Trends in Genetics
Volume 18, Issue 8, 1 August 2002, Pages 420-425
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Review
Substance abuse vulnerability loci: converging genome scanning data

https://doi.org/10.1016/S0168-9525(02)02719-1Get rights and content

Abstract

Classical genetic studies suggest strong complex genetic contributions to a predisposition to abuse multiple addictive substances. Until recently, there were no reproducible genome scanning data identifying chromosomal positions likely to contain allelic variants that predispose the carrier to illegal substance addiction. Nominal results of linkage-based genome scanning studies for ethanol and nicotine addictions failed to display much agreement. Our recent data from association-based genome scans for illegal addictions, and reanalyses of previous results now provide a substantial body of converging results. The 15 reproducible chromosomal loci identified here are good candidates to harbor allelic variants that alter human substance abuse vulnerabilities. We discuss several approaches to identifying the specific gene variants that underlie these convergent association and linkage observations, and the impact that these convergent observations should have on understanding important human addictive disorders.

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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