Tuesday, Nov. 5, 2013
“What do future addicts look like as kids?”
This is one question that drives the research efforts of Danielle Dick, Ph.D., associate professor of psychiatry, psychology and human and molecular genetics in the Virginia Commonwealth University School of Medicine.
Dick’s lab does longitudinal studies on alcoholism. After sampling the genes of teens, children or even infants, these studies track them through adolescence to adulthood to see when in the lifespan genes have the most impact on drug use and abuse, and what social factors put teens most at risk for becoming addicts.
“The ability to become an alcoholic is dependent on access to alcohol,” Dick said.
“When a kid reaches age 21, alcohol becomes available and most people experiment with it — but few become alcoholics. Young adulthood is a period of experimentation, but most people outgrow it. Alcoholics don’t outgrow that phase.”
Dick wants to know what genes mark drinkers who won’t grow out of it, and how these genetic predispositions are affected by experience.
At the Virginia Institute for Psychiatric and Behavioral Genetics at VCU, in collaboration with its director, psychiatrist Kenneth Kendler, M.D., Dick conducts “gene identification studies” — looking at an alcoholic’s family members’ DNA to find genes more common in families with a history of alcoholism — as well as twin studies, and her longitudinal research.
The main gene identification study in Dick’s lab focuses on families densely affected with alcohol dependence that have been identified through treatment centers across the United States. It is called the Collaborative Study on the Genetics of Alcoholism, and has 10 sites across the U.S. Dick leads the VCU site.
Tracking people through time
Longitudinal studies are Dick’s second area of focus – that is, tracking people through time. Most people in college try alcohol, but only a minority become alcoholics. What distinguishes the genes and experience of those who become addicted? Dick follows people to find out.
The data Dick’s lab works with at the VIPBG is international and often collaborative.
The Finnish Twin Studies, for example, have tracked more than 10,000 twins in Finland from early adolescence to adulthood. The Avon Longitudinal Study of Parents and Children is tracking 10,000 children (and their parents) from the womb to young adulthood. The Mobile Youth Study follows kids ages 10 to 18 in high-risk, impoverished neighborhoods in Mobile, Alabama. The Child Development Project has followed a sample of approximately 600 children from three sites in the Midwest since they were 5 years old in 1987.
In all these studies, Dick is interested to see how environmental factors, such as parental neglect, divorce, peer attitudes, religion, hobbies and neighborhoods, interact with genetic predispositions over the course of the lifespan.
Another of her longitudinal studies is happening right here at VCU.
The “Spit for Science: The VCU Student Survey” project, which Dick started at VCU in fall 2010, is tracking the genes and experience of college students. VCU incoming freshmen donate saliva samples – on a voluntary basis – for genotyping, then fill out surveys about their experience with drugs and alcohol and their family histories. When the students return to fill out follow-up surveys later in college, Dick and her colleagues can see what genes put young people most at risk, and what social factors – such as family factors, peers’ attitudes, religion, childhood behavior or mood problems, hobbies – mitigate or exacerbate this risk.
In addition, Dick uses the massive database of twin information at the VIPBG to compare identical and fraternal twins. Her goal is to see to what extent genetic versus environmental factors are relevant to substance use and abuse at different stages of development.
Genes bent by experience
Dick’s findings thus far suggest that the strength of genes to make us vulnerable to illness can fluctuate across the lifespan.
Genes predisposing people to disorders such as addiction seem to have a different impact in different stages of life. A person’s high alcohol tolerance, anxious temperament or thrill-seeking personality, for example, may put him or her more at risk for addiction — or for that matter, for depression or conduct problems — in his/her teen years than later in life.
“Risk genes” may also have more effect under different circumstances. If you grow up in poverty or a broken home, if you are abused or exposed to alcohol at a young age, your latent “alcoholism” genes may be more likely to be expressed than if your childhood is stable.
Problem kids, alcoholic adults?
Dick also is finding that the risk genes for addiction overlap those for other mental disorders, particularly conduct disorder in adolescents.
A 2009 study, published by Dick and colleagues, identified a gene, GABRA2, associated with alcoholism in adulthood, and childhood conduct disorder. Previous studies had tied the same variant of the gene to antisocial personality disorder and drug dependence.
Dick’s group’s finding arose from the Childhood Development Project — a sample of almost 600 children from the Midwest, recruited when they were 5 years old, in 1987, and followed up to age 22 with annual interviews. DNA samples were collected from the children’s’ saliva in 2006-07. Every two years, the children had been evaluated by their parents on the “Externalizing Scale” — a list of statements about delinquency and aggression: from severe bad behavior, such as getting into fights, running away and stealing, to more mild conduct problems, such as arguing, being loud and bragging. Parental monitoring was measured when the children were 11 years old by a “Mother Questionnaire” to determine how often the parents were around at home.
Of the 585 children, 81 percent of them showed a decrease in bad behavior from adolescence into adulthood. The 17 percent who continued to misbehave were more likely to have a particular variant of the GABRA2 gene — the same version often held by people with alcoholism, drug addiction or antisocial personality disorder.
Moreover, Dick and her colleagues found that this genetic bias was curbed by parental monitoring: If a child with the GABRA2 mutation was well supervised by his parents, he was less likely to remain a problem child or to develop alcohol problems later.
“What is the shared element between conduct disorder in kids and alcoholic adults?” Dick asked. She calls it “a predisposition toward acting out.”
The variation of the GABRA2 gene, Dick believes, influences a person’s impulsivity, creating a “hyper-excitability or dis-inhibition of the brain, which may manifest differently at different developmental stages and in different environments.”
This impulsiveness is common to childhood behavior problems, adult alcoholism, addiction and criminal behavior. Fighting, stealing, arguing with authority, running away, taking drugs, all involve a problem with self control that may be caused by this gene.
Impulse control: Addiction on the spectrum
The gene association Dick discovered fits into a broader picture of mental illnesses caused by a pattern of overlapping genes.
A 2003 paper led by Kendler found that the genes predisposing people to seven common mental illnesses fell into two broad categories. “Internalizing” disorders, including depression, generalized anxiety disorder and phobias, seem to be triggered by genes coding for introspective tendencies, rumination and “self-thought.” “Externalizing” disorders, on the other hand, include alcohol dependence, drug abuse, conduct disorder in children and adult antisocial disorder. These all seem to be caused by an overlapping group of genes coding for, as Dick calls it, “acting out.”
What this range of disorders have in common is impulsivity — an inability to control impulses: to shout out in class; to drink or use drugs; to assault someone who angers you; to steal a thing, or rape a woman you want. Like autism and Asperger’s spectrum disorders, which psychiatrists are coming to see as a single disorder in different degrees, “externalizing disorders” may result from individual differences in genes for self-control.
This weakness of impulse control, Dick, Kendler and other alcoholism researchers suspect, may be one underlying genetic cause of addiction.
We’re all different: Drunk worms, personalized treatment for alcoholism
According to Dick, different environments affect individual alcoholics differently.
“Alcoholics look different, and drink for different reasons,” she said.
Some drink as a coping mechanism, or “self-medication,” to fight depression or anxiety. Others have naturally “sensation-seeking” personalities, and are thus drawn to social binge drinking, which can lead to even heavier drinking and eventually dependence. A third category of alcoholics has an innately high alcohol tolerance — a genetic low sensitivity to alcohol. For these “less sensitive” people, it takes more alcohol to produce the same buzz — and the heavier drinking they need to do to feel drunk with friends may lead to dependence.
We call all of these people “alcoholics,” but the underlying genetic causes of each person’s illness may be very different. Each person has his own “polygenic risk profile” as Dick calls it: a unique pattern of genes that shapes his personality and his risk.
You can see these individual differences even in worms, she said. When exposed to alcohol, a transparent roundworm known as Caenorhabditiselegans moves in a different sinusoidal pattern and lays its eggs in a disturbed pattern, but individual worms vary in how much alcohol it takes to get them “drunk.” By looking at the gene profiles of “sensitive” or “high-tolerance” worms, we may get clues to what genetic constellation differentiates human alcoholics.
“Genetics has expanded so rapidly in recent years,” Dick explained. “We’re seeing that single genes have a small effect. It’s the interaction of multiple genes – hundreds or even thousands – that matters.”
What Dick aims to do is assess an individual’s risk profile based on his pattern of genes.
“Alcohol prevention programs now are ‘one size fits all’,” Dick said.
What she wants is a more personalized addiction medicine – one based on an individual alcoholic’s particular drinking pattern and genetic profile.
“Only in the past few years have people studied gene/environment interactions (in alcoholism),” Dick said. “In college students, what environments are important and for whom? When we understand that, we can design interventions tailored to individual need.”
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