In a systematic evaluation of the familial relationship between ADHD and PSUD using a well-characterized, large, longitudinal sample of ADHD girls and their first-degree relatives, we found that ADHD in the proband was consistently associated with a significantly increased risk for ADHD in relatives irrespective of comorbidity with PSUD. Likewise, PSUD in the proband predicted PSUD in relatives irrespective of the comorbidity with ADHD. There was no evidence for co-segregation or non-random mating between these disorders. Taken together these findings are most consistent with the hypothesis of independent transmission between ADHD and PSUD in girls with ADHD (hypothesis 1).
The findings of familial association between ADHD and PSUD identified in this sample of girls with ADHD are remarkably consistent with those previously reported by our group in a sample of boys with ADHD using identical ascertainment and assessment methodology. These results support the hypothesis that the nature of the familial association between ADHD and PSUD is not moderated by gender.
However, although not reaching our threshold for statistical significance, the risk for PSUD in relatives was also increased in ADHD probands without PSUD. Thus, although our results are most consistent with the hypothesis of independent transmission between ADHD and PSUD, considering that the probands are still young and transiting through the age of risk for PSUD, we cannot rule out the variable expressivity hypothesis (hypothesis 2) positing that ADHD and PSUD may share common risk factors. Future long-term follow-up findings will help clarify this important issue.
In contrast, other hypotheses can be rejected more clearly. The hypothesis that ADHD with PSUD is, from a familial perspective, a more severe form of ADHD can be rejected, because it incorrectly predicts a higher risk for ADHD and PSUD among the relatives of probands with ADHD with PSUD compared with relatives of probands with only ADHD. Furthermore, since there was no evidence of co-segregation between ADHD and PSUD in relatives, it is unlikely that ADHD with PSUD represents a distinct familial subtype. Likewise we can reject the hypothesis that the association between ADHD and PSUD is due to non-random mating, since we detected no significant evidence that parents with ADHD were more likely to be married to someone with PSUD, and vice versa. Thus, these results should be viewed as preliminary until replicated in larger clinical samples and in community samples.
Our findings should be interpreted in the context of several limitations. While probands and their siblings were assessed at baseline and follow-up assessments, parents were assessed only at baseline. Thus, it is possible that additional cases of substance use disorders emerged in the parents during the follow-up period. However, the use of Cox models to calculate age-adjusted rates somewhat mitigates this concern. In addition, the retrospective reports of ADHD symptoms in parents may have been subject to recall bias and therefore had an effect on the precision of our findings. Our sample was originally ascertained with DSM-III-R criteria, so findings may have differed had DSM-IV been used. However, Biederman et al. (1997)
showed that 93% of children with a DSM-III-R diagnosis also received a DSM-IV diagnosis. Power limitations precluded our ability to examine individual PSUDs. Future long-term studies could benefit from such analyses. Since the sample consisted of largely Caucasian subjects, our findings may not generalize to other minority or ethnic groups. Finally, community based studies should determine if these findings extend to the general population.
Despite these considerations, in a sample of pediatrically and psychiatrically referred adolescent girls with ADHD, familial risk analysis suggests that the association between ADHD and PSUD is most consistent with the hypothesis of independent transmission between these disorders. Longer follow-ups are needed to confirm this finding and examine the alternative possibility of variable expressivity between ADHD and PSUD.