Evidence for a two-stage model of dependence using the NESARC and its implications for genetic association studies

Abstract

Some twin studies suggest that substance initiation and dependence are part of a complex, two-stage process and that some genetic influences are stage-specific, acting on either the transition from abstinence to initiation, or on the transition from use to dependence. However, questions remain about the two-stage model, especially for illicit drugs. Using a familial aggregation design, we tested the hypothesized two-stage model of dependence on illicit substances and alcohol in a large, nationally representative sample. Family history of drug or alcohol problems is significantly associated with initiation that does not progress to dependence (i.e., conditional initiation). Furthermore, family history of drug or alcohol problems is significantly associated with dependence even after conditioning on factors influencing initiation (i.e., conditional dependence). These results suggest that substance initiation and dependence involve at least partially distinct familial factors. The possibility that different genetic factors affect initiation and dependence has important implications for control group selection in case-control genetic association studies, and may explain some inconsistent results for drug dependence. If some genetic factors are stage-specific (i.e., not common across initiation and dependence), inclusion of abstainers in the control group may mix the genetic effects for initiation with those for transition to dependence, providing unclear results. Depending on the specific question about the nature of the genetic effect (whether on initiation, on dependence, or both), investigators designing case-control genetic association studies should carefully consider inclusion and exclusion criteria of the control group.

Personality Disorders and the 3-Year Course of Alcohol, Drug, and Nicotine Use Disorders

“…Family history of alcohol or drug problems was defined as positive if experienced by parents or siblings; NESARC family history methodology is described in detail elsewhere 70 . Since treatment in naturalistic, non-randomized studies may indicate more severe or persistent disorders 7 , we also controlled for treatment status at baseline for alcohol or drug problems (treatment for nicotine dependence was not ascertained).…”

Effects of State-Level Tobacco Environment on Cigarette Smoking are Stronger Among Those With Individual-Level Risk Factors

“…56 "Parental problems with alcohol or drug use" were ascertained as described previously. 57,58 In separate modules, interviewers described observable manifestations of alcohol or drug use disorder diagnostic criteria, which are most likely to be apparent to offspring, [58][59][60] and then asked separately whether the participant's biological father or mother experienced such problems with alcohol or drugs. These measures show excellent reliability 43,47 and validity.…”

Parental Alcohol History Differentially Predicts Offspring Disorders in Distinct Subgroups in Israel

“…In the parental history module, interviewers read examples of the respective diagnostic criteria, including readily observable manifestations of the disorder, because these are most likely to be known to offspring (Andreasen et al, 1977;Heiman et al, 2008;Slutske et al, 1996). Then the interviewers asked separately about whether respondents' biological father or mother experienced the condition as defi ned.…”