Linkage analyses of stimulant dependence, craving, and heavy use in American Indians

Abstract

Amphetamine-type substances are the second most widely used illicit drugs in the United States. There is evidence to suggest that stimulant use (cocaine and methamphetamine) has a heritable component, yet the areas of the genome underlying these use disorders are yet to be identified. This study's aims were to map loci linked to stimulant dependence, heavy use, and craving in an American Indian community at high risk for substance dependence. DSM diagnosis of stimulant dependence, as well as indices of stimulant "craving," and "heavy use," were obtained using the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA). Genotypes were determined for a panel of 791 microsatellite polymorphisms in 381 members of multiplex families using SOLAR. Stimulant dependence, stimulant "craving," and "heavy stimulant use," were all found to be heritable. Analyses of multipoint variance component LOD scores, failed to yield evidence of linkage for stimulant dependence. For the stimulant "craving" phenotype, linkage analysis revealed a locus that had a LOD score of 3.02 on chromosome 15q25.3-26.1 near the nicotinic receptor gene cluster. A LOD score of 2.05 was found at this same site for "heavy stimulant use." Additional loci with LOD scores above 2.00 were found for stimulant "craving" on chromosomes 12p13.33-13.32 and 18q22.3. These results corroborate the importance of "craving" as an important phenotype that is associated with regions on chromosome 12, 15, and 18, that have been highlighted in prior segregation studies in this and other populations for substance dependence-related phenotypes.

Figure 1

Multipoint Linkage Analysis for the heavy stimulant usage (HEAVY USE) stimulant craving (CRAVING) and stimulant dependence (DEPENDENCE) phenotypes for the entire genome. Results for each chromosome are aligned end to end with the p terminus on the left. Log of the Odds (LOD) score is plotted on the Y-axis. Horizontal dashed lines indicated the cutoffs for suggestive evidence of linkage (LOD > 2.00) and the empirically determined threshold for genomewide significant evidence of linkage (LOD > 3.33). The numbers above on the X-axis indicate the chromosome number. Vertical lines indicate the boundaries between the chromosomes.

Figure 2

Multipoint Linkage Analysis for the heavy stimulant usage (HEAVY USE) stimulant craving (CRAVING) and stimulant dependence (DEPENDENCE) phenotypes for chromosome 15. Log of the Odds (LOD) score (Y-axis) is plotted for the chromosome location map (in centimorgans (cM), X-axis). Locations of the markers across the peak are presented. The following numbers indicate the location of previous linkage and association findings: 1 - Alcohol Withdrawal (Ehlers et al., 2004b), 2 - Anxious Drinking (Dick et al., 2002), 3 - Cannabis Craving (Ehlers et al., 2010a), 4 - CHRN gene cluster: Lung Cancer (Truong et al., 2010), Cigarette Smoking (Bierut, 2010; Saccone et al., 2009).