May 20, 2014

NEW YORK (GenomeWeb) — A study appearing inTranslational Psychiatry today describes a panel of genes that may distinguish alcoholics from non-alcoholics.

Researchers led by Alexander Niculescu at Indiana University School of Medicine drew on genome-wide association study data, human gene expression levels studies, and animal model findings to whittle a list of disease-associated genes to a set of 11 genes that may be able to identify people at risk of alcoholism.

That set, the researchers said, includes the synuclein alpha (SNCA) gene that encodes a pre-synaptic chaperone that is thought to modulate brain plasticity, neurogenesis, and neurotransmissions. Additionally, they noted that top candidate genes were involved in signaling, nerve transmission, and cocaine addiction pathways.

“[T]his work sheds light on the genetic architecture and pathophysiology of alcoholism, provides mechanistic targets for therapeutic intervention and has implications for genetic testing to assess risk for illness before the illness manifests itself clinically, opening the door for enhanced prevention strategies at a young age,” Niculescu and his colleagues wrote in their paper.

According to the US National Institute on Alcohol Abuse and Alcoholism, some 17 million people in the US have an alcohol-use disorder, including alcoholism, and about 85,000 people die each year in the US from alcohol-related causes. As Niculescu and his colleagues noted, both environment and genes affect alcoholism risk.

Through their convergent functional genomics approach, the researchers pulled together data from a discovery genome-wide association study, animal model studies, and human studies, including postmortem brain gene expression data, to develop their list of candidate genes linked to alcoholism.

Drawing on a GWAS conducted in a German cohort of 411 cases and 1,307 controls, the researchers identified more than 6,000 genes linked to alcoholism, and more than 3,100 of those genes had additional lines of evidence, such as linkage data or animal model genetic data, linking them to alcohol dependence.

The researchers then prioritized this list of potentially associated genes based on the percent of SNPs within those genes that were linked to the disease and whether there was additional evidence linking those genes to alcoholism, combining them to generate a CFG risk score. Using these scores, the researchers generated a new set of 135 high-scoring genes that they then tested in a second, independent German cohort, where the researchers noted a trend toward significance for distinguishing alcohol-dependent individuals from controls.

To refine that set of 135 genes, the researches turned to a stress-reactive animal model of alcoholism, a D-box binding protein knockout mouse, they developed.
Using this mouse model, the researchers examined which of those 135 candidate genes also had different expression levels in the mouse model.

Through this approach, they homed in on a panel of 11 genes that included 66 relevant SNPs.

In three additional independent cohorts from Germany and the US, this panel could distinguish alcoholics from controls.

“Our results indicate that panels of SNPs in top genes identified and prioritized by CFG analysis and by a behaviorally relevant animal model can differentiate between alcoholics and controls at a population level, although at an individual level the margin may be small,” the researchers said.

At the top of the researchers’ list of candidate alcoholism genes was SNCA, which has been implicated as a susceptibility gene for alcohol cravings.

Alcoholics, Niculescu and his colleagues noted, carry a version of the gene that leads to reduced baseline gene expression. Low levels of SNCA, they said, may lead to less protection against oxidative stress, while high levels may have a role in neurodegenerative diseases like Parkinson’s disease.

In a rat and a mouse model of alcoholism, SNCA is down-regulated in the brain before any exposure to alcohol. And in humans, monkeys, and rats, it is upregulated in the blood after alcohol consumption, the researchers said.

“We may infer that, whereas low levels of SNCA may predispose to cravings for alcohol and consequent alcoholism … excessive alcohol consumption then increases SNCA expression beyond that seen in non-alcohol-consuming controls, potentially compounding risk for neurodegenerative diseases in individuals that have mutations that lead to its aggregation,” Niculescu and his team added. “This observation is also biologically consistent with the fact that dementia is often observed late in the course of alcohol dependence.”

Other genes included on the panel include an astrocyte intermediate filament-type protein GFAP, the dopamine receptor D2, and GRM3, which is also involved in neurotransmitter signaling.

Further, pathway analysis of the top candidate genes implicated Gαi signaling, cocaine addiction, and nerve impulse transmission pathways in alcoholism risk.

In addition to the pathway overlap, a number of the genes included on the panel overlapped with ones linked to other psychiatric disorders, including schizophrenia, anxiety, and bipolar disorder.

“These results led us to develop a heuristic, testable model of alcoholism,” the researchers added. “Some people may drink to be calm, mitigating the effects of stress and anxiety, some people may drink to be happy, the common drive with bipolar disorder, and some people may drink to be drunk, to disconnect from reality and/or get unstuck from internal obsessions and ruminations.”


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