Pooled association genome scanning: validation and use to identify addiction vulnerability loci in two samples

Abstract

Association genome scanning is of increasing interest for identifying the chromosomal regions that contain gene variants that contribute to vulnerability to complex disorders, including addictions. To improve the power and feasibility of this approach, we have validated "10k" microarray-based allelic frequency assessments in pooled DNA samples and have used this approach to seek allelic frequency differences between heavy poly-substance abusers and well characterized control individuals. Thirty-eight loci contain SNPs that display robust allele frequency differences between abusers and controls in both European- and African-American samples. These loci identify an alcohol/acetaldehyde dehydrogenase gene cluster and genes implicated in cellular signaling, gene regulation, development, "cell adhesion," and Mendelian disorders. The results converge with previous linkage and association results for addictions. Pooled association genome scanning provides a useful tool for elucidating molecular genetic underpinnings of complex disorders and identifies both previously understood and previously unanticipated mechanisms for addiction vulnerability.

Fig. 1.

Main axes: Chromosomal distributions (labels 1-22 and X) that map abuser/control ratios to the chromosomal position of each corresponding SNP for European- (blue) and African-American (red) samples. The positions of the SNPs whose data yield outlier abuser/control values are indicated by larger symbols. Supplementary axes (right of main axes): SNPs for which abuser/control differences display t values that lie in the upper 5% of all t values (nominal P < 0.0497 and P < 0.057 for European- (red) and African-American (blue) samples. SNPs highlighted in yellow display convergent outlier abuser/control and t values, as noted in the text. Scale: chromosomal positions are based on National Center for Biotechnology Information mapviewer coordinates and supplemental data from NetAffx.