title: Genomewide linkage scan for cocaine dependence and related traits: significant linkages for a cocaine-related trait and cocaine-induced paranoia.
abstract: Risk for cocaine dependence (CD) is genetically influenced. We recruited a sample of small nuclear families (528 full and 155 half sibpairs) with at least one subject affected with CD. The sample was classified via Bayesian clustering as 45.5% European American (EA) and 54.5% African American (AA). Assessment, via the Semi-Structured Assessment for Drug Dependence and Alcoholism, allowed for detailed evaluation of substance dependence-related traits. To define subgroups with increased genetic homogeneity, consistent with our a priori analytic plan, we used cluster analytic methods to identify six cocaine-related symptom clusters; membership was shown to be significantly heritable. We then completed a genomewide linkage scan (409 markers) for the CD diagnosis, cocaine-induced paranoia (CIP; an outcome that occurs in some cocaine users) and the clusters (three of which contained >80% of the CD subjects). We observed a "suggestive" linkage signal on chromosome 10 for the trait of CD in the full sample; and two "suggestive" linkage signals at different locations on chromosome 3, in the EA part of the sample. We observed a genomewide-significant lod score of 3.65 for the trait of CIP on chromosome 9, in the AA part of the sample only. Our strongest results were observed for the cluster membership traits, including a lod score of 4.66 for membership in the "Heavy Use, Cocaine Predominant" cluster on chromosome 12 (in EAs only) and a lod score of 3.35 for membership in the "Moderate Cocaine and Opioid Abuse" cluster on chromosome 18. These results provide a basis for the identification of specific genes contributing to risk for these traits.
authors.affiliation: Yale University School of Medicine, Department of Psychiatry, Division of Human Genetics; and VA CT Healthcare Center, West Haven, CT 06516, USA. joel.gelernter@yale.edu
authors.forename: Joel
authors.initials: J
authors.lastname: Gelernter
authors.forename: Carolien
authors.initials: C
authors.lastname: Panhuysen
authors.forename: Roger
authors.initials: R
authors.lastname: Weiss
authors.forename: Kathleen
authors.initials: K
authors.lastname: Brady
authors.forename: Victor
authors.initials: V
authors.lastname: Hesselbrock
authors.forename: Bruce
authors.initials: B
authors.lastname: Rounsaville
authors.forename: James
authors.initials: J
authors.lastname: Poling
authors.forename: Marsha
authors.initials: M
authors.lastname: Wilcox
authors.forename: Lindsay
authors.initials: L
authors.lastname: Farrer
authors.forename: Henry R
authors.initials: HR
authors.lastname: Kranzler
mesh_terms: D000328:Adult; D000437:Alcoholism / Q000150:complications / Q000235:genetics; D001499:Bayes Theorem; D019970:Cocaine-Related Disorders / Q000145:classification / Q000150:complications / Q000235:genetics*; D005192:Family Health; D005260:Female; D005787:Gene Frequency; D008040:Genetic Linkage / Q000235:genetics*; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D008957:Models, Genetic; D010259:Paranoid Disorders / Q000209:etiology / Q000235:genetics; D010641:Phenotype