Externalizing disorders in American Indians: Comorbidity and a genome wide linkage analysis

Abstract

Alcohol dependence is one of the leading causes of morbidity and mortality in Native Americans. Externalizing disorders such as conduct disorder (CD) and antisocial personality disorder (ASPD) have been demonstrated to have significant comorbidity with alcohol dependence in the general population. This study's aims were to: assess the comorbidity of DSM-III-R ASPD and CD with alcohol dependence, to map susceptibility loci for ASPD and CD, and to see if there is overlap with loci previously mapped for alcohol dependence phenotypes in 587 American Indians. Alcohol dependence was found to be comorbid with DSM-III-R ASPD but not CD. However, the amount of alcohol dependence in the population attributable to ASPD and/or CD is low. ASPD and the combined phenotype of participants with ASPD or CD were both found to have significant heritability, whereas no significant evidence was found for CD alone. Genotypes were determined for a panel of 791 micro-satellite polymorphisms in 251 of the participants. Analyses of multipoint variance component LOD scores, for ASPD and ASPD/CD, revealed six locations that had a LOD score of 2.0 or above: on chromosome 13 for ASPD and on chromosomes 1,3,4,14,17 and 20 for ASPD/CD. These results corroborate the importance of several chromosomal regions highlighted in prior segregation studies for externalizing diagnoses. These results also further identify new regions of the genome, that do not overlap with alcohol dependence phenotypes previously identified in this population, that may be unique to either the phenotypes evaluated or this population of American Indians.

Genome-wide scan for self-rating of the effects of alcohol in American Indians

“…Finally, on chromosome 17 a location was identified at 101cM with a LOD score of 2.87 that was also found in this Indian population for an ASPD/CD phenotype (Ehlers et al ., 2008a). Thus it appears that areas on chromosomes 6,9,10,11,12,17 may harbor genes for both the SRE FIRST FIVE phenotype as well as a number of substance related traits observed in this Indian population as well as in other population samples.…”

“…Additionally, the area on chromosome 12 that was identified in the present linkage analyses for the “FIRST FIVE” SRE phenotype was also found previously in a genome scan for a the severity of alcohol dependence drinking symptomatology phenotype (Ehlers et al ., 2004b) and also an antisocial personality disorder/conduct disorder phenotype in this Indian population (Ehlers et al, 2008a). A region near this site was also identified in a genome scan in the Irish Affected Sib Pair Study for a maximum drinking phenotype (Kuo et al ., 2006).…”

“…The lifetime prevalence of substance dependence in this Indian population is high and evidence for heritability and linkage to specific chromosome locations and associations with candidate genes has been demonstrated (see Wall et al, 2003; Ehlers et al, 2004b, 2006b, 2007a,b,c, 2008a,b, 2009a,b, 2010a; Ehlers and Wilhelmsen, 2005, 2007; Wilhelmsen and Ehlers, 2005). The current study’s aims were to: (1) map loci linked to SRE phenotypes and (2) to determine if there was overlap of the loci identified for SRE phenotypes and loci previously mapped for alcohol and other substance dependence in this American Indian community.…”

Behavioral genetics in antisocial spectrum disorders and psychopathy: A review of the recent literature

“…Regarding CD and vulnerability to SUDs, the investigators reported significant evidence for linkage on Chromosome 9 (9q34, near markers D9S1826 and D9S1838), and evidence suggestive of linkage on Chromosomes 3 (3q24-3q25, near D3S1279 and D3S1614) and 17 (17q12, near D17S798). Ehlers and colleagues used CD and antisocial personality disorder (ASPD) as the primary phenotype in the analysis of a group of 251 adults from 41 families, with a high frequency of alcohol dependence, and found no areas of significant linkage, though they found some peaks in areas that they deemed similar to those seen by Dick on Chromosome 2 and Stallings on Chromosome 3 (Ehlers, Gilder, Slutske, Lind, & Wilhelmsen, 2008). Overall, there was little replication among these studies, of CD has also been examined in co-occurrence with ADHD.…”

Linkage analyses of cannabis dependence, craving, and withdrawal in the San Francisco family study

“…Using the same population of adolescents, Stallings et al [2003, 2005], conducted linkage scans for the average number of dependence symptoms, conduct disorder symptoms and a composite index of antisocial substance dependence, and also found evidence for linkage to the chromosome 9q34 region (LOD = 3.15) and 3q24-3q25 (LOD = 3.27) for the composite index. The site on chromosome 3q was within 30 cM of a site identified for antisocial personality disorder/conduct disorder in an American Indian community [Ehlers et al, 2008]. The site identified on chromosome 3q for cannabis craving in the UCSF family study (LOD = 4.5) was also within 30 cM of the site identified on that chromosome by Stallings et al [2005].…”