title: Autosomal linkage scan for loci predisposing to comorbid dependence on multiple substances.
abstract: Multiple substance dependence (MSD) trait comorbidity is common, and MSD patients are often severely affected clinically. While shared genetic risks have been documented, so far there has been no published report using the linkage scan approach to survey risk loci for MSD as a phenotype. A total of 1,758 individuals in 739 families [384 African American (AA) and 355 European American (EA) families] ascertained via affected sib-pairs with cocaine or opioid or alcohol dependence were genotyped using an array-based linkage panel of single-nucleotide polymorphism markers. Fuzzy clustering analysis was conducted on individuals with alcohol, cannabis, cocaine, opioid, and nicotine dependence for AAs and EAs separately, and linkage scans were conducted for the output membership coefficients using Merlin-regression. In EAs, we observed an autosome-wide significant linkage signal on chromosome 4 (peak lod = 3.31 at 68.3 cM; empirical autosome-wide P = 0.038), and a suggestive linkage signal on chromosome 21 (peak lod = 2.37 at 19.4 cM). In AAs, four suggestive linkage peaks were observed: two peaks on chromosome 10 (lod = 2.66 at 96.7 cM and lod = 3.02 at 147.6 cM] and the other two on chromosomes 3 (lod = 2.81 at 145.5 cM) and 9 (lod = 1.93 at 146.8 cM). Three particularly promising candidate genes, GABRA4, GABRB1, and CLOCK, are located within or very close to the autosome-wide significant linkage region for EAs on chromosome 4. This is the first linkage evidence supporting existence of genetic loci influencing risk for several comorbid disorders simultaneously in two major US populations.
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Bao-Zhu
authors.initials: BZ
authors.lastname: Yang
authors.forename: Shizhong
authors.initials: S
authors.lastname: Han
authors.forename: Henry R
authors.initials: HR
authors.lastname: Kranzler
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Farrer
authors.forename: Robert C
authors.initials: RC
authors.lastname: Elston
authors.forename: Joel
authors.initials: J
authors.lastname: Gelernter
mesh_terms: D001741:Black or African American / Q000235:genetics; D000437:Alcoholism / Q000453:epidemiology / Q000235:genetics; D002877:Chromosomes, Human / Q000235:genetics*; D016000:Cluster Analysis; D019970:Cocaine-Related Disorders / Q000453:epidemiology / Q000235:genetics; D015897:Comorbidity; D005260:Female; D017143:Fuzzy Logic; D008040:Genetic Linkage; D056426:Genetic Loci / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008126:Lod Score; D008297:Male; D009293:Opioid-Related Disorders / Q000235:genetics; D010641:Phenotype; D019966:Substance-Related Disorders / Q000453:epidemiology* / Q000235:genetics*; D014481:United States / Q000453:epidemiology; D044465:White People / Q000235:genetics