Genetic Studies Offer Clues to Addiction

A growing body of evidence is starting to reveal how genetics and epigenetics contribute not only to an individual’s predisposition for becoming addicted to alcohol, nicotine, or other drugs, but also their ability to kick such habits.

Andrea Anderson of GenomeWeb Daily News writes that experts say genetics is poised to impact clinical treatments for addiction in the near future, with researchers already identifying genetic variants that may eventually help guide smoking-cessation therapy.

“[T]he rapid advances in the genetics of addiction hold great promise for developing treatments for addiction and reducing the enormous health burden of addiction,” Jonathon Pollock, chief of the National Institute of Drug Abuse’s genetics and molecular neurobiology research branch, and Trinity College geneticist Mani Ramaswami wrote in a preface to a special issue of the Journal of Neurogenetics earlier this year.

Alcohol abuse, nicotine dependence, and other drug addictions belong to a group of psychiatric conditions that not only tend to overlap with one another but also frequently co-occur with conditions such as schizophrenia, bipolar disorder, depression, post-traumatic stress disorder, and some personality disorders.

Over the years, twin and sibling studies, genetic linkage scans, and genome-wide association studies have confirmed that genetics play a role in addiction. But while co-morbidity between various addictions suggests they might share some of the same risk genes, so far the candidate gene and genome-wide studies used to identify genes involved in these conditions have found specific variants and risk loci for each type of addiction, Joel Gelernter, a psychiatry, genetics and neurobiology researcher at Yale University, told GenomeWeb Daily News.

Nevertheless, unlike some other complex diseases, environmental factors are also very important to all types of addiction. “Substance abuse is one of the ultimate gene-environment exposures,” Pollock said.

Studies aimed at getting to the bottom of addiction genetics focus on many different aspects of addiction behavior, from an individual’s risk of moving from initial substance use to addiction to his or her levels of use and ability to quit.

For instance, an online paper in the International Journal of Epidemiology in September suggested that a chromosome 15 region called 15q25 is associated with the number of cigarettes an individual smokes.

A number of studies may also have implications for helping smokers quit. For instance, several studies on the genetic variation of nicotine metabolism suggest slow nicotine metabolism may be more common in non-smokers and light smokers—and these slow metabolizers also seem to have an easier time quitting.

Other studies suggest genetics could help predict which individual will fall back into the habit of smoking after they quit.

“The ultimate goal is to select the type, dose, and duration of therapy for smokers based on individual genetic and biological factors,” Lerman said in an e-mail message. But, she emphasized, while many genetic markers have been associated with treatment success, these findings must be validated in multiple independent clinical trials before they can be translated to clinical practice.

Genetic factors affecting metabolism seems to play a role in alcohol dependence as well. For instance, polymorphisms in the genes coding for the alcohol dehydrogenase enzymes that converts ethanol to acetaldehyde and the aldehyde dehydrogenase enzymes that further metabolizes acetaldehyde can affect an individual’s reaction to alcohol — and, subsequently, their propensity to continue using it.

But genes from other pathways are also turning up in alcohol addiction studies. Among them: GABRA2, which codes a subunit of a receptor for the inhibitory neurotransmitter gamma-aminobutyric acid, and CHRM2, a gene coding for a muscarinic cholinergic receptor that’s also thought to contribute to processes such as memory and cognition.

More generally, twin, sibling, and linkage studies have implicated several chromosomal regions, including parts of chromosomes 4, 6, 12, 15, and 16, in alcohol use and withdrawal.

Joel Gelernter, a psychiatry, genetics, and neurobiology researcher at Yale University, was lead author on a Biological Psychiatry study last January in which researchers used a linkage approach to identify a region on chromosome 10 that was associated with alcohol dependence in African American families tested.

“Regardless of whether such a risk locus would affect outcome exclusively in [African Americans] or generalizes to other populations,” the researchers concluded, “it might be expected to point to mechanisms of action for risk that apply globally.”

Finding such risk loci is just the first step, experts say. In order to fully understand various addictions and come up with ways to treat them most effectively, researchers not only need to identify risk variants, but also delve into the functional consequences of such changes as well as the epigenetic patterns contributing to addiction-related gene regulation.

While these epigenetic and imprinting studies are currently at an earlier stage, Pollock explained, they are expected to provide an even more refined view of how an individual’s environment and genetic predispositions coalesce during the process of addiction.

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