Gene Variant Increases Risk For Alcoholism Following Childhood Abuse

"With this study we see yet again that nature and nurture often work together, not independently, to influence our overall health and well-being," says NIH Director Elias A. Zerhouni, M.D.

"This finding underscores the central role that gene-environment interactions play in the pathogenesis of complex diseases such as alcoholism," adds NIAAA Director Ting-Kai Li, M.D. A report of the study appears in the June 26, 2007 advance online publication of Molecular Psychiatry.

Previous studies have shown that childhood sexual abuse increases the risk for numerous mental health problems in adulthood. However not all abused children develop such problems, a likely indication that genetic factors also play a role. Recent studies have linked the monoamine oxidase A (MAOA) gene with adverse behavioral outcomes stemming from childhood mistreatment.

"MAOA is an enzyme that metabolizes various neurotransmitters that regulate the body's response to stress," explains first author Francesca Ducci, M.D., a visiting fellow in NIAAA's Laboratory of Neurogenetics in Bethesda, Maryland. DNA variations occur within a regulatory area -- the MAOA-linked polymorphic region (MAOA-LPR) -- of the MAOA gene. Two such MAOA-LPR variants occur most frequently and result in high or low MAOA enzyme activity. In a recent study, researchers found that maltreated boys who possessed the low activity MAOA-LPR variant were more likely to develop behavior problems than boys with the high activity variant.

"Our aim was to test whether this low activity variant influences the impact of childhood sexual abuse on alcoholism and antisocial personality disorder (ASPD) in women," says Dr. Ducci.

She and her colleagues analyzed DNA samples from a group of American Indian women living in a community in which rates of alcoholism and ASPD are about six times higher than the average rates among all U.S. women. Childhood sexual abuse is also prevalent in this population, reported by about half of the women in the community, compared with a U.S. average of 13 percent.

"The high rates of sexual abuse and alcoholism in this population make it particularly suitable for studying the interaction of genes and stressful environmental exposures," explains senior author David Goldman, M.D., chief of the NIAAA Laboratory of Neurogenetics.

Analyses of MAOA-LPR genotypes in this study revealed that women who had been sexually abused in childhood were much more likely to develop alcoholism and antisocial behavior if they had the low activity variant whereas the high activity variant was protective. In contrast, there was no relationship between alcoholism, antisocial behavior and MAOA-LPR genotype among non-abused women.

"Our findings show that MAOA seems to moderate the impact of childhood trauma on adult psychopathology in females in the same way as previously shown among males," says Dr. Ducci. "The MAOA-LPR low activity allele appears to confer increased vulnerability to the adverse psychosocial consequences of childhood sexual abuse."

Dr. Ducci and her colleagues suggest that the effect of MAOA on the hippocampus, a brain region which is involved in the processing of emotional experience, may underlie the interaction between MAOA and childhood trauma. They note that previous research showed that people with the low activity variant at the MAOA-LPR locus have hyperactivation of the hippocampus when retrieving negative emotional information.

Other co-authors of the study include Mary-Anne Enoch, M.D., Colin Hodgkinson, Ph.D. and Ke Xu, MD, Ph.D., of the NIAAA Laboratory of Neurogenetics, Mario Catena, MD, of the Department of Psychiatry, University of Pisa, Italy, and Robert W. Robin, Ph.D., of the Center for the Prevention and Resolution of Violence in Tucson, Arizona.