNP = 1.00, s.e. = 0.09, p < 0.00001).

Conclusions: Overall, common single nucleotide polymorphisms accounted for a large proportion of the genetic influences on ND-related phenotypes that have been observed in twin studies. Genetic contributions across distinct ND scales were largely influenced by shared genetic factors.

Keywords: Addiction; genetics; single nucleotide polymorphism heritability; substance dependence.

Figure 1

Confirmatory Factor Analysis of DSM-IV and FTND symptoms in the entire SAGE sample (Final-CFA-Model-I with Higher-order factor). Each standardized path loading (with 95% confidence interval) could not be dropped from the model without a significant loss in model fit. Abbreviations: DSM1-Tolerance; DSM2-Withdrawal; DSM3-Using more than intended; DSM4-Unsuccesful attempts to cut down; DSM5-Great time spent using/recovering; DSM6-Activities foregone; DSM7-Continued use despite problems; FTND1-Time to first cigarette; FTND2- Difficulty refraining; FTND3- Most difficult cigarette to quit; FTND4- Cigarettes per day; FTND5- Timing of greatest smoking frequency; FTND6- Smoking while ill. Notation: * - The unstandardized path loading from DSM to NIC DEP was fixed to 1.00 in the Mplus model, thus the standardized loading presented does not have standard error. The product of the standardized laodings on NIC DEP is equal to the phenotypic correlation between the two factors (r_DSM-FTND = 0.545 [95% CI: 0.50–0.60]).