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Recent preclinical findings revealed transgenerational transmission of prenatal nicotine exposure (PNE)-induced hyperactivity in mice without direct nicotine exposure (J. Zhu, Lee, Spencer, Biederman, & Bhide, 2014). These findings suggested that nicotine exposure may adversely impact germ lines, supporting a novel hypothesis for the propagation of environmentally induced ADHD phenotypes in the population that includes paternal smoking during conception. The main aim of the present study was to investigate whether paternal smoking at conception is a risk factor for ADHD in offspring. To this end, we analyzed data on paternal smoking during conception from an opportunistic existing dataset of girls with and without ADHD that had detailed data on paternal smoking. Based on the preclinical findings, we hypothesized that paternal smoking at conception would be a risk factor for ADHD in the offspring. Participants were derived from an existing opportunistic longitudinal, case-control family study of girls with and without ADHD in which detailed information about paternal smoking was systematically collected. Detailed study methodology has been previously reported (Biederman et al., 1999). Briefly, probands were age 6 to 18 years with (N = 140) and without (N = 122) Diagnostic and Statistical Manual of Mental Disorders–revised 3rd edition (DSM-III-R; American Psychiatric Association, 1987) ADHD and their first-degree relatives (ADHD firstdegree relatives: N = 417; control first-degree relatives: N = 369). We excluded potential probands if they had been adopted, if their nuclear family was not available for study, or if they had major sensorimotor handicaps (paralysis, deafness, blindness), psychosis, autism, inadequate command of the English language, or a Full Scale Intelligent Quotient (IQ) < 80. Parents provided written informed consent, and children and adolescents provided written assent. The institutional review board approved this study. Psychiatric assessments of probands and siblings were made with the Schedule for Affective Disorders and Schizophrenia for School-Age Children–Epidemiologic Version (K-SADS-E; Orvaschel & Puig-Antich, 1987). Indirect interviews were conducted with the participant’s parent or guardian. Direct interviews were conducted with subjects older than 12 years. Diagnostic assessments of parents were based on direct interviews with each parent using the Structured Clinical Interview for DSM-III-R (SCID; Spitzer, Williams, Gibbon, & First, 1992). Socioeconomic status (SES) was established using categories delineated by Hollingshead (Hollingshead, 1975). We used information collected from the SCID about paternal smoking status, smoking onset, and smoking offset to derive a variable for paternal smoking at conception. We categorized a father as smoking at conception if he met diagnostic criteria for smoking addiction (t1 pack of cigarettes per day) on the SCID and his age at conception fell within the age range of his smoking onset and offset. Because of their uncertain smoking status, fathers with subthreshold smoking (N = 13) were excluded from the analysis. We used Pearson’s chi-square tests to analyze the rates of paternal smoking at conception and paternal ADHD in probands. Multiple logistic regressions were used to examine the relationship between proband ADHD status and paternal smoking at conception while controlling for paternal ADHD. All analyses were two-tailed and performed using Stata® (Version 14.0). We considered results statistically significant if the p value was less than or equal to .05. Results Out of the 262 probands, 23 did not have the information needed to determine paternal smoking at conception, and 13 had fathers with uncertain smoking status. Thus, our final sample consisted of 121 ADHD probands, 105 control probands, and their 226 fathers. As shown in Table 1, ADHD and control probands were of similar age and SES. As shown in Figure 1, ADHD probands had a significantly higher rate of paternal smoking at conception than controls (35% vs. 23%, χ2 = 3.82, p = .05; Figure 1A). Although the odds ratio (OR) of paternal smoking at conception was 1.5, the association between paternal smoking at conception and proband ADHD status lost significance after controlling for paternal ADHD (OR = 1.50, χ2 = 1.58, p = .21), most likely due to limited statistical power. Discussion Based on findings from preclinical work (J. Zhu, Lee, et al., 2014) showing that epigenetic changes in parental germ cells induced by nicotine exposure mediate the risk for ADHD in rodent offspring, we investigated whether paternal smoking is a risk for ADHD in the offspring. While preliminary, findings suggest that paternal smoking at conception may be a risk factor for ADHD in the offspring. More work is needed to further evaluate this intriguing finding in both sexes controlling for other risk factors including maternal smoking during pregnancy and comorbidity. While ours is the only study that addressed the effects of paternal smoking at conception as a risk for ADHD in the offspring, of the five previous studies that examined this issue, all but one identified paternal smoking as a risk for ADHD in offspring. While two of these studies (Han et al., 2015; Zhu, Olsen, et al., 2014) found that exposure to paternal smoking during pregnancy was associated with a small but significantly increased risk for ADHD in offspring in epidemiological samples, they did not control for ADHD in the parents, making it difficult to assess whether the observed effects were due to correlated genetic risk factors rather than being soley environmental. Langley, Heron, Smith, and Thapar (2012) found similar risks for ADHD in the offspring conferred by prenatal paternal and maternal smoking, suggesting that the associations may be due to genetic risk factors rather than to environmental effects. The finding that fathers who smoked at conception were also more likely to have ADHD is not surprising considering the clearly documented significant association between ADHD and smoking (Kollins, McClernon, & Fuemmeler, 2005), and genes involved in dopamine function and nicotinic receptor activity have also been found to be associated with both ADHD and smoking addiction. Taken together, findings suggest that there may be a gene by environment interaction between ADHD and nicotine exposure that mediates the association between paternal nicotine exposure and risk for ADHD in the offspring. Such a possibility was suggested by Altink et al. (2009) using data from the International Multi-Centre ADHD Gene project (IMAGE), which found that while paternal smoking had a negative effect on attentional control in children with ADHD, this effect appeared to be mediated by genetic risk factors. Clearly, more work is needed to disentangle the environmental effects of paternal smoking at conception from genetic contributions. Our findings should be viewed in light of important methodological limitations. Our results relied on an opportunistic sample of girls with and without ADHD that had available detailed information on paternal smoking at conception not available in other datasets. Thus, we do not know if our findings would generalize to boys with ADHD. Although the sample size was large, the number of probands exposed to paternal smoking at conception was very small, limiting our statistical power, including our ability to adequately examine interaction effects between paternal ADHD and paternal exposure to smoking at conception. However, it is important to note that the effect of paternal smoking at conception was still evident in our study given the odds ratio of 1.5. Because our sample was referred and overwhelmingly Caucasian, our results may not generalize to community samples or other ethnic groups Although preliminary and in need of replication, this pilot study adds to a small literature suggesting that paternal smoking at conception may be a risk for ADHD in offspring. Clearly, more work is needed to disentangle the environmental effects of paternal smoking at conception from genetic contributions, extend it to both sexes, and control for other risk factors, including maternal smoking during pregnancy and comorbidity.