It appears that the prevalences of externalizing diagnoses may differ depending on the population sampled. Rates of ASPD in the Epidemiologic Catchment Area (ECA) Study (Regier et al, 1990
) (2.6%) were lower than the National Co-morbidity Survey (NCS) (3.5%) (Agosti et al., 2002
; Kessler et al., 1994
). In the national epidemiologic survey on alcohol and related conditions (NESARC) the lifetime prevalences of ASPD, and CD were 1.1% and 3.6%, respectively (Compton et al., 2005
). In that survey they found that Native Americans were more likely to have ASPD than any other ethnic group.
While there have been some well sampled large epidemiological studies of Native American tribes, prevalences of ASPD or CD in those populations have not been reported (Beals et al., 2005
). However, there have been some smaller samples that have estimated rates within a specific tribe or a treatment subsample. In this American Indian sample, the lifetime prevalence's of ASPD (11.0%) and CD (7%) were high but were not higher than those reported by Hesselbrock and colleagues (2000
in Alaska Native alcoholics, in treatment, using the same diagnostic instrument as the present study (ASPD=35%; CD=39%). Duclos et al., (1998)
reported that 16.7% of American Indian adolescent detainees on a Northern Plains reservation had a diagnosis of CD. In a southeastern American Indian tribe substance abuse treatment center, 74.2% of the adolescents sampled were found to have a CD diagnosis (Fisckenschjer and Novins, 2003; Novins et al., 2006
). In the “Flower of Two Soils Project”, Canadian First Nations children were found to have high rates of CD but low rates of depression (Dion et al., 1998
; Sack et al., 1993
). Interestingly, low rates of depression and anxiety disorders have also been reported previously in this American Indian population (Gilder et al., 2004
Perhaps the most informative data on conduct disorder and substance dependence in American Indians has been published by Kunitz and colleagues (1998
. In a study of the Navajo they reported that the prevalence of CD was 22.2% in men and 12.3% in women and the prevalence of alcohol dependence was 70% among men and 29% among women. (Kunitz et al., 1999a
). They also reported that CD was not simply a risk factor for alcohol dependence but also for more extreme forms of alcohol- and non-alcohol related problems (Kunitz et al., 1999a
). Risk factors for CD in that population were: histories of physical and sexual abuse in childhood; abusive maternal drinking, a small number of households per camp; younger age; and being male (Henderson et al., 1998
; Kunitz et al., 1999b
). They further speculate that the decline of the livestock economy and the development of a cash economy, and the movement from multiple household camps to agency and border towns causing the disruption of the network of obligations to kin, may have resulted in social structural risk factors for excessive drinking (Kunitz and Levy, 1994
) and other externalizing disorders.
ASPD and ASPD/CD were both found to be highly heritable in this American Indian population. There have been few studies of the heritability of the diagnosis of ASPD published previously. In one study, of the Vietnam Era Twin Sample, a heritability of 0.67 was found, similar to the estimated heritability of that trait in this population of American Indians (0.76) (Slutske, 2001
). However, significant evidence for a heritable component for CD was not found in this American Indian population. A number of authors have suggested that genetic influences may impact antisocial behaviors in adulthood more than during childhood or adolescence (Cloninger and Gottesman, 1987
). Lyons et al., (1995)
reported a lower heritability estimate for a CD symptoms scale than a scale of adult antisocial behavior symptoms. Additionally, Hesselbrock and Hesselbrock (1994)
noted that among patients being treated for alcohol dependence, associations of the clinical characteristics of alcohol dependence with CD were much less striking that those with ASPD. Thus, it appears that in some populations that a history of childhood conduct symptoms without subsequent adult antisocial symptomatology may be less associated with alcohol dependence and also may be less genetically regulated. While a larger sample size may uncover evidence for a genetic component for CD in this American Indian population, sources of environmental risk factors should also be considered in understanding the etiology of childhood CD.
Sack et al., (1993)
has suggested that cultural disparity, minority status and poverty may be important factors in the genesis of CD in First Nations people, and further speculated that CD rates may be a “barometer of socio-cultural stress” akin to the way neonatal mortality rate is seen as a measure of the quality of overall healthcare. In this regard, Costello et al., (2003)
reported on a natural experiment in an American Indian community in the Smoky Mountains where the opening of a casino provided an income supplement that moved 14% of their study families out of poverty. Children in the study were evaluated 4 years before and 4 years after the casino opened. The effect of moving out of poverty was found to be specific to reducing symptoms of conduct and oppositional defiant disorders, whereas anxiety and depression symptoms were unaffected. Taken together these studies provide some support for a social causation explanation of the high prevalence of CD seen in some American Indian communities.
A variety of genetically influenced characteristics may also contribute to the increased risk for substance dependence and other externalizing disorders seen in adulthood, such as ASPD. This study provides some support for this hypothesis through the identification of several sites in the genome that may harbor genes for antisocial behaviors. Analyses of multipoint variance component LOD scores for the dichotomous DSM-III-R phenotypes of ASPD and ASPD/CD revealed six locations, on chromosome 13 for ASPD and on chromosomes 1, 3, 4, 14, 17 and 20 for ASPD/CD that had a LOD score of 2 or above. Only some genetic loci were found to be in common for the two heritable phenotypes (ASPD, ASPD/CD) in this American Indian population. This may be somewhat explained by prior findings in twins where it was demonstrated that genetic influences that contributed to the risk for adult antisocial behaviors also contributed to those same behaviors in childhood but that additional genetics risk factors came into play in adolescence and adulthood that could ultimately result in ASPD and alcohol dependence (Jacobson et al., 2002
; Lyons et al., 1995
Although this is the first published genome scan for ASPD in any population, there are several reports of genome wide scans for “conduct symptoms” and CD that have been previously published (see Dick et al., 2004
; Kendler et al., 2006
; Stallings et al., 2005
). One linkage study, in adolescents, found preliminary evidence for linkage on chromosomes 3 and 9 (Stallings et al., 2003
) for both a “dependence vulnerability” phenotype that consisted of “the average number of dependence symptoms across all classes of substances divided by the number of substances used repeatedly” and a phenotype that indexed the number of DSM-III-R CD symptoms. In another study, evidence suggestive of linkage was identified on chromosomes 2 and 19 and other regions of interest on chromosomes 3 and 12 using the COGA pedigrees (Dick et al., 2004
), and in a third study, of Irish alcohol affected sibpairs, evidence suggestive of linkage to CD was found on chromosome 1 and 14 (Kendler et al., 2006
While it is difficult to compare data between studies, there are two loci of interest for the ASPD phenotype found in this American Indian study that were also identified within the same general chromosome locations in previously published linkage analyses of conduct disorder. A location on chromosome 2, found in the present study, was in the general location to regions on chromosome 2 reported previously for CD symptoms phenotypes in the COGA study (Dick et al., 2004
) and in the Irish alcohol affected sibpairs study (Kendler et al., 2006
). Another locus on chromosome 10 seen in the present study is generally with a region previously identified in a linkage analyses conducted using the Irish affected sibpairs study (Kendler et al., 2006
There are three loci of interest for the ASPD/CD phenotype found in this American Indian study that were in a similar location to those identified in previously published linkage analyses for externalizing behaviors. A broad region on chromosome 3 supporting evidence suggestive of linkage for ASPD/CD in these American Indians was found in a similar location (within 30 cM) by another study for conduct symptoms (Stallings et al., 2005
) and drug abuse vulnerability (Stallings et al., 2003
While the ASPD and ASPD/CD phenotypes were found to be highly significantly comorbid with alcohol dependence in these American Indians it should be noted that the amount of alcohol dependence in this population that is actually attributable to those phenotypes is low. This finding was also highlighted in the studies by Kunitz and colleagues in the Navajo where high rates of CD and alcohol dependence were found but the amount of alcohol dependence that was attributable to CD was low (Kunitz et al., 1999a
). This suggests that while ASPD/CD may be highly associated with alcohol dependence and may explain risk for alcohol dependence in a segment of the population other risk factors most likely explain a larger amount of genetic and environmental variance for alcohol dependence in the larger aggregate population.
Only a few chromosome locations found to be associated with the ASPD and ASPD/CD phenotypes were also found to overlap with those reported previously for alcohol related phenotypes in this population (see Ehlers et al., 2004b
). One site on chromosome 4 that was identified for the ASPD/CD phenotype in these American Indians was near to a locus previously reported by Long et al., (1998)
for alcohol dependence in Southwest Indians. Additionally, a site on chromosome 12 that was reported by Ehlers et al., (2004b)
in this American Indian population for the “severity of alcohol dependence drinking symptomatology” was found to be associated with ASPD/CD in the present genome scan. Bivariate analysis of ASPD/CD with severity of alcohol dependence drinking symptomatology (LOD score 1.7) produced a combined maximum LOD score of 2.7 at that site on chromosome 12, however, but was insufficient power to exclude coincident linkage. Taken together these studies suggest that current evidence does not support the existence of areas of the genome that have significant common influence on alcohol dependence and ASPD, CD, or ASPD/CD, in this American Indian population.
However, the concordance between studies in identifying general areas in the genome that are associated with externalizing phenotypes suggests that the search for candidate genes within those locations may be productive in identifying some general mechanisms that may underlie these behaviors. In one recent study, for instance, Dick et al., (2006)
found that the GABRA2
gene was associated with childhood conduct disorder symptoms in children and adolescents. GABRA2
is located on chromosome 4 in the general region that an area of interest for the ASPD/CD phenotype in these American Indians was found, and which Long et al., (1998)
found linked to alcohol dependence in Southwest Indians. One region that may be intriguing is the area on chromosome 3 reported by Stallings et al., (2003
for conduct symptoms and drug abuse vulnerability. This general location was also uncovered in the present study and it harbors genes for the 5-hydroxytyrptamine receptor 3 (HTR3D, HTR3E
). Preclinical studies have demonstrated the important role of serotonin pathways in drug abuse liability and as such 5-HT receptors may be an important target of study (see Barr and Goldman, 2006
; Johnson, 2004
). Unfortunately, at this time it is not possible to know what genes may actually be contributing to the linkage peaks identified in this study or in any other studies that have uncovered areas of the genome linked to externalizing phenotypes. However, future studies employing whole genome association analyses may contribute to the identification of such genes.
In conclusion, these data represent the first genome-wide scan using ASPD as a phenotype. The results corroborated the possible importance of several chromosomal regions highlighted in prior linkage studies for conduct disorder and other externalizing phenotypes and identify new regions of the genome. The results of this study should be interpreted in the context of several limitations. First, the sample size was limited and replication of the findings in a larger sample within this population is necessary. Second, the findings may not generalize to other Native Americans. Third, comparisons of linkage findings to non-Indian populations may be limited by differences in a host of potential genetic and environmental variables. Fourth, the underlying assumption that these phenotypes are normally distributed, an assumption of variance component analyses, may not be warranted. Finally, because this population has significant admixture, estimates of allele frequencies may produce biased LOD scores. Despite these limitations, this report represents an important first step in an ongoing investigation to understand the genetic determinants associated with the development of substance use disorders in this high risk and understudied ethnic group.