In order to allow for a single test of mediation, we conducted a principal components analysis48 of the mature phenotypes of persistent heavy smoking (pack years smoked at age 38 years), nicotine dependence (total number of symptoms across all assessments), and cessation failure (number of assessments with relapse). This analysis indicated that the mature phenotypes were positively and significantly correlated (Supplemental Table 3) and could be summarized in a single component that explained 78% of the variance in the three measures (factor loading for persistent heavy smoking=0.61; for nicotine dependence=0.60; for cessation failure=0.52). We used this component as the dependent variable in our mediation analysis. Analyses were adjusted for sex and conducted using Stata 11.0.49 Panel-data models were fitted to longitudinal repeated-measures data using “XT” and “ST” commands in Stata 11.0. Unless otherwise noted, effect-sizes are presented for one-unit increases in the genetic-risk Z-score (GRS).
