Trends in Genetics
ReviewSubstance abuse vulnerability loci: converging genome scanning data
Section snippets
Molecular genetic genome scans and convergence of results
Linkage-based genome scans for markers of alleles that predispose to addiction to legal substances have been reported by Long et al. (172 sib-pairs, 517 markers) [22], Reich et al. (225 sib-pairs, 291 markers) [23], Foroud et al. (266 additional sib-pairs, 351 markers) [24], and Straub et al. (391 sib-pairs, 451 markers) [25], using affected sib-pairs from US and New Zealand populations of several discrete ethnicities. The first association-based scan for illegal addictions in unrelated abuser
Candidate substance abuse (SA) loci
In studies of the complex genetics of other common disorders, abbreviations have been assigned to candidate loci when convergent data to support these loci has been obtained [27]. The convergence documented here suggests that these candidate loci should now be labeled with rSA names, to designate their replicated ability to mark potential sites for substance abuse vulnerability alleles (Table 1; Fig. 1).
Evidence for oligogenic versus polygenic factors
One notable feature of the association and linkage findings (Table 1) is what they do not contain. Table 1 fails to provide evidence for any gene of major effect. No locus seems to display such a large magnitude of linkage or association results that it alone accounts for a major fraction of the genetic influence on addiction vulnerability. The data instead provide evidence of polygenic inheritance for substance abuse vulnerability in the populations studied. Genetic contributions to
Ways forward: moving from loci to genes, haplotypes and allelic variants
No single path has invariably led from locus to gene in studies of complex disorders. A combination of approaches that take into account both addiction genetics and addiction biology appears to provide the highest chances for success. More replications and extensions of the above results in different populations, as well as use of higher and higher marker densities for association genome scanning studies, will add to our confidence in and narrow the chromosomal regions of interest cited in
Potential impact
The importance and complexity of genetic contributions to addiction continues to motivate efforts to identify allelic variants that contribute to addiction vulnerability, even if each allelic variant contributes only a modest fraction to this whole problem. Knowledge of genotypes at loci containing vulnerability alleles could improve the management of vulnerable individuals and thus the cost-effectiveness of addiction prevention and treatment. Individual and societal suffering could be
Acknowledgements
We acknowledge helpful comments from Laura Beirut, Mary-Jeanne Kreek, Elliot Gardner, F. Scott Hall and Wade Berrettini. Our personal studies cited here have benefitted from exceptional help from Judith Hess, Bruce O'Hara, Antonio Persico, Donna Walther, Fely Carillo-London, Brenda Campbell, Linda Kahler, Fred Snyder, Carlo Contoreggi, Larry Rodriguez, Robert Grow, David Gorelick, Zhicheng Lin, Andrew Shapiro, Leslie Cope and Cheryl Mayo, and financial support from NIDA and from NSF (DQN,
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