Background: A large linkage peak for alcohol dependence (AD) was detected on chromosome 4q in the Irish Affected Sib Pair Study of Alcohol Dependence (IASPSAD). Are the susceptibility genes underlying this peak specific for AD or do they increase risk for externalizing disorders more generally? Can we, in the IASPSAD, replicate prior evidence for linkage to conduct disorder (CD)?
Methods: The 733 all possible sibling pairs in IASPSAD were typed for 1,020 short-tandem-repeat genetic markers. Univariate and bivariate linkage analyses were conducted by the program sequential oligogenic linkage analysis routines (SOLAR), for both the raw and the transformed number of symptoms of AD (ADsx) and number of symptoms of CD (CDsx). In the bivariate analyses, specificity was assessed by the ratio of the variance accounted for in ADsx and CDsx by the quantitative trait locus.
Results: In the univariate linkage analyses, no evidence for linkage to CDsx was found under the 4q peak for ADsx and the largest peaks for CDsx were seen on chromosomes 1q (LOD=3.16) and 14p (LOD=2.36). In the bivariate linkage analysis, the 4q peak had high specificity for AD (AD/CD ratio of 39.9). Several smaller peaks, on chromosomes 1, 7, and 10, had moderate specificity for CD but also impacted on risk for AD, with AD/CD ratios of 0.18 to 0.32.
Conclusions: Genes under the 4q linkage peak for AD in the IASPSAD impact specifically on risk for AD rather than more broadly on risk for externalizing syndromes. Suggestive linkages were found in several locations for CD, 2 of which broadly replicate prior findings. The bivariate analyses identified genomic locations containing susceptibility loci that impacted on risk for both CDsx and ADsx.