"Higher order" addiction molecular genetics: convergent data from genome-wide association in humans and mice.
Family, adoption and twin data each support substantial heritability for addictions. Most of this heritable influence is not substance-specific. The overlapping genetic vulnerability for developing dependence on a variety of addictive substances suggests large roles for "higher order" pharamacogenomics in addiction molecular genetics. We and others have now completed genome-wide association (GWA) studies of DNAs from individuals with dependence on a variety of addictive substances versus appropriate controls. Recently reported replicated GWA observations identify a number of genes based on comparisons between controls and European-American and African-American polysubstance abusers. Here we review the convergence between these results and data that compares control samples and (a) alcohol-dependent European-Americans, (b) methamphetamine-dependent Asians and (c) nicotine dependent samples from European backgrounds. We also compare these human data to quantitative trait locus (QTL) results from studies of addiction-related phenotypes in mice that focus on alcohol, methamphetamine and barbiturates. These comparisons support a genetic architecture built from largely polygenic contributions of common allelic variants to dependence on a variety of legal and illegal substances. Many of the gene variants identified in this way are likely to alter specification and maintenance of neuronal connections.
Uhl
George R
GR
Molecular Neurobiology Branch, NIH-IRP (NIDA), Suite 3510, 333 Cassell Drive Baltimore, MD 21224, USA. guhl@intra.nida.nih.gov
Drgon
Tomas
T
Johnson
Catherine
C
Fatusin
Oluwatosin O
OO
Liu
Qing-Rong
QR
Contoreggi
Carlo
C
Li
Chuan-Yun
CY
Buck
Kari
K
Crabbe
John
J
D001741:Black or African American; D000818:Animals; D001244:Association; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006801:Humans; D051379:Mice; D008967:Molecular Biology; D010597:Pharmacogenetics; D010641:Phenotype; D040641:Quantitative Trait Loci; D013045:Species Specificity; D019966:Substance-Related Disorders / Q000235:genetics*; D044465:White People