Gene Variant Linked to Depression in Alcohol-Dependent Individuals

Jacquelyn K. Beals, PhD

November 04, 2010

November 4, 2010 (Washington, DC) — A study highlighting the co-occurrence of alcohol dependence and depressive symptoms was presented here at the American Society of Human Genetics 60th Annual Meeting by first author Darlene A. Kertes, PhD, from the Department of Psychology, University of Florida, Gainesville.

The study demonstrated the value of considering comorbidities when designing genetic association studies. The research also highlighted the association between a variant of GABRA2 and depressive symptoms in alcohol-dependent populations.

Dr. Kertes described the high level of co-occurrence between depression and alcohol dependence; in people who have one disorder, the risk of developing the other is 2 to 4 times higher. This comorbidity is important clinically, as evidenced in the higher relapse frequency of alcohol-dependent individuals who also experience symptoms of depression.

The causes of this comorbidity are not well understood, although there is considerable overlap between the biologic systems involved in alcohol dependence and in severe depression. For example, corticotropin-releasing hormone (CRH) participates in responses to both physical and psychological stressors.

Perhaps genetic complexity is typical of this field. "For this [neuropsychiatric disease] session, the general theme was the polygenic effect of a lot of genes connecting a lot of different phenotypes, related phenotypes," observed comoderator Gyungah Jun, PhD, from the Departments of Medicine (Genetics Program), Ophthalmology, and Biostatistics, Boston University School of Medicine, Massachusetts, in talking with Medscape Medical News. "That's kind of a message I got in this session."

In the study by Dr. Kertes and colleagues, an initial set of 120 genes, with previous evidence of associations with addiction, anxiety, or depression, was screened in an alcohol-dependent population (from the Irish Affected Sib-Pair Study of Alcohol Dependence). The functions of these 120 genes included involvement in neurotransmission (e.g., dopamine, serotonin, GABA, and glutamate), the biology of stress, cell signaling, and pharmacokinetics.

The researchers then focused on 19 genes with at least a "nominally significant" association in the screening, testing their association with depressive symptoms in an independent population of alcohol-dependent participants from the Collaborative Study on the Genetics of Alcoholism (COGA). The COGA participants (n = 847) were recruited from treatment facilities, and age distribution was similar to that of the Irish study. Markers in 12 of the 19 genes assessed demonstrated an association with symptoms of depression.

When the test groups were evaluated for depressive symptoms, scores were distributed similarly in both populations (a U-shaped, not a normal, distribution). Symptom distribution was also similar in the 2 groups, supporting the validity of directly comparing the 2 populations.

Replication in the COGA group demonstrated a significant association (P < .05) between depressive symptoms and a variant of GABRA2 (the alpha-2 subunit of the GABA receptor); there was also a trend toward significance for the beta-1 subunit. GABA is the major inhibitory neurotransmitter in the brain, and can inhibit neurons that elaborate CRH when a stress response is being initiated. The same single-nucleotide polymorphism was significant in both groups, and its effect was in the same direction.

To this point, the study had maintained the separation of depressive symptoms, rather than a "lumped" diagnosis of depression, to maintain the power of the analysis. "In most cases, the individuals who are alcohol-dependent and showing symptoms of depression . . . would meet the criteria for an independent diagnosis of depression as well," Dr. Kertes told Medscape Medical News.

"The strength in looking at symptomatology, as opposed to just disorder, is that there are different degrees of severity that someone's going to experience [for] a particular problem. If we just collapse all individuals as being this one uniform category, that's very artificial," said Dr. Kertes. "We're preserving a lot more information about the population we're studying when we can look at gradations of symptomatology."

However, when the same markers were tested for an association with a diagnosis of depression, the analysis did yield nominally significant evidence that a decreasing number of copies of a minor allele was linked to an increased risk of being diagnosed with severe depression. This was borne out in both test populations.

An additional approach to statistical analysis highlighted a marker in 1 gene — CRHBP (which encodes the CRH binding protein, and regulates the availability of CRH to act at its receptors) — linked to depressive symptoms.

"The initial analysis, which focused on the depressive symptomatology, identified one interesting marker in CRHBP. Some follow-up analyses looking at depression diagnosis actually revealed multiple markers within that gene that were linked to depression diagnosis," Dr. Kertes pointed out. "One of those markers actually showed a reasonably strong relationship, such that all of the individuals who were homozygous for the minor allele . . . actually had a history of having major depressive disorder!"

Across the 2 datasets, the investigators found replication of results for GABRA2. The association is modest, but identified a single allele associated with symptoms of depression, and was significant when looking at both the symptoms and a diagnosis of depression. At the gene level, CHRBP's association with symptoms of depression and with diagnosis was also replicated.

In her summary, Dr. Kertes noted that "GABRA2 and CHRHBP variants may predict depression symptomatology in 2 very independent samples of alcohol-dependent individuals," a prediction with potential value for identifying alcohol-dependent patients at greater risk for relapse.

Dr. Kertes and Dr. Jun have disclosed no relevant financial relationships.

American Society of Human Genetics (ASHG) 60th Annual Meeting: Abstract 71. Presented November 3, 2010.

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