Heritability and a genome-wide linkage analysis of a Type II/B cluster construct for cannabis dependence in an American Indian community

Abstract

Subtyping of substance dependence disorders holds promise for a number of important research areas including phenotyping for genetic studies, characterizing clinical course, and matching treatment and prevention strategies. This study sought to investigate whether a dichotomous construct similar to Babor's Types A/B and Cloninger's Types I/II for alcohol dependence can be identified for cannabis dependence in a Native American sample. In addition, heritability of this construct and its behavior in a genetic linkage analyses were evaluated. Information on cannabis use and dependence symptoms and other psychiatric disorders was obtained using the Semi-Structured Assessment for the Genetics of Alcoholism from a community sample of 606 American Indians. Hierarchical average linkage and K means cluster analysis was used, and a three-cluster solution was found to generate the best separation of variables. Ninety-one per cent of cannabis-dependent participants fell into one of the two subtypes: Type A/I cluster (n = 114, 56%) and Type B/II cluster (n = 70, 35%). Heritability (estimated using Sequential Oligogenic Linkage Analysis Routines) was only significant for the Type B/II cluster (h(2) = 0.44, SE = 0.18, P < 0.01). Evidence for linkage was found for the Type B/II cluster (versus no diagnosis) on chromosome 16 [at 139 centimorgans (cM), Log of the Odds (LOD) score = 4.4], and on chromosome 19 (at 74 cM, LOD score = 6.4). Regions of interest for this phenotype (LOD > 1.5) were also located on chromosomes 14, 21, 22. These findings suggest that a Type B/II cannabis dependence phenotype can be identified in this population and that it is in part heritable and linked to areas of the genome identified previously for drug dependence phenotypes in this population as well as in other studies.

Figure 1

Multipoint Linkage Analysis for Type II/B Cannabis cluster phenotype for chromosome 16. The analysis assumes a latent normally distributed variable with a threshold above which an individual is affected. Log of the Odds (LOD) score (Y-axis) is plotted for the chromosome location map (in centimorgans (cM), X-axis).

Figure 2

Multipoint Linkage Analysis for the Type II/B Cannabis cluster phenotype for chromosome 19. The analysis assumes a latent normally distributed variable with a threshold above which an individual is affected. Log of the Odds (LOD) score (Y-axis) is plotted for the chromosome location map (in centimorgans (cM), X-axis).

Figure 3

Multipoint Linkage Analysis for Type II/B Cannabis cluster phenotype for the entire genome. Results for each chromosome are aligned end to end with the p terminus on the left. Vertical lines indicate the boundaries between the chromosomes. The numbers above on the X-axis indicate the chromosome locations.