Autosomal linkage scan for loci predisposing to comorbid dependence on multiple substances

Bao Zhu Yang, Shizhong Han, Henry R. Kranzler, Lindsay A. Farrer, Robert C. Elston, Joel Gelernter

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


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 68.3cM; empirical autosome-wide P=0.038), and a suggestive linkage signal on chromosome 21 (peak lod=2.37 at 19.4cM). In AAs, four suggestive linkage peaks were observed: two peaks on chromosome 10 (lod=2.66 at 96.7cM and lod=3.02 at 147.6cM] and the other two on chromosomes 3 (lod=2.81 at 145.5cM) and 9 (lod=1.93 at 146.8cM). 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.

Original languageEnglish (US)
Pages (from-to)361-369
Number of pages9
JournalAmerican Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
Volume159 B
Issue number4
StatePublished - Jun 2012
Externally publishedYes


  • Chromosome 4
  • Comorbidity
  • Fuzzy clustering
  • Multiple substance dependence

ASJC Scopus subject areas

  • Genetics(clinical)
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience


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